ORCID Profile
0000-0001-5434-590X
Current Organisation
Københavns Universitet
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Physical Chemistry (Incl. Structural) | Colloid and Surface Chemistry | Pharmaceutical Sciences | Nanotechnology | Pharmacology and Pharmaceutical Sciences | Nanobiotechnology | Colloid And Surface Chemistry | Nanochemistry and Supramolecular Chemistry | Nanomaterials | Nanomedicine | Nanotechnology | Biological And Medical Chemistry | Synthesis of Materials | Powder and Particle Technology | Receptors and Membrane Biology | Pharmaceutical Sciences And Pharmacy | Horticultural Crop Protection (Pests, Diseases and Weeds) | Condensed Matter Physics—Structural Properties | Biomedical Instrumentation | Macromolecular and Materials Chemistry | Biomaterials | Nanoscale Characterisation | Fertilisers And Agrochemicals (Application Etc.)
ANZSRC Socio-Economic Objective (SEO)
Human Pharmaceutical Treatments (e.g. Antibiotics) | Treatments (e.g. chemicals, antibiotics) | Human Diagnostics | Nutraceuticals and Functional foods | Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Biological Sciences | Unprocessed or Minimally Processed Milk | Field crops | Horticultural crops | Canola | Wheat | Processed Milk and Cream (incl. Powder, Evaporated and Condensed) | Inherited Diseases (incl. Gene Therapy) | Biological sciences | Chemical sciences | Concentrating processes of other base metal ores | Digestive System Disorders | Cancer and Related Disorders | Manufactured products not elsewhere classified | Organic industrial chemicals not classified elsewhere | Soaps and cosmetics | Maize | Diagnostic methods | Processed food products and beverages not elsewhere classified | Expanding Knowledge in Technology | Agricultural chemicals | Diagnostic Methods | Expanding Knowledge in Engineering |
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Publications
Packing and mobility of hydrocarbon chains in phospholipid lyotropic liquid crystalline lamellar phases and liposomes: characterisation by positron annihilation lifetime spectroscopy (PALS)
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4CP03822C
Abstract: PALS is sensitive to bilayer chemical structure and nanostructure thereby assisting understanding of dynamics, diffusion and permeability of biological membranes.
Nano-fats for bugs: the benefits of lipid nanoparticles for antimicrobial therapy
Publisher: Springer Science and Business Media LLC
Date: 05-03-2021
Nonequilibrium interfacial diffusion across microdroplet interface
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2LC00326K
Abstract: Increases in complexity attainable in molecular self-assembly necessitates both advanced molecular design as well as microenvironmental control.
External manipulation of nanostructure in photoresponsive lipid depot matrix to control and predict drug release in vivo
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.JCONREL.2016.02.042
Abstract: On-demand drug delivery systems are highly promising to control the time-course of drug release and ultimately optimize drug concentration time profiles in patients. Lipid based lyotropic liquid crystalline mesophases have demonstrated exceptional responsiveness to external stimuli such as heat, pH and light. Our objective was to quantitatively characterize the time-course of light activated drug release from near infrared (NIR) activated photothermal systems using ex vivo and in vivo studies. Photoresponsive hybrid gold nanorod-liquid crystalline matrices were prepared and loaded into custom-made implants which were inserted into subcutaneous tissues in rats. Time resolved SAXS studies showed the abdomen to be the best site of implantation to achieve in vivo activation of the subcutaneous dose from by the NIR laser. External control of drug release was achieved via NIR laser light and plasma concentrations of the model drug were determined over time. Laser activation achieved a phase change of the photoresponsive formulations and thereby a considerable change in the rate of drug release. Population pharmacokinetic modeling of all results simultaneously revealed a two stage release process unique to these liquid crystalline matrices. The developed structural model was able to successfully describe also the results of our previous study in 2009 where a change in temperature was utilized to trigger subcutaneous drug release. Thus, modeling of the data proved to be a valuable analytical tool which provided a quantitative understanding of the time-course of drug release in vivo and will be essential in the development of these matrices as on-demand release systems.
Drug Solubilization Behavior During in Vitro Digestion of Suspension Formulations of Poorly Water-Soluble Drugs in Triglyceride Lipids
Publisher: Springer Science and Business Media LLC
Date: 02-2004
DOI: 10.1023/B:PHAM.0000016283.87709.A9
Abstract: The purpose of this study was to characterize the solubilization and precipitation characteristics of a range of poorly water-soluble drugs during the in vitro digestion of long-chain or medium-chain triglyceride (TG) lipid suspension formulations. TG suspensions of model drugs (present at double their equilibrium solubilities in the respective lipid) were digested in vitro and the drug solubilization and precipitation pattern in the resulting digests analyzed. For griseofulvin, diazepam, and danazol, solubilization of the small mass of drug originally presented in the TG lipid was efficient with only a small proportion of the dose precipitating and being recovered in the pellet phase after digestion of the TG lipid. For the more lipophilic and lipid-soluble drugs (cinnarizine, halofantrine), in which higher drug loadings were possible, significant enhancement in drug solubilization in the postdigestion aqueous phase was not apparent compared with simple TG lipid solutions. Suspensions of drugs, which are poorly soluble in water and TG lipid, may prove beneficial as the relatively high solubilizing capacity of the colloidal phases produced on TG digestion will likely exceed the mass of drug that could have been administered as a simple lipid solution. However, for more lipid-soluble drugs, suspension formulations may offer little benefit as sufficiently high drug loadings can otherwise be achieved with simple solution formulations that still provide for adequate solubilization after TG digestion.
Size and Rigidity of Cylindrical Polymer Brushes Dictate Long Circulating Properties In Vivo
Publisher: American Chemical Society (ACS)
Date: 29-01-2015
DOI: 10.1021/NN505125F
Abstract: Studies of spherical nanoengineered drug delivery systems have suggested that particle size and mechanical properties are key determinants of in vivo behavior however, for more complex structures, detailed analysis of correlations between in vitro characterization and in vivo disposition is lacking. Anisotropic materials in particular bear unknowns in terms of size tolerances for in vivo clearance and the impact of shape and rigidity. Herein, we employed cylindrical polymer brushes (CPBs) to answer questions related to the impact of size, length and rigidity on the in vivo behavior of PEGylated anisotropic structures, in particular their pharmacokinetics and biodistribution. The modular grafting assembly of CPBs allowed for the systematic tailoring of parameters such as aspect ratio or rigidity while keeping the overall chemical composition the same. CPBs with altered length were produced from polyinitiator backbones with different degrees of polymerization. The side chain grafts consisted of a random copolymer of poly[(ethylene glycol) methyl ether methacrylate] (PEGMA) and poly(glycidyl methacrylate) (PGMA), and rendered the CPBs water-soluble. The epoxy groups of PGMA were subsequently reacted with propargylamine to introduce alkyne groups, which in turn were used to attach radiolabels via copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC). Radiolabeling allowed the pharmacokinetics of intravenously injected CPBs to be followed as well as their deposition into major organs post dosing to rats. To alter the rigidity of the CPBs, core-shell-structured CPBs with polycaprolactone (PCL) as a water-insoluble and crystalline core and PEGMA-co-PGMA as the hydrophilic shell were synthesized. This modular buildup of CPBs allowed their shape and rigidity to be altered, which in turn could be used to influence the in vivo circulation behavior of these anisotropic polymer particles. Increasing the aspect ratio or altering the rigidity of the CPBs led to reduced exposure, higher clearance rates, and increased mononuclear phagocytic system (MPS) organ deposition.
Traumatic brain injury opens blood–brain barrier to stealth liposomes via an enhanced permeability and retention (EPR)-like effect
Publisher: Informa UK Limited
Date: 16-06-2015
Doxorubicin-Conjugated PEGylated Dendrimers Show Similar Tumoricidal Activity but Lower Systemic Toxicity When Compared to PEGylated Liposome and Solution Formulations in Mouse and Rat Tumor Models
Publisher: American Chemical Society (ACS)
Date: 27-01-2012
DOI: 10.1021/MP200522D
Abstract: PEGylated polylysine dendrimers show promise as novel drug delivery systems with the potential to direct site specific deposition patterns and to reduce toxicity at nontarget sites. Here the activity and toxicity profiles of a generation 5 polylysine dendrimer with 50% surface conjugation of PEG1100 and 50% surface conjugation of doxorubicin (via an acid labile 4-hydrazinosulfonyl benzoic acid linker) have been compared in a Walker 256 rat tumor model and a human MDA-MB231 xenograft in mice. A direct comparison was also made to a PEGylated liposomal formulation of doxorubicin and a doxorubicin solution. In both rat and mouse breast cancer models, the dendrimer formulation gave equivalent antitumor efficacy when compared to the liposomal or solution doxorubicin formulations and administration of all three doxorubicin formulations resulted in a significant reduction (>75%) in tumor growth in both models at doses ranging from 2 to 10 mg/kg doxorubicin equivalents. The dendrimer formulation, however, was better tolerated by both rats and mice, and approximately 2-fold higher doses were required to induce similar levels of toxicity (as assessed by organ weight, peripheral white cell counts, body weight and survival curves) when compared to administration of the doxorubicin solution or PEGylated liposomal doxorubicin. In rats the appearance of palmar plantar erythematosis (PPE), or hand foot syndrome, was also less evident after administration of dendrimer doxorubicin when compared to the liposome. Finally, even after administration to mice at 2-fold higher doses, dendrimer-doxorubicin resulted in a reduced incidence of cardiotoxicity when compared with a simple solution formulation of doxorubicin. The data suggest that dendrimer-based doxorubicin formulations may provide advantage over solution and liposomal formulations of doxorubicin via a reduction in systemic toxicity.
Lipidated polymers for the stabilization of cubosomes: nanostructured drug delivery vehicles
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7CC05842J
Abstract: We report a straightforward approach for preparing polymers with lipidic chain ends, and show their application in stabilising nanostructured drug delivery vehicles.
Formation of drug nanocrystals under nanoconfinement afforded by liposomes
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C5RA25898G
Abstract: In response to freeze–thaw, liposome-encapsulated antibiotic (A) is converted into nanocrystalline form (B) resulting in an attenuated drug release profile.
Alphaxalone Reformulated
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2015
The Impact of Molecular Weight and PEG Chain Length on the Systemic Pharmacokinetics of PEGylated Poly l -Lysine Dendrimers
Publisher: American Chemical Society (ACS)
Date: 05-04-2008
DOI: 10.1021/MP7001208
Abstract: The impact of PEGylation on the pharmacokinetics and biodistribution of (3)H-labeled poly l-lysine dendrimers has been investigated after intravenous administration to rats. The volumes of distribution, clearance and consequently the plasma half-lives of the PEGylated dendrimers were markedly dependent on the total molecular weight of the PEGylated dendrimer, but were not specifically affected by the PEG chain length alone. In general, the larger dendrimer constructs (i.e. >30 kDa) had reduced volumes of distribution, were poorly renally cleared and exhibited extended elimination half-lives ( t 1/2 1-3 days) when compared to the smaller dendrimers (i.e. <20 kDa) which were rapidly cleared from the plasma principally into the urine ( t 1/2 1-10 h). At later time points the larger dendrimers concentrated in the organs of the reticuloendothelial system (liver and spleen) however, the absolute extent of accumulation was low. Size exclusion chromatography of plasma and urine s les revealed that the PEGylated dendrimers were considerably more resistant to biodegradation in vivo than the underivatized poly l-lysine dendrimer cores. The results suggest that the size of PEGylated poly l-lysine dendrimer complexes can be manipulated to optimally dictate their pharmacokinetics, biodegradation and bioresorption behavior.
Determination of physical and chemical stability in pressurised metered dose inhalers: potential new techniques
Publisher: Informa Healthcare
Date: 12-06-2015
DOI: 10.1517/17425247.2015.1046834
Abstract: Pressurised metered dose inhalers (pMDIs) are subject to rigorous physical and chemical stability tests during formulation. Due to the time and cost associated with product development studies, there is a need for online techniques to fast screen new formulations in terms of physical and chemical (physico-chemical) stability. The problem with achieving this is that pMDIs are by their definition, pressurised, making the direct observation of physico-chemical properties in situ difficult. This review highlights the characterisation tools that can enhance the product development process for pMDIs. Techniques investigated include: laser diffraction, Raman spectroscopy, isothermal oule calorimetry, titration calorimetry and gas perfusion calorimetry. The operational principles behind each technique are discussed and complemented with ex les from the literature. Laser diffraction is well placed to analyse real-time physical stability as a function of particle size however, its use is restricted to suspension pMDIs. Raman spectroscopy can be potentially used to attain both suspension and solution pMDI spectra in real time however, the majority of experiments are ex-valve chemical composition mapping. Calorimetry is an effective technique in capturing both chemical and physical degradations of APIs in real time but requires redevelopment to withstand pressure for the purposes of pMDI screening.
Isothermal calorimetry: A predictive tool to model drug-propellant interactions in pressurized metered dose systems
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.IJPHARM.2013.11.055
Abstract: The purpose of this work was to evaluate gas perfusion isothermal calorimetry (ITC) as a method to characterize the physicochemical changes of active pharmaceutical ingredients (APIs) intended to be formulated in pressurized metered dose inhalers (pMDIs) after exposure to a model propellant. Spray dried s les of beclomethasone dipropionate (BDP) and salbutamol sulphate (SS) were exposed to controlled quantities of 2H,3H-decafluoropentane (HPFP) to determine whether ITC could be used as a suitable analytical method for gathering data on the behavioural properties of the powders in real time. The crystallization kinetics of BDP and the physiochemical properties of SS were successfully characterized using ITC and supported by a variety of other analytical techniques. Correlations between real and model propellant systems were also established using hydrofluoroalkane (HFA-227) propellant. In summary, ITC was found to be suitable for gathering data on the crystallization kinetics of BDP and SS. In a wider context, this work will have implications on the use of ITC for stability testing of APIs in HFA-based pMDIs.
Prodrug and nanomedicine approaches for the delivery of the camptothecin analogue SN38
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.JCONREL.2013.07.022
Abstract: SN38 (7-ethyl-10-hydroxy c tothecin) is a prominent and efficacious anticancer agent. It is poorly soluble in both water and pharmaceutically approved solvents therefore, the direct formulation of SN38 in solution form is limited. Currently, the water soluble prodrug of SN38, irinotecan (CPT-11), is formulated as a low pH solution and is approved for chemotherapy. However, CPT-11, along with most other water-soluble prodrugs shows unpredictable inter-patient conversion to SN38 in vivo, instability in the physiological environment and variable dose-related toxicities. More recently, macromolecular prodrugs (i.e. EZN-2208, IMMU-130) and nanomedicine formulations (i.e. nanoemulsions, polymeric micelles, lipid nanocapsule/nanoparticle, and liposomes) of SN38 have been investigated for improved delivery to cancer cells and tissues. Specifically, these carriers can take advantage of the EPR effect to direct drug preferentially to tumour tissues, thereby substantially improving efficacy and minimising side effects. Furthermore, oral delivery has been shown to be possible in preclinical results using nanomedicine formulations (i.e. dendrimers, lipid nanocapsules, polymeric micelles). This review summarizes the recent advances for the delivery of SN38 with a focus on macromolecular prodrugs and nanomedicines.
Controlling the size and shape of liposomal ciprofloxacin nanocrystals by varying the lipid bilayer composition and drug to lipid ratio
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.JCIS.2019.07.081
Abstract: Drug nanocrystals precipitated inside liposomes are of increasing interest in liposomal drug delivery. For liposomal nanocrystal formulations, the size and shape of the drug nanocrystals can influence the apparent drug release properties, providing opportunities for developing tailored liposomal drug release systems. Small angle X-ray scattering (SAXS) and quantitative transmission electron microscopy (TEM) can be used to analyse the size distributions of the nanoparticles. In this study, by changing the fluidity of the membrane through the use of different membrane phospholipids with varying cholesterol content, the impact of lipid phase, fluidity and permeability on the size distribution of ciprofloxacin nanocrystals were investigated using standard TEM and SAXS as orthogonal techniques. The results show that the phospholipid phase behaviour has a direct effect on the nanocrystal size distribution, where shorter and thinner nanocrystals were formed in liposomes made from hydrogenated soy phosphatidylcholine (HSPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) phospholipids with higher phase transition temperatures than 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) with lower transition temperatures. This is mainly due to the phase behaviour of the liposome during nanocrystal formation. The addition of cholesterol that reduces fluidity and permeability of the DOPC liposomes was also shown to restrict the growth of the ciprofloxacin nanocrystals. Moreover, increasing the drug loading of the liposomes made from HSPC and DPPC produced longer and wider nanocrystals. The findings open new opportunities to tailor nanocrystal size distributions, as well as the aspect ratio of the enclosing liposomes with potential to alter drug release and in vivo behaviour.
Naphthalocyanine as a New Photothermal Actuator for Lipid-Based Drug Delivery Systems
Publisher: American Chemical Society (ACS)
Date: 30-01-2018
Abstract: One approach to address the substantial global burden of ocular diseases such as aged related macular degeneration is using light-activated drug delivery to obviate the need for highly invasive and frequent, costly intravitreal injections. To enable such systems, new light responsive materials are required. This communication reports the use of silicon 2,3-naphthalocyanine bis(trihexylsilyloxide) (SiNC), a small molecule photosensitizer, as a new actuator for triggering light responsive lipid-based drug delivery systems. Small-angle X-ray scattering was used to confirm that the addition of SiNC imparted light sensitivity to the lipid systems, resulting in a complete phase transition within 20 s of near-infrared irradiation. The phase transition was also reversible, suggesting the potential for on-demand drug delivery. When compared to the phase transitions induced using alternative light responsive actuators, gold nanorods and graphene, there were some differences in phase behavior. Namely, the phytantriol with SiNC system transitioned directly to the inverse micellar phase, skipping the intermediate inverse hexagonal structure. The photodynamic properties and efficiency in controlling the release of drug suggest that SiNC-actuated lipid systems have the potential to reduce the burden of repeated intravitreal injections.
Sustained absorption of delamanid from lipid-based formulations as a path to reduced frequency of administration
Publisher: Springer Science and Business Media LLC
Date: 15-09-2020
DOI: 10.1007/S13346-020-00851-Z
Abstract: Delamanid is a poorly water-soluble drug currently being used for the treatment of tuberculosis. The high frequency of dosing leads to poor adherence for patients who live in lower economic and nomadic populations. Non-digestible self-assembling lipids as a formulation approach for poorly water-soluble drugs have previously been shown to extend the window of absorption through gastric retention. We hypothesise that this approach could lead to the reduction of dosing frequency for delamanid and thereby has potential to improve adherence. Formulations of delamanid were prepared in selachyl alcohol and phytantriol as non-digestible self-assembling lipid vehicles, and their behaviour was compared with reconstituted milk powder, as a digestible lipid-based formulation, and an aqueous suspension. The self-assembly of selachyl alcohol and phytantriol in aqueous media in the presence of delamanid was studied using small angle X-ray scattering and produced the inverse hexagonal (H 2 ) and inverse bicontinuous cubic (V 2 ) liquid crystal structures, respectively. The times at which maximum delamanid levels in plasma were observed (T max ) after oral administration of the phytantriol, selachyl alcohol and reconstituted milk powder formulations of delamanid to rats were 27 ± 3, 20 ± 4 and 6.5 ± 1.0 h, respectively, compared with the aqueous suspension formulation with a T max of 3.4 ± 1 h, which confirms the hypothesis of an extended duration of absorption after administration in non-digestible self-assembling lipids. The digestion products of the triglycerides in the milk formulation increased the solubilisation of delamanid in the gastrointestinal tract, leading to an increase in exposure compared with the aqueous suspension formulation but did not significantly extend T max . Overall, the non-digestible nanostructured lipid formulations extended the duration of absorption of delamanid well beyond that from milk or suspension formulations.
Correction: Formation of drug nanocrystals under nanoconfinement afforded by liposomes
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6RA90006B
Abstract: Correction for ‘Formation of drug nanocrystals under nanoconfinement afforded by liposomes’ by D. Cipolla et al. , RSC Adv. , 2016, 6 , 6223–6233.
Drug Solubilization Behavior During in Vitro Digestion of Simple Triglyceride Lipid Solution Formulations
Publisher: Springer Science and Business Media LLC
Date: 02-2004
DOI: 10.1023/B:PHAM.0000016282.77887.1F
Abstract: The purpose of this study was to characterize the solubilization and precipitation characteristics of a range of poorly water-soluble drugs during digestion of either long-chain or medium-chain triglyceride (TG) lipid formulations. TG solution formulations of five selected drugs (griseofulvin, diazepam, danazol, cinnarizine, and halofantrine) were digested in ritro and drug distribution/solubilization behavior in the resulting digests assessed. For the less lipophilic drugs, the mass of drug dissolved in either medium or long-chain TG was low and the drugs partitioned rapidly into the aqueous digestion phase. For the higher log P drugs, drug transfer to the aqueous phase was limited by accumulation in undigested long-chain TG. In contrast, medium-chain TG was digested completely producing a dispersed aqueous phase that was capable, at least in the case of the high log P drugs, of supporting supersaturated drug concentrations. The solubilization behavior of lipophilic drugs on digestion of simple TG lipid formulations is a function of the lipophilicity of the drug (which dictates the drug dose and the partitioning behavior), the nature of the colloidal phases produced on digestion of the different formulation lipids, and the kinetics of drug transfer between the digesting formulation and the colloidal phases produced.
Porous nanostructure controls kinetics, disposition and self-assembly structure of lipid digestion products
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6RA16028J
Abstract: Combining 1 H NMR and sSAXS to discriminate the speciation and structure evolution of lipolysis products for submicron lipid droplets and lipid loaded in porous silica particles.
Colloidal characteristics and formulation of pure protein particulate vaccines
Publisher: Oxford University Press (OUP)
Date: 29-05-2012
DOI: 10.1111/J.2042-7158.2012.01513.X
Abstract: We recently reported that dense gas processing of the protein ovalbumin (OVA) resulted in the formation of particles that were insoluble in water and which retained their immunogenicity in vivo. In the present study, the colloidal properties of these pure protein particles were investigated to in part inform rational formulation approaches. The colloidal properties of the particles, in terms of size, zeta potential and pH-dependent surface and solution properties, were examined. In phosphate-buffered saline (pH 7.4), flocculation of the particles was observed, which was prevented when particles were suspended in acetate buffer at pH lower than 4. The resulting particle size was 300 nm with low polydispersity and zeta potential of 22.9 ± 3.1 mV (mean ± SEM, n = 3) at pH 3. Dense gas OVA particles were also prevented from flocculation using steric stabilisation with Pluronic F127. In this form the particles were stable in Krebs–Henseleit solution for 48 h at room temperature. These findings indicate that insoluble pure protein particles produced by dense gas processing have desirable characteristics as particulate vaccines, including consistency of particle size under controlled conditions and high colloid stability.
Formation of Liquid-Crystalline Structures in the Bile Salt–Chitosan System and Triggered Release from Lamellar Phase Bile Salt–Chitosan Capsules
Publisher: American Chemical Society (ACS)
Date: 31-07-2014
DOI: 10.1021/AM502192T
Abstract: Nanostructured capsules comprised of the anionic bile salt, sodium taurodeoxycholate (STDC), and the biocompatible cationic polymer, chitosan, were prepared to assess their potential as novel tailored release nanomaterials. For comparison, a previously studied system, sodium dodecyl sulfate (SDS), and polydiallyldimethylammonium chloride (polyDADMAC) was also investigated. Crossed-polarizing light microscopy (CPLM) and small-angle X-ray scattering (SAXS) identified the presence of lamellar and hexagonal phase at the surfactant-polymer interface of the respective systems. The hydrophobic and electrostatic interactions between the oppositely charged components were studied by varying temperature and salt concentration, respectively, and were found to influence the liquid-crystalline nanostructure formed. The hexagonal phase persisted at high temperatures, however the lamellar phase structure was lost above ca. 45 °C. Both mesophases were found to dissociate upon addition of 4% NaCl solution. The rate of release of the model hydrophilic drug, Rhodamine B (RhB), from the lamellar phase significantly increased in response to changes in the solution conditions studied, suggesting that modulating the drug release from these bile salt-chitosan capsules is readily achieved. In contrast, release from the hexagonal phase capsules had no appreciable response to the stimuli applied. These findings provide a platform for these oppositely charged surfactant and polymer systems to function as stimuli-responsive or sustained-release drug delivery systems.
Pseudomonas infection responsive liquid crystals for glycoside hydrolase and antibiotic combination
Publisher: American Chemical Society (ACS)
Date: 13-07-2018
Enhanced Extravasation, Stability and in Vivo Cardiac Gene Silencing via in Situ siRNA–Albumin Conjugation
Publisher: American Chemical Society (ACS)
Date: 19-12-2011
DOI: 10.1021/MP2002522
Abstract: A potential barrier to progression of siRNA therapeutics to the clinic is the ability of these agents to cross the vascular endothelium to reach target cells. This study aimed to bypass the endothelial barrier by harnessing the extravasation capability of the serum protein albumin to allow siRNA to reach cardiomyocytes. A strategy for conjugating siRNA to albumin in vivo was developed that involved activating 3'-amine, 2'-O-methyl, phosphorothioate modified siRNA with succinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate (SMCC) to yield maleimide-functionalized siRNA ("activated siRNA") this thiol-reactive species can then irreversibly link to the single surface-exposed cysteine residue of endogenous albumin following intravenous administration. An IGF-I-receptor (IGF-IR) siRNA sequence which was effective in vitro was used to test the ability of the siRNA-albumin conjugate to bypass the endothelial barrier in Balb/C mice and produce silencing. In situ conjugation of maleimide-functionalized siRNA to albumin in mouse serum occurred within minutes of addition, and the resulting conjugate was found to be nuclease stable by SDS-PAGE analysis. In Sprague-Dawley rats, activated siRNA showed a significantly enhanced elimination half-life (75.9 ± 18.2 min) compared to unactivated siRNA (5.1 ± 0.2 min). Intravenous injection of this activated siRNA (1 mg/kg daily for four days) significantly reduced left ventricle IGF-IR mRNA to 64.1 ± 4.1% of that in vehicle-treated animals (mean ± SEM), while the control siRNA (unconjugated) had no effect (n = 4, P > 0.05). Imaging of microvessels from mice treated with fluorescein-labeled activated siRNA showed clear evidence of extravasation and cellular uptake in capillary endothelial cells, cardiomyocytes and vascular smooth muscle cells for mice treated with the activated siRNA but not mice treated with the unactivated siRNA. siRNA-albumin constructs are therefore capable of extravasation to the myocardium resulting in silencing in this otherwise silencing-resistant organ.
Coupling in vitro cell culture with synchrotron SAXS to understand the bio-interaction of lipid-based liquid crystalline nanoparticles with vascular endothelial cells
Publisher: Springer Science and Business Media LLC
Date: 29-01-2020
DOI: 10.1007/S13346-020-00718-3
Abstract: Nonlamellar lipid-based liquid crystalline (LLC) nanoparticles possessing different internal nanostructures, specifically the 3D-ordered cubosomes (V
Chemistry and Geometry of Counterions Used in Hydrophobic Ion Pairing Control Internal Liquid Crystal Phase Behavior and Thereby Drug Release
Publisher: American Chemical Society (ACS)
Date: 03-03-2021
Visible light-triggered cargo release from donor acceptor Stenhouse adduct (DASA)-doped lyotropic liquid crystalline nanoparticles
Publisher: Elsevier BV
Date: 12-2202
DOI: 10.1016/J.JCIS.2019.04.032
Abstract: Light-responsive nanocarriers are applicable as non-invasive, highly tunable and precisely controlled drug delivery systems. Here, we report a new nanocarrier system, achieved by doping D1, a type of green light-responsive donor acceptor Stenhouse adduct (DASA), into a lipid-based lyotropic liquid crystalline system. Time-resolved small angle X-ray scattering was used to confirm that the matrix underwent a rapid and fully reversible phase transition from lamellar to inverse cubic phase upon irradiation with green light (532 nm), reverting back on removal of light. Fluorescein isothiocyanate-dextran (FD4) was used as a model hydrophilic cargo. The release of cargo upon varying irradiation parameters was investigated in vitro which showed that irradiation can trigger a burst release of FD4 upon phase transition. This additive shows promise for the development of new visible light-activated, "on demand" drug delivery systems.
Nanostructured Liquid Crystalline Particles As an Alternative Delivery Vehicle for Plant Agrochemicals
Publisher: American Chemical Society (ACS)
Date: 04-03-2013
DOI: 10.1021/AM303208T
Abstract: Agrochemical spray formulations applied to plants are often mixed with surfactants that facilitate delivery of the active ingredient. However, surfactants cause phytotoxicity and off-target effects in the environment. We propose the use of nanostructured liquid crystalline particles (NLCP) as an alternative to surfactant-based agrochemical delivery. For this, we have compared the application of commercial surfactants, di (2-ethylhexyl) sulfosuccinate and alkyl dimethyl betaine, with NLCP made from phytantriol, at concentrations of 0.1%, 1% and 5% on the adaxial surface of leaves of four plant species Ttriticum aestivum (wheat), Zea mays (maize), Lupinus angustifolius (lupin), and Arabidopsis thaliana. In comparison with the application of surfactants there was less phytotoxicity on leaves of each species following treatment with NLCP. Following treatment of leaves with NLCP analysis of cuticular wax micromorphology revealed less wax solubilization in the monocot species. The results clearly show that there are advantages in the use of NLCP rather than surfactants for agrochemical delivery.
Preparation of phytantriol cubosomes by solvent precursor dilution for the delivery of protein vaccines
Publisher: Elsevier BV
Date: 09-2011
DOI: 10.1016/J.EJPB.2010.12.034
Abstract: Different delivery strategies to improve the immunogenicity of peptide rotein-based vaccines are currently under investigation. In this study, the preparation and physicochemical characterisation of cubosomes, a novel lipid-based particulate system currently being explored for vaccine delivery, was investigated. Cubosomes were prepared from a liquid precursor mixture containing phytantriol or glycerylmonooleate (GMO), F127 for particle stabilisation, and a hydrotrope (ethanol or polyethylene glycol (PEG(200)) or propylene glycol (PG)). Several liquid precursors were prepared, and the effect of varying the concentrations of F127 and the hydrotrope on cubosome formation was investigated. Formulations were prepared by fragmentation for comparison. The model protein ovalbumin (Ova) was also entrapped within selected formulations. Submicron-sized particles (180-300 nm) were formed spontaneously upon dilution of the liquid precursors, circumventing the need for the preformed cubic phase used in traditional fragmentation-based methods. The nanostructure of the phytantriol dispersions was determined to be cubic phase using SAXS whilst GMO dispersions had a reverse hexagonal nanostructure coexisting with cubic phase. The greatest entrapment of Ova was within phytantriol cubosomes prepared from liquid precursors. Release of Ova from the various formulations was sustained however, release was significantly faster and the extent of release was greater from fragmented dispersions compared to liquid precursor formulations. Taken together, these results suggest that phytantriol cubosomes can be prepared using liquid precursors and that it is a suitable alternative to GMO. Furthermore, the high entrapment and the slow release of Ova in vitro highlight the potential of phytantriol cubosomes prepared using liquid precursors as a novel vaccine delivery system.
Silica nanoparticles to control the lipase-mediated digestion of lipid-based oral delivery systems
Publisher: American Chemical Society (ACS)
Date: 20-01-2010
DOI: 10.1021/MP9002442
Abstract: We investigate the role of hydrophilic fumed silica in controlling the digestion kinetics of lipid emulsions, hence further exploring the mechanisms behind the improved oral absorption of poorly soluble drugs promoted by silica-lipid hybrid (SLH) microcapsules. An in vitro lipolysis model was used to quantify the lipase-mediated digestion kinetics of a series of lipid vehicles formulated with caprylic/capric triglycerides: lipid solution, submicrometer lipid emulsions (in the presence and absence of silica), and SLH microcapsules. The importance of emulsification on lipid digestibility is evidenced by the significantly higher initial digestion rate constants for SLH microcapsules and lipid emulsions (>15-fold) in comparison with that of the lipid solution. Silica particles exerted an inhibitory effect on the digestion of submicrometer lipid emulsions regardless of their initial location, i.e., aqueous or lipid phases. This inhibitory effect, however, was not observed for SLH microcapsules. This highlights the importance of the matrix structure and porosity of the hybrid microcapsule system in enhancing lipid digestibility as compared to submicrometer lipid emulsions stabilized by silica. For each studied formulation, the digestion kinetics is well correlated to the corresponding in vivo plasma concentrations of a model drug, celecoxib, via multiple-point correlations (R(2) > 0.97). This supports the use of the lipid digestion model for predicting the in vivo outcome of an orally dosed lipid formulation. SLH microcapsules offer the potential to enhance the oral absorption of poorly soluble drugs via increased lipid digestibility in conjunction with improved drug dissolution/dispersion.
PD-L1– and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease
Publisher: American Society for Clinical Investigation
Date: 19-09-2019
The Curious Case of the OZ439 Mesylate Salt: An Amphiphilic Antimalarial Drug with Diverse Solution and Solid State Structures
Publisher: American Chemical Society (ACS)
Date: 20-03-2018
Nanostructured liquid crystalline particle assisted delivery of 2,4-dichlorophenoxyacetic acid to weeds, crops and model plants
Publisher: Elsevier BV
Date: 04-2016
Systematic Investigation of Metabolic Oligosaccharide Engineering Efficiency in Intestinal Cells Using a Dibenzocyclooctyne‐Monosaccharide Conjugate
Publisher: Wiley
Date: 24-05-2023
Abstract: Metabolic oligosaccharide engineering (MOE) of cells with synthetic monosaccharides can introduce functionality to the glycans of cell membranes. Unnatural sugars (e. g., peracetylated mannose‐azide) can be expressed on the cell surface with the azide group in place. After MOE, the azide group can participate in a copper‐free click reaction with an alkyne (e. g., dibenzocyclooctyne, DBCO) probe. This allows the metabolic fate of monosaccharides in cells to be understood. However, in a drug delivery context it is desirable to have azide groups on the probe (e. g. a drug delivery particle) and the alkyne (e. g. DBCO) on the cell surface. Consequently, the labelling efficiency of intestinal cell lines (Caco‐2 and HT29‐MTX‐E12) treated with N‐dibenzocyclooctyne‐tetra‐acetylmannosamine, and the concentration‐ and time‐dependent labelling were determined. Furthermore, the labelling of mucus in HT29‐MTX‐E12 cells with DBCO was shown. This study highlights the potential for using MOE to target azide‐functionalised probes to intestinal tissues for drug delivery applications.
Cubosomes containing the adjuvants imiquimod and monophosphoryl lipid A stimulate robust cellular and humoral immune responses
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.JCONREL.2012.10.020
Abstract: New generation vaccines increasingly utilize highly purified peptides and proteins as the target antigen, however these are often poorly immunogenic. One of the most promising strategies for improving immunogenicity of such subunit vaccines is through incorporation into particulate carriers. Here we report the preparation, physicochemical characterization and in vivo immunological activity of cubosomes, a novel lipid-based nanostructured particulate carrier, modified to include the Toll-like receptor agonists monophosphoryl lipid A and imiquimod. The immunological activity of cubosome formulations was compared to that of liposome and alum formulations. Sustained release of the model antigen ovalbumin (Ova) was observed in vitro and in vivo from cubosomes. Cubosomes+adjuvants induced robust CD8⁺ and CD4⁺ T cell proliferation and interferon-γ production, as well as the production of Ova-specific antibodies. Cubosomes+adjuvants were more efficient at generating Ova-specific cellular responses and were equally as effective in generating humoral responses when compared to liposomes+adjuvants and alum. Overall, the results show that cubosomes have the potential to act as effective sustained release vaccine delivery systems.
Bacterial lipase triggers the release of antibiotics from digestible liquid crystal nanoparticles
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.JCONREL.2019.12.037
Abstract: In the advent of the post-antibiotic era, new strategies are urgently required to improve the efficacy of antimicrobials and outsmart multi-drug resistant bacteria. Exploiting a basic survival mechanism of bacteria, lipase production, monoolein liquid crystal nanoparticles (MO-LCNPs) were investigated as a bacterial-triggered drug delivery system for three different antimicrobial compounds and compared with model sn-1/3 regiospecific and non-regiospecific lipases via pH-stat titration, proton nuclear magnetic resonance and in situ synchrotron small-angle X-ray scattering. The release of model hydrophobic (rif icin) and macromolecular (alginate lyase) antimicrobials were triggered from MO-LCNPs at 82-fold and 7-fold higher rates (respectively) due to bacterial lipase digestion of MO-LCNPs, which could not be stimulated with a small hydrophilic antibiotic (ciprofloxacin HCl) or non-digestible, phytantriol-LCNPs. While sn-1/3 regiospecific lipase rapidly digested MO-LCNPs in a two-phase process, the single-phase digestion kinetics of the non-regiospecific lipase steadily digested the cubic Im3m structure and gave rise to lamellar structures that ultimately stimulated the triggered antibiotic release. Accordingly, MO-LCNPs have an application for localised Pseudomonas aeruginosa and Staphylococcus aureus infections that produce non-regiospecific lipases and for concentration-dependent antibiotics that have macromolecular (MW ~ 30 kDa) or hydrophobic (logP ~ 4) chemistries, as a triggered bolus release would be clinically efficacious for improved bacterial eradication.
Preliminary consultation on preferred product characteristics of benzathine penicillin G for secondary prophylaxis of rheumatic fever
Publisher: Springer Science and Business Media LLC
Date: 27-07-2016
DOI: 10.1007/S13346-016-0313-Z
Abstract: Rheumatic fever is caused by an abnormal immune reaction to group A streptococcal infection. Secondary prophylaxis with antibiotics is recommended for people after their initial episode of rheumatic fever to prevent recurrent group A streptococcal infections, recurrences of rheumatic fever and progression to rheumatic heart disease. This secondary prophylaxis must be maintained for at least a decade after the last episode of rheumatic fever. Benzathine penicillin G is the first line antibiotic for secondary prophylaxis, delivered intramuscularly every 2 to 4 weeks. However, adherence to recommended secondary prophylaxis regimens is a global challenge. This paper outlines a consultation with global experts in rheumatic heart disease on the characteristics of benzathine penicillin G formulations which could be changed to improve adherence with secondary prophylaxis. Characteristics included dose interval, pain, administration mechanism, cold chain independence and cost. A s le target product profile for reformulated benzathine penicillin G is presented.
Dendrimer pharmacokinetics: the effect of size, structure and surface characteristics on ADME properties
Publisher: Future Medicine Ltd
Date: 08-2011
DOI: 10.2217/NNM.11.67
Abstract: Dendrimers show increasing promise as drug-delivery vectors and can be generated with a wide range of scaffold structures, sizes and surface functionalities. To this point, the majority of studies of dendrimer-based drug-delivery systems have detailed pharmacodynamic outcomes, or have followed the pharmacokinetics of a solubilized or conjugated drug. By contrast, detailed commentary on the in vivo fate of the dendrimer carrier is less evident, even though the pharmacokinetics of the carrier will likely dictate both pharmacodynamic and toxicokinetic outcomes. In the current article, the influence of size, structure and surface functionality on the absorption, distribution, metabolism and elimination (ADME) properties of dendrimers have been examined and the implications of these findings for delivery system design are discussed.
Pulmonary Delivery of the Kv1.3-Blocking Peptide HsTX1[R14A] for the Treatment of Autoimmune Diseases
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.XPHS.2015.10.025
Abstract: HsTX1[R14A] is a potent and selective Kv1.3 channel blocker peptide with the potential to treat autoimmune diseases. Given the typically poor oral bioavailability of peptides, we evaluated pulmonary administration of HsTX1[R14A] in rats as an alternative route for systemic delivery. Plasma concentrations of HsTX1[R14A] were measured by liquid chromatography coupled with tandem mass spectrometry in rats receiving intratracheal administration of HsTX1[R14A] in solution (1-4 mg/kg) or a mannitol-based powder (1 mg/kg) and compared with plasma concentrations after intravenous administration (2 mg/kg). HsTX1[R14A] stability in rat plasma and lung tissue was also determined. HsTX1[R14A] was more stable in plasma than in lung homogenate, with more than 90% of the HsTX1[R14A] remaining intact after 5 h, compared with 40.5% remaining in lung homogenate. The terminal elimination half-life, total clearance, and volume of distribution of HsTX1[R14A] after intravenous administration were 79.6 ± 6.5 min, 8.3 ± 0.6 mL/min/kg, and 949.8 ± 71.0 mL/kg, respectively (mean ± SD). After intratracheal administration, HsTX1[R14A] in solution and dry powder was absorbed to a similar degree, with absolute bioavailability values of 39.2 ± 5.2% and 44.5 ± 12.5%, respectively. This study demonstrated that pulmonary administration is a promising alternative for systemically delivering HsTX1[R14A] for treating autoimmune diseases.
Susceptibility to Lipase-Mediated Digestion Reduces the Oral Bioavailability of Danazol After Administration as a Medium-Chain Lipid-Based Microemulsion Formulation
Publisher: Springer Science and Business Media LLC
Date: 08-2004
DOI: 10.1023/B:PHAM.0000036914.22132.CC
Abstract: To investigate the impact of lipidic formulation type on in vitro dispersion and digestion properties and the relationship to oral bioavailability, using danazol as a model lipophilic poorly water-soluble drug. Three lipid-based danazol formulations [a long-chain triglyceride solution (LCT-solution) and self-microemulsifying drug delivery systems (SMEDDS) based on long-chain (C18) lipids (LC-SMEDDS) and medium-chain (C8-C10) lipids (MC-SMEDDS)] were administered to fasted beagle dogs and compared with a micronized danazol formulation administered postprandially and in the fasted state. In vitro dispersion and particle size data for the two SMEDDS were compared, and the distribution/solubilization patterns of danazol across the various phases produced during in vitro digestion quantified. The LCT-solution and LC-SMEDDS formulations significantly enhanced the oral bioavailability of danazol when compared to fasted administration of the powder formulation. In contrast, and despite displaying excellent dispersion properties, the MC-SMEDDS resulted in little enhancement in danazol bioavailability. In support of the in vivo findings, in vitro digestion of the medium-chain formulation resulted in significant drug precipitation when compared with the long-chain lipid formulations. Digestion of microemulsion preconcentrate formulations based on medium-chain lipids may limit in vivo utility when compared with similar formulations based on long chain lipids.
Application of Low-Frequency Raman Scattering Spectroscopy to Probe in Situ Drug Solubilization in Milk during Digestion
Publisher: American Chemical Society (ACS)
Date: 23-04-2019
Pharmacokinetics and Tumor Disposition of PEGylated, Methotrexate Conjugated Poly-l -lysine Dendrimers
Publisher: American Chemical Society (ACS)
Date: 10-06-2009
DOI: 10.1021/MP900049A
Abstract: Dendrimers have potential for delivering chemotherapeutic drugs to solid tumors via the enhanced permeation and retention (EPR) effect. The impact of conjugation of hydrophobic anticancer drugs to hydrophilic PEGylated dendrimer surfaces, however, has not been fully investigated. The current study has therefore characterized the effect on dendrimer disposition of conjugating alpha-carboxyl protected methotrexate (MTX) to a series of PEGylated (3)H-labeled poly-l-lysine dendrimers ranging in size from generation 3 (G3) to 5 (G5) in rats. Dendrimers contained 50% surface PEG and 50% surface MTX. Conjugation of MTX generally increased plasma clearance when compared to conjugation with PEG alone. Conversely, increasing generation reduced clearance, increased metabolic stability and reduced renal elimination of the administered radiolabel. For constructs with molecular weights >20 kDa increasing the molecular weight of conjugated PEG also reduced clearance and enhanced metabolic stability but had only a minimal effect on renal elimination. Tissue distribution studies revealed retention of MTX conjugated smaller (G3-G4) PEG(570) dendrimers (or their metabolic products) in the kidneys. In contrast, the larger G5 dendrimer was concentrated more in the liver and spleen. The G5 PEG(1100) dendrimer was also shown to accumulate in solid Walker 256 and HT1080 tumors, and comparative disposition data in both rats (1 to 2% dose/g in tumor) and mice (11% dose/g in tumor) are presented. The results of this study further illustrate the potential utility of biodegradable PEGylated poly-l-lysine dendrimers as long-circulating vectors for the delivery and tumor-targeting of hydrophobic drugs.
Enabling Noninvasive Systemic Delivery of the Kv1.3-Blocking Peptide HsTX1[R14A] via the Buccal Mucosa
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.XPHS.2016.05.008
Abstract: The peptide HsTX1[R14A] is a potent and selective blocker of the voltage-gated potassium channel Kv1.3, a well-recognized therapeutic target for autoimmune diseases. To overcome the poor oral absorption and consequent need for regular injections, the potential of the buccal mucosa for systemic delivery of HsTX1[R14A] was investigated. For in vitro studies, FITC-HsTX1[R14A] and HsTX1[R14A], in solution or formulated in a mucoadhesive chitosan-based gel (3%, w/v) with or without cetrimide (5%, w/w), were applied to porcine buccal epithelium mounted between Ussing chambers and buccal mucosal permeation assessed. HsTX1[R14A] was also administered to Swiss outbred mice at a dose of 10 mg/kg in the same formulations. In vitro, administration of FITC-HsTX1[R14A] and HsTX1[R14A] in the chitosan gel containing cetrimide resulted in detectable buccal permeation with 0.75% and 0.58%, respectively, of the applied dose appearing in the receptor chamber over 5 h. After buccal administration to mice, HsTX1[R14A] was detected in plasma, with the presence of cetrimide in the gel further enhancing plasma exposure, with area under the plasma concentration-time curve values of 77.9 ± 9.7 and 31.0 ± 2.3 nM·h, respectively. The buccal mucosa is a promising alternative administration route for the systemic delivery of HsTX1[R14A] for the treatment of autoimmune diseases.
The impact of digestion is essential to the understanding of milk as a drug delivery system for poorly water soluble drugs
Publisher: Elsevier BV
Date: 12-2018
Clickable Cubosomes for Antibody-Free Drug Targeting and Imaging Applications
Publisher: American Chemical Society (ACS)
Date: 20-12-2017
DOI: 10.1021/ACS.BIOCONJCHEM.7B00659
Abstract: The combination of copper-free click chemistry with metabolic labeling offers new opportunities in drug delivery. The objective of this study was to determine whether cubosomes functionalized with azide or dibenzocyclooctyne (DBCO) groups are able to undergo copper-free click chemistry with a strained cyclooctyne or azide, respectively. Phytantriol-based cubosomes were functionalized using phospholipids bearing an azide or DBCO group. The modified cubosome dispersions were characterized using dynamic light scattering, cryo-TEM, and small-angle X-ray scattering. The efficiency of "clickability" was assessed by reacting the cubosomes with a complementary dye and determining bound and unbound dye via size exclusion chromatography. The clickable cubosomes reacted specifically and efficiently with a click-Cy5 dye with minor changes to the size, shape, and structure of the cubosomes. This indicates that cubosomes can retain their unique internal structure while participating in copper-free click chemistry. This proof of concept study paves the way for the use of copper-free click chemistry and metabolic labeling with cubosomes for targeted drug delivery and imaging.
Association of Chemotherapeutic Drugs with Dendrimer Nanocarriers: An Assessment of the Merits of Covalent Conjugation Compared to Noncovalent Encapsulation
Publisher: American Chemical Society (ACS)
Date: 26-01-2012
DOI: 10.1021/MP2005966
Abstract: Cancer is a leading cause of death within developed nations, and part of this morbidity is due to difficulties associated with its treatment. Currently, anticancer therapy relies heavily upon the administration of small molecule cytotoxic drugs that attack both cancerous and noncancerous cells due to limited selectivity of the drugs and widespread distribution of the cytotoxic molecules throughout the body. The antitumor efficacy and systemic toxicity of existing chemotherapeutic drugs can, however, be improved by employing formulation and particle engineering approaches. Thus, drug delivery systems can be developed that more specifically target tumor tissue using both passive (such as the enhanced permeation and retention effect) and active (through the use of cancer targeting ligands) modalities. Dendrimers are one such system that can be developed with high structural monodispersity, long plasma circulation times and precise control over surface structure and biodistribution properties. Chemotherapeutic drugs can be associated with dendrimers via covalent conjugation to the surface, or via encapsulation of drugs within the structure. Each of these approaches has demonstrated therapeutic benefit relative to the administration of free drug. Thus far, however, there has not been a systematic review toward which drug association approach will provide the best outcomes in terms of antitumor efficacy and systemic toxicity. Hence, the current literature is reviewed here and recommendations are proposed as to the suggested approach to develop dendrimers as tumor targeted drug-delivery vectors.
Application of positron annihilation lifetime spectroscopy (PALS) to study the nanostructure in amphiphile self-assembly materials: phytantriol cubosomes and hexosomes
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4CP04343J
Abstract: Schematic of the mechanism of positron annihilation spectroscopy (PALS) showing (1) thermalisation (2) diffusion and (3) trapping and annihilation events.
Dynamic formation of nanostructured particles from vesicles via invertase hydrolysis for on-demand delivery
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C6RA26688F
Abstract: Controlled hydrolysis via invertase action alters molecular shape and therefore lipid curvature, consequently triggering the release of encapsulated drug.
The Effect of Administered Dose of Lipid-Based Formulations on the In Vitro and In Vivo Performance of Cinnarizine as a Model Poorly Water-Soluble Drug
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1002/JPS.23384
Nature‐Inspired Design and Application of Lipidic Lyotropic Liquid Crystals
Publisher: Wiley
Date: 20-06-2019
Abstract: Amphiphilic lipids aggregate in aqueous solution into a variety of structural arrangements. Among the plethora of ordered structures that have been reported, many have also been observed in nature. In addition, due to their unique morphologies, the hydrophilic and hydrophobic domains, very high internal interfacial surface area, and the multitude of possible order-order transitions depending on environmental changes, very promising applications have been developed for these systems in recent years. These include crystallization in inverse bicontinuous cubic phases for membrane protein structure determination, generation of advanced materials, sustained release of bioactive molecules, and control of chemical reactions. The outstanding erse functionalities of lyotropic liquid crystalline phases found in nature and industry are closely related to the topology, including how their nanoscopic domains are organized. This leads to notable ex les of correlation between structure and macroscopic properties, which is itself central to the performance of materials in general. The physical origin of the formation of the known classes of lipidic lyotropic liquid crystalline phases, their structure, and their occurrence in nature are described, and their application in materials science and engineering, biology, medical, and pharmaceutical products, and food science and technology are exemplified.
A closer look at the behaviour of milk lipids during digestion
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.CHEMPHYSLIP.2017.10.009
Abstract: Milk has recently been reported to form complex self-assembled liquid crystalline structures during digestion by lipolytic enzymes. The formation of cubic phases at the endpoint of digestion was of particular interest as this requires a fine balance in self-assembly. This manuscript probes the robustness of the kinetic structural behaviour when milk is subjected to a range of processes that are encountered by milk and/or are relevant to the use of milk in pharmaceutical applications (homogenisation, lyophilisation, freeze-thawing and freeze-drying) using time-resolved small angle X-ray scattering (TR-SAXS). The nature of the persistent lamellar phase that occurs during digestion is elucidated using SAXS and X-ray photoelectron spectroscopy, and the interplay between the formation of structured mesophases and the evolution of particle size during digestion is determined using laser light scattering studies. This closer look at milk lipids during digestion establishes the dependence of the structural behaviour of milk on lipid composition and not processing, and clarifies the phase behaviour and kinetic effects on particle size distribution under lipolytic conditions.
Confocal laser scanning microscopy elucidation of the micromorphology of the leaf cuticle and analysis of its chemical composition
Publisher: Springer Science and Business Media LLC
Date: 25-02-2015
DOI: 10.1007/S00709-015-0777-6
Abstract: Electron microscopy techniques such as transmission electron microscopy (TEM) and scanning electron microscopy (SEM) have been invaluable tools for the study of the micromorphology of plant cuticles. However, for electron microscopy, the preparation techniques required may invariably introduce artefacts in cuticle preservation. Further, there are a limited number of methods available for quantifying the image data obtained through electron microscopy. Therefore, in this study, optical microscopy techniques were coupled with staining procedures and, along with SEM were used to qualitatively and quantitatively assess the ultrastructure of plant leaf cuticles. Leaf cryosections of Triticum aestivum (wheat), Zea mays (maize), and Lupinus angustifolius (lupin) were stained with either fat-soluble azo stain Sudan IV or fluorescent, diarylmethane Auramine O and were observed under confocal laser scanning microscope (CLSM). For all the plant species tested, the cuticle on the leaf surfaces could be clearly resolved in many cases into cuticular proper (CP), external cuticular layer (ECL), and internal cuticular layer (ICL). Novel image data analysis procedures for quantifying the epicuticular wax micromorphology were developed, and epicuticular waxes of L. angustifolius were described here for the first time. Together, application of a multifaceted approach involving the use of a range of techniques to study the plant cuticle has led to a better understanding of cuticular structure and provides new insights into leaf surface architecture.
Minimum information reporting in bio-nano experimental literature
Publisher: Springer Science and Business Media LLC
Date: 09-2018
Spontaneous Self-Assembly of Thermoresponsive Vesicles Using a Zwitterionic and an Anionic Surfactant
Publisher: American Chemical Society (ACS)
Date: 29-06-2020
Towards mesoporous silica as a pharmaceutical treatment for obesity - impact on lipid digestion and absorption
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.EJPB.2022.02.001
Abstract: Mesoporous silica particles (MSPs) are emerging as an interesting option to reduce calorific uptake as a treatment for obesity and other metabolic conditions. However, their further development under the pharmaceutical regulatory framework is hindered by poor understanding of the mechanisms by which they exert their effects. In the current study the interaction of MSPs with the lipid digestion process is investigated, specifically interactions with lipase enzymes and lipid digestion products as a key contributing factor to lipid absorption and calorific intake. The impact of exposing lipase to MSPs on the enzyme activity was assessed directly using the tributyrin digestion test. The extent of interaction of digestion products with MSPs was studied using selectively radiolabeled bile components and lipids, while the impact on in vivo absorption of lipids was studied by incorporation of radiolabelled lipid (triolein) into milk and administration with and without particles. The studies showed that particles that inhibited lipase activity also tended to interact more extensively with lipid digestion products. In vitro X-ray scattering studies revealed the interaction of some MSPs with lipid digestion products through changes in lipid self-assembly during digestion. The MSPs led to reduced lipid absorption in vivo compared to the control particles and MSP-free milk. While the specific properties of the MSPs that drive the differences between the behavior of MSPs during lipid digestion remain elusive, the studies highlight that interactions with the lipid digestion and absorption pathways are a likely mechanism for reducing calorific uptake.
A Simple Quantitative Approach for the Determination of Long and Medium Chain Lipids in Bio-relevant Matrices by High Performance Liquid Chromatography with Refractive Index Detection
Publisher: Springer Science and Business Media LLC
Date: 04-06-2013
A novel approach to enhance the mucoadhesion of lipid drug nanocarriers for improved drug delivery to the buccal mucosa
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.IJPHARM.2014.05.044
Abstract: Targeted drug delivery to the buccal mucosa offers distinct advantages over oral delivery to the gastrointestinal tract including by-passing hepatic first-pass metabolism. However, the buccal route is often limited by low bioavailability, low drug loading and reduced residence time due to salivary excretion and clearance. To overcome these limitations, a novel mucoadhesive formulation based on liquid crystalline nanoparticles was designed. Utilising a pH induced in situ transition from a stable vesicle formulation to dispersed inverse hexagonal phase nanoparticles (hexosomes) enhanced adsorption onto the mucosal surface was enabled. Firstly, the phase behaviour of the hiphilic lipid phytantriol (PHY) and oleic acid (OA) was assessed from pH 2-9 using small-angle X-ray scattering (SAXS) and cryo-transmission electron microscopy (cryo-TEM) to determine the appropriate composition for the vesicle to hexosome transition. The colloidal stability of the formulation was determined using turbidity studies. Dispersions comprising 30% w/w OA in PHY were able to form stable vesicles at pH 8 and transition to hexosomes when exposed to pH<7 (as encountered on the buccal mucosal surface). Subsequent ex vivo studies utilising excised porcine buccal tissue indicated significant retention of the in situ-formed PHY/OA hexosomes when compared to control DOPC vesicles (p<0.005), confirmed independently using confocal fluorescence microscopy, radioactive scintillation counting and HPLC analysis for incorporated drug. Thus, a novel approach providing a stable vesicle formulation, with in situ transformation to mucoadhesive hexosomes has been identified with the potential to enhance drug delivery to mucosal surfaces.
Hybrid nanomaterials that mimic the food effect : controlling enzymatic digestion for enhanced oral drug absorption
Publisher: Wiley
Date: 13-04-2012
Self‐Assembled Nanostructured Lipid Systems: Is There a Link between Structure and Cytotoxicity?
Publisher: Wiley
Date: 12-11-2018
Direct Comparison of Standard Transmission Electron Microscopy and Cryogenic-TEM in Imaging Nanocrystals Inside Liposomes
Publisher: American Chemical Society (ACS)
Date: 27-02-2019
DOI: 10.1021/ACS.MOLPHARMACEUT.8B01308
Abstract: The use of electron microscopy techniques in the understanding of shape and size of nanoparticles are commonly applied to drug nanotechnology, but the type of microscopy and suitability for the particles of interest can have a significant impact on the result. The size and shape of the nanoparticles are crucial in clinical applications however, direct comparison of the results from standard transmission electron microscopy (TEM) and cryo-TEM have rarely been reported. As a useful case for comparison, liposomal drug nanocrystals are studied here. In this study, the effect of thawing temperature on the size and shape of the ciprofloxacin nanocrystals was determined. A quantitative standard TEM assay was developed to allow for high-throughput particle size analysis. These results were compared to size and shape information obtained using the cryo-TEM method. The results showed broad agreement between the two TEM methods and that ciprofloxacin nanocrystals formed shorter and thinner crystals inside the liposomes at higher thawing temperatures. The results provide confidence in the use of standard TEM to determine the size and shape distribution of solid nanoparticles (in this case, encapsulated inside liposomes) from aqueous media without fear of s le preparation altering the conclusions.
Peptide-based biosensors
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.TALANTA.2014.12.020
Abstract: Peptides have been used as components in biological analysis and fabrication of novel biosensors for a number of reasons, including mature synthesis protocols, erse structures and as highly selective substrates for enzymes. Bio-conjugation strategies can provide an efficient way to convert interaction information between peptides and analytes into a measurable signal, which can be used for fabrication of novel peptide-based biosensors. Many sensitive fluorophores can respond rapidly to environmental changes and stimuli manifest as a change in spectral characteristics, hence environmentally-sensitive fluorophores have been widely used as signal markers to conjugate to peptides to construct peptide-based molecular sensors. Additionally, nanoparticles, fluorescent polymers, graphene and near infrared dyes are also used as peptide-conjugated signal markers. On the other hand, peptides may play a generalist role in peptide-based biosensors. Peptides have been utilized as bio-recognition elements to bind various analytes including proteins, nucleic acid, bacteria, metal ions, enzymes and antibodies in biosensors. The selectivity of peptides as an enzymatic substrate has thus been utilized to construct enzyme sensors or enzyme-activity sensors. In addition, progress on immobilization and microarray techniques of peptides has facilitated the progress and commercial application of chip-based peptide biosensors in clinical diagnosis.
Kinetic Resolution of the Interactions between Agrochemical Products and Adjuvant Systems upon Mixing
Publisher: American Chemical Society (ACS)
Date: 02-08-2016
Abstract: The addition of an adjuvant to a pesticide usually occurs in a mix-tank, before spray application to the crop. Their interaction is potentially crucial to overall efficacy but has received little attention from a physical-chemical perspective. Study was undertaken by laser diffraction, Raman spectroscopy, and small-angle X-ray scattering to resolve these physical processes. It was shown that migration of the pesticide into the adjuvant droplet occurred in all cases studied. The level of transfer was dependent upon adjuvant level, adjuvant solubility, and surfactant level. For suspension pesticides, dissolution of crystallites within the droplet occurred to a degree limited by solubility. The results directly demonstrate the transfer of the pesticide into the adjuvant carrier. This indicates that for emulsion-based pesticides, application to the target is likely as a homogeneously mixed droplet, whereas for suspension pesticides, solubility may limit transfer and dissolution, leading to heterogeneity in the applied particles.
A novel cubic phase of medium chain lipid origin for the delivery of poorly water soluble drugs
Publisher: Elsevier BV
Date: 09-2004
Mesoporous Titanium Zirconium Oxide Nanospheres with Potential for Drug Delivery Applications
Publisher: American Chemical Society (ACS)
Date: 22-10-2013
DOI: 10.1021/AM4031104
Abstract: Mesoporous titanium zirconium (TiZr) oxide nanospheres with variable Ti to Zr ratios were synthesized using sol-gel chemistry followed by solvothermal treatment. These oxide nanospheres exhibited similar diameters (~360 nm), high surface areas (from 237 ± 2 to 419 ± 4 m(2) g(-1)), and uniform pore diameters (~3.7 nm). Three drugs, ibuprofen, dexamethasone, and erythromycin, were loaded into the TiZr oxide nanospheres. The TiZr oxide nanospheres exhibited a high loading capacity, up to 719 mg g(-1), and sustained release profiles in phosphate buffered saline (PBS) at pH 7.4. The mesoporous TiZr oxide nanospheres also exhibited hydrolytic stability, as evidenced by the retention of the integrity of the mesostructures after drug release in PBS for 21 days.
Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: Studies with halofantrine
Publisher: Elsevier BV
Date: 05-2004
DOI: 10.1002/JPS.20039
Comparison of bulk and microfluidic methods to monitor the phase behaviour of nanoparticles during digestion of lipid-based drug formulations using in situ X-ray scattering
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9SM01440C
Abstract: Microfluidics affords more control over transformations than current setups to monitor the digestion of lipid-based formulations with X-ray scattering techniques.
Liquid Crystalline Coated Drug Particles as a Potential Route to Long Acting Intravitreal Steroids
Publisher: Bentham Science Publishers Ltd.
Date: 08-2009
DOI: 10.2174/156720109789000564
Abstract: The aim of this study was to investigate the potential for coating drug particles with liquid crystalline lipids with a view to modifying drug dissolution behaviour in the particle form. Firstly, dissolution of a simple salicylic acid layer on a microscope slide, as a model system was shown to be hindered by the liquid crystal layer and was sensitive to the type of liquid crystal nanostructure present. Particles of sodium salicylate (hydrophilic) and triamcinolone acetonide (hydrophobic) were produced, and lipids applied to the drug surface using either mechanofusion or co-spray drying approaches. The coated sodium salicylate particles dissolved extremely rapidly. Triamcinolone acetonide particles on the other hand dissolved very slowly compared to uncoated triamcinolone acetonide particles, which indicated that the coating was in fact intact, and that drug solubility in the aqueous channels likely controlled the transport of drug into the dissolution medium. Whilst more investigation is required, these initial studies demonstrate a potentially useful strategy for controlling drug dissolution for applications such as intravitreal steroid injections.
Understanding the photothermal heating effect in non-lamellar liquid crystalline systems, and the design of new mixed lipid systems for photothermal on-demand drug delivery
Publisher: Royal Society of Chemistry (RSC)
Date: 17-10-2014
DOI: 10.1039/C4CP03635B
Abstract: Lipid-based liquid crystalline systems are showing potential as stimuli-responsive nanomaterials, and NIR-responsive gold nanoparticles have been demonstrated to provide control of transitions in non-lamellar phases. In this study, we focus on a deeper understanding of the photothermal response of both lamellar and non-lamellar phases, and new systems formed by alternative lipid systems not previously reported, by linking the photothermal heating to the bulk thermal properties of the materials. Dynamic photothermal studies were performed using NIR laser irradiation and monitoring the structural response using time resolved small angle X-ray scattering for the bulk phases and hexosomes. In addition, cryoFESEM and cryoTEM were used to visualise and assess the effect of GNR incorporation into hexagonal phase nanostructures. The ability of the systems to respond to photothermal heating was correlated with the thermal phase behaviour and heat capacities of the different structures. Access to alternative phase transitions in these systems and understanding the likely photothermal response will facilitate different modes of application of these hybrid nanomaterials for on-demand drug delivery applications.
In Situ Monitoring of Drug Precipitation from Digesting Lipid Formulations Using Low-Frequency Raman Scattering Spectroscopy
Publisher: MDPI AG
Date: 17-07-2023
Synergistic role of self-emulsifying lipids and nanostructured porous silica particles in optimizing the oral delivery of lovastatin
Publisher: Future Medicine Ltd
Date: 12-2014
DOI: 10.2217/NNM.14.37
Abstract: Aim: To investigate the role of self-emulsifying lipids and porous silica particles in enhancing supersaturated drug loading and biopharmaceutical performance of nanostructured silica–lipid hybrid (SLH) systems. Materials & methods: Two lovastatin (LOV)-SLHs were engineered from self-emulsifying lipid (Gelucire ® 44/14 Gattefossé, Lyon, France) and Aerosil ® 380 (SLH-A Evonik Industries, Essen, Germany) or Syloid ® 244FP silica (SLH-S Grace Davison Discovery Sciences, Rowville, Australia). Results & discussion: The LOV-SLHs encapsulated LOV at 10% w/w, which is ≥3-fold higher than typical lipid formulations in the absence of porous silica. The LOV-SLHs retained self-emulsifying lipid-associated solubilization benefits and improved drug solubilization by twofold in simulated intestinal condition. SLH-S, with larger surface area (299 m 2 /g), was superior to SLH-A (184 m 2 /g) in optimizing oral bioavailability, suggesting a critical role of the silica geometry. Bioavailability of SLH-S was 2.8- and 1.3-fold higher than pure drug and drug suspension in Gelucire 44/14, respectively. Conclusion: In conclusion, SLHs profit from advantages associated with both self-emulsifying lipids and porous silica, and provide potentially improved therapy against coronary artery disease.
Construction of a Synthetic Colostrum Substitute and Its Protection of Intestinal Cells against Inflammation in an In Vitro Model of Necrotizing Enterocolitis
Publisher: American Chemical Society (ACS)
Date: 22-07-2023
Development of a sustained release implant of benzathine penicillin G for secondary prophylaxis of rheumatic heart disease
Publisher: Elsevier BV
Date: 08-2023
Influence of the intermediate digestion phases of common formulation lipids on the absorption of a poorly water‐soluble drug
Publisher: Elsevier BV
Date: 03-2005
DOI: 10.1002/JPS.20260
Nonspherical Nanocapsules as Long-Circulating Drug Delivery Systems
Publisher: American Chemical Society (ACS)
Date: 03-2022
Polymers with Dithiobenzoate End Groups Constitutively Release Hydrogen Sulfide upon Exposure to Cysteine and Homocysteine
Publisher: American Chemical Society (ACS)
Date: 26-03-2020
Lipid-based drug delivery systems in the treatment of wet age-related macular degeneration
Publisher: Springer Science and Business Media LLC
Date: 18-05-2016
DOI: 10.1007/S13346-016-0299-6
Abstract: Recent advances in drug delivery technology have lified potential opportunities to treat the debilitating diseases that affect the posterior segment of the eye in a less invasive and more efficient manner. Current methods for effective drug delivery to the back of the eye are hindered by many barriers and limitations. As a consequence, considerable efforts have been directed towards developing new materials to selectively deliver drug directly to the target site. This review focuses on lipid-based delivery systems which show promise in improving treatment for the most common disease of the posterior segment of the eye in the developed world, age-related macular degeneration, with an emphasis upon on-demand delivery systems as they have greater potential to overcome the current limitations.
Using a selective cadmium-binding peplipid to create responsive liquid crystalline nanomaterials
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.JCIS.2014.11.063
Abstract: A specific metal ion-responsive lipid liquid crystalline (LLC) dispersion system was fabricated, which can work in buffer solutions. The LLC matrix was prepared from phytantriol which spontaneously forms the reversed bicontinuous cubic phase in water, and a novel peptide-lipid conjugate (peplipid) consists of a myristate alkyl chain for anchoring into the phytantriol-based cubic bilayer and a peptide sequence for capturing a specific metal ion. The peplipid in its unbound state, when added into the phytantriol-based cubic system induces a positive effect on the bilayer curvature, resulting in the formation of the lamellar phase (vesicles) and the dispersion was transparent in appearance. Upon binding of the cadmium ion, the peplipid induces a negative effect on the lipid bilayer curvature and consequently leading to the formation of cubic phase and opaque appearance. In contrast, other metal ions, including buffering salts, could not sufficiently trigger the phase transition due to weak interaction with the peplipid. The high selectivity of metal ion interaction and triggered phase transition provide potential applications, such as in colloidal-mineral separation, triggered drug release and treatment of cadmium (II) pollution.
Low-Frequency Raman Scattering Spectroscopy as an Accessible Approach to Understand Drug Solubilization in Milk-Based Formulations during Digestion
Publisher: American Chemical Society (ACS)
Date: 03-02-2020
Solubilisation behaviour of poorly water-soluble drugs during digestion of solid SMEDDS
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.EJPB.2018.07.006
Abstract: Lipid based-formulations can enhance the bioavailability of poorly water-soluble lipophilic drugs through enhanced solubilisation of drugs in the gastrointestinal (GI) tract during digestion. This study investigates the solubilisation behaviour of poorly water-soluble drugs upon digestion of solid self-microemulsifying drug delivery system (S-SMEDDS). The S-SMEDDS were prepared using two different core lipids, Gelucire® 44/14 (GEL) or glyceryl monooleate (GMO), and were loaded with two model drugs, fenofibrate (FEN) and cinnarizine (CINN). S-SMEDDS formulations were characterized using wide-angle X-ray scattering (WAXS) and Raman spectroscopy, and their structural behaviour and drug solubilisation behaviour were monitored using drug-related diffraction peaks during digestion under fasted and fed simulated intestinal conditions using time-resolved small and wide-angle X-ray scattering (SAXS/WAXS). The concentrations of FEN and CINN released into the aqueous phase (AP) during digestion were quantified using high-performance liquid chromatography (HPLC). Both model drugs, FEN and CINN, had greater solubility in the GMO-based S-SMEDDS formulations and were partially solubilised into lipid matrix and uniformly distributed in solid formulations. The extent of digestion was greater for the GEL-based systems (92-94%) than GMO-based systems (65-75%) as was the rate of digestion. GEL-based S-SMEDDS formulations formed a lamellar phase during digestion in the fasted state and formed mixed micelles in the fed state. In contrast, the GMO-based system formed the mixed micelles in both intestinal conditions. The time-resolved SAXS profiles revealed solubilisation of crystalline drugs into the lipolysis products. Synchrotron SAXS results were in correlation with the HPLC measurements, confirming the ability of the SAXS technique to monitor drug behaviour and showing that the digestion of S-SMEDDS can enhance drug solubilisation.
Differences in colloidal structure of PEGylated nanomaterials dictate the likelihood of accelerated blood clearance
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1002/JPS.22682
Positron annihilation lifetime spectroscopy (PALS): a probe for molecular organisation in self-assembled biomimetic systems
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5CP01921D
Abstract: Positron annihilation lifetime spectroscopy (PALS) has been shown to be highly sensitive to conformational, structural and microenvironmental transformations arising from subtle geometric changes in molecular geometry in self-assembling biomimetic systems.
pH-responsive lyotropic liquid crystals and their potential therapeutic role in cancer treatment
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4CC10274F
Abstract: A weak hiphilic base, pyridinylmethyl linoleate, is blended with monolinolein, yielding mesophases with a pH-induced hexagonal-to-cubic transition at pH ≤ 5.5.
Nanostructure of liquid crystalline matrix determines in vitro sustained release and in vivo oral absorption kinetics for hydrophilic model drugs
Publisher: Elsevier BV
Date: 05-01-2009
DOI: 10.1016/J.IJPHARM.2008.08.022
Abstract: Nanostructured lipid-based liquid crystalline systems have been proposed as sustained oral drug delivery systems, but the interplay between their intrinsic release rates, susceptibility to digestive processes, and the manner in which these effects impact on their application in vivo, are not well understood. In this study, two different bicontinuous cubic phases, prepared from glyceryl monooleate and phytantriol, and a reversed hexagonal phase formed by addition of a small amount of vitamin E to phytantriol (Q(II GMO), Q(II PHYT) and H(II PHYT+VitEA), respectively) were prepared. The release kinetics for a number of model hydrophilic drugs with increasing molecular weights (glucose, Allura Red and FITC-dextrans) was determined in in vitro release experiments. Diffusion-controlled release was observed in all cases as anticipated from previous studies with liquid crystalline systems, and it was discovered that the release rates of each drug decreased as the matrix was changed from Q(II GMO) to Q(II PHYT) to H(II PHYT+VitEA). Formulations containing (14)C-glucose, utilized as a rapidly absorbed marker of drug release, were then orally administered to rats to determine the relative in vivo absorption rates from the different formulations. The results showed a trend by which the rate of absorption of (14)C-glucose followed that observed in the corresponding in vitro release studies, providing the first indication that the nanostructure of these materials may provide the ability to tailor the absorption kinetics of hydrophilic drugs in vivo, and hence form the basis of a new drug delivery system.
Large Hexosomes from Emulsion Droplets: Particle Shape and Mesostructure Control
Publisher: American Chemical Society (ACS)
Date: 15-10-2018
DOI: 10.1021/ACS.LANGMUIR.8B02638
Abstract: Soft, rotationally symmetric particles of dispersed hexagonal liquid crystalline phase are produced using a method previously developed for cubosome microparticle production. The technique forms hexosome particles via removal of ethanol from emulsion droplets containing monoolein, water, and one of the various hydrophobic molecules: vitamin E, hexadecane, oleic acid, cyclohexane, or inylbenzene. The unique rotational symmetry of the particles is characterized by optical microscopy and small-angle X-ray scattering to link particle phase, shape, and structure to composition. Rheology of the soft particles can be varied independently of shape, enabling control of transport, deformation, and biological response by controlling composition and molecular structure of the additives. The direct observations of formation, and the resultant hexosome shapes, link the particle-scale and mesoscale properties of these novel self-assembled particles and broaden their applications. The micron-scale hexosomes provide a route to understanding the effects of particle size, crystallization rate, and rheology on the production of soft particles with liquid crystalline structure and unique shape and symmetry.
In Vivo Formation of Cubic Phase in Situ after Oral Administration of Cubic Phase Precursor Formulation Provides Long Duration Gastric Retention and Absorption for Poorly Water-Soluble D
Publisher: American Chemical Society (ACS)
Date: 04-12-2015
DOI: 10.1021/ACS.MOLPHARMACEUT.5B00784
Abstract: Lipid-based liquid crystalline systems based on the combination of digestible and nondigestible lipids have been proposed as potential sustained release delivery systems for oral delivery of poorly water-soluble drugs. The potential for cubic phase liquid crystal formation to induce dramatically extended gastric retention in vivo has been shown previously to strongly influence the resulting pharmacokinetics of incorporated drug. In vitro studies showing the in situ formation of cubic phase from a disordered precursor comprising a mixture of digestible and nondigestible lipids under enzymatic digestion have also recently been reported. Combining both concepts, here we show the potential for such systems to form in vivo, increasing gastric retention, and providing a sustained release effect for a model poorly water-soluble drug cinnarizine. A mixture of phytantriol and tributyrin at an 85:15 mass ratio, shown previously to form cubic phase under the influence of digestion, induced a similar pharmacokinetic profile to that in the absence of tributyrin, but completely different from tributyrin alone. The gastric retention of the formulation, assessed using micro-X-ray CT imaging, was also consistent with the pharmacokinetic behavior, where phytantriol alone and with 15% tributyrin was greater than that of tributyrin in the absence of phytantriol. Thus, the concept of precursor lipid systems that form cubic phase in situ during digestion in vivo has been demonstrated and opens new opportunities for sustained release of poorly water-soluble drugs.
Separation and Characterization of the Colloidal Phases Produced on Digestion of Common Formulation Lipids and Assessment of Their Impact on the Apparent Solubility of Selected Poorly Water-Soluble Dr
Publisher: Elsevier BV
Date: 03-2003
DOI: 10.1002/JPS.10329
Correlating Digestion-Driven Self-Assembly in Milk and Infant Formulas with Changes in Lipid Composition
Publisher: American Chemical Society (ACS)
Date: 04-05-2020
Nanostructured reverse hexagonal liquid crystals sustain plasma concentrations for a poorly water-soluble drug after oral administration
Publisher: Springer Science and Business Media LLC
Date: 18-11-2011
DOI: 10.1007/S13346-011-0045-Z
Abstract: Reverse hexagonal (H2) liquid crystals formed from selachyl alcohol were demonstrated to sustain the absorption of the poorly water-soluble drug cinnarizine (CZ) after oral administration to rats. When CZ was administered as a bolus lipid solution in selachyl alcohol, the T max was observed to be 23.5 ± 5.9 h, significantly longer than the control suspension (1 h). Administration of selachyl alcohol as dispersed nanoparticles (hexosomes) also resulted in a sustained plasma profile, with drug concentrations maintained from 20 to 40 ng/mL over the first 24 h after administration. Sustained absorption of CZ from the selachyl alcohol hexosomes led to a significant enhancement (p < 0.05) in oral bioavailability (F% = 17%) compared to the control CZ suspension (9%). Analysis of selachyl alcohol hexosomes using small-angle x-ray scattering indicated that neither the presence of CZ (7 mg/g) nor simulated intestinal fluid altered the H2 nanostructure. Selachyl alcohol is not susceptible to digestion. Prolonged absorption from the selachyl alcohol-based H2 systems was attributed to the non-digestible nature of the lipid, similar to non-digestible phytantriol cubic (V2) systems previously reported. Furthermore, the likely presence of non-sink conditions in the gastric compartment provides a drug reservoir requiring gastric emptying to stimulate drug release from the formulation. This study highlights the potential use of non-digestible liquid crystalline systems generally and nanostructured liquid crystalline particles in particular as novel sustained oral drug delivery systems.
TAILOR-MS, a Python Package that Deciphers Complex Triacylglycerol Fatty Acyl Structures: Applications for Bovine Milk and Infant Formulas
Publisher: American Chemical Society (ACS)
Date: 02-04-2021
Recent advances in the delivery of hydrogen sulfide via a macromolecular approach
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8PY00938D
Abstract: This mini review highlights recent advances in the design of macromolecular materials that can deliver hydrogen sulfide either spontaneously or in response to chemical and physical triggers.
Impact of pasteurization on the self-assembly of human milk lipids during digestion
Publisher: Elsevier BV
Date: 05-2022
Lipid Compositions in Infant Formulas Affect the Solubilization of Antimalarial Drugs Artefenomel (OZ439) and Ferroquine during Digestion
Publisher: American Chemical Society (ACS)
Date: 23-06-2020
Phospholipid-based self-assembled mesophase systems for light-activated drug delivery
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5CP01229E
Abstract: Biocompatible phospholipid–cholesterol matrix undergoes photothermal transition on irradiation with near infrared light for drug release applications.
Generation of Geometrically Ordered Lipid-Based Liquid-Crystalline Nanoparticles Using Biologically Relevant Enzymatic Processing
Publisher: American Chemical Society (ACS)
Date: 09-05-2014
DOI: 10.1021/LA5003447
Abstract: High-symmetry lipid nanoparticles with internal bicontinuous cubic phase structure (cubosomes) are prepared from a simple emulsion containing a mixture of a nondigestible lipid (phytantriol) and a digestible short-chained triglyceride using enzymatic lipolysis of the incorporated short-chained triglyceride. The lipolytic products partition away from the nondigestible lipid, resulting in crystallization of the cubic-phase internal structure. Time-resolved small-angle X-ray scattering revealed the kinetics of the disorder-to-order transition, with cryo-transmission electron microscopy showing an absence of liposomes. The new approach offers a new "sideways" method for the generation of lipid-based nanostructured materials that avoids the problems of top-down and bottom-up approaches.
Extending the Excitation Wavelength of Potential Photosensitizers via Appendage of a Kinetically Stable Terbium(III) Macrocyclic Complex for Applications in Photodynamic Therapy
Publisher: American Chemical Society (ACS)
Date: 06-07-2017
DOI: 10.1021/ACS.INORGCHEM.7B00677
Abstract: The development of viable photodynamic therapy protocols is often hindered by photosensitizers that require high-energy UV irradiation that has limited potential for clinical use due to its low tissue penetration. Herein, we report a strategy for extending the excitation wavelength of potential photosensitizers via the covalent attachment of a terbium(III)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate complex (DO3A-Tb). The method was systematically demonstrated with a series of polycyclic aromatic hydrocarbons (naphthalene, phenanthrene, anthracene, pyrene, and fluoranthene) to prepare six new complexes (Tb1-Tb6) with bathochromic shifts that extended into the visible region. Determination of their quantum yields for singlet oxygen (
Lessons learned in the development of sustained release penicillin drug delivery systems for the prophylactic treatment of rheumatic heart disease (RHD)
Publisher: Springer Science and Business Media LLC
Date: 05-02-2018
DOI: 10.1007/S13346-018-0482-Z
Abstract: The current prophylactic treatment to prevent rheumatic heart disease requires four-weekly intramuscular injection of a suspension of the poorly soluble benzathine salt form of penicillin G (BPG) often for more than 10 years. In seeking to reduce the frequency of administration to improve adherence, biodegradable polymer matrices have been investigated. Poly(lactide-co-glycolide) (PLGA)-based in situ forming precursor systems containing N-methyl-2-pyrrolidone as solvent and PLGA-based monolithic implants for surgical implantation containing BPG were developed. Long-term release studies indicated low and plateaued release of penicillin G, but continual favourable release profiles for the benzathine counterion, indicating degradation of the polymer and generation of acidic microenvironment being detrimental to penicillin stability. In order to avoid the issue of the acidic product, poly(caprolactone)(PCL) implants were also investigated, with favourable penicillin G release behaviour being achieved, and slow release over 180 days. However, when taking into account the mass of polymer, and the total dose of drug calculated from literature pharmacokinetic parameters for penicillin G, we concluded that an implant size of over 7 g would still be required. This may preclude clinical deployment of a polymer matrix type delivery system for this indication in children and adolescents. Therefore, we have learned that biodegradable PLGA-type systems are not suitable for development of sustained release BPG treatments and that although the PCL system provides favourable release behaviour, the total size of the implant may still present a hurdle for future development.
Implications of the Digestion of Milk-Based Formulations for the Solubilization of Lopinavir/Ritonavir in a Combination Therapy
Publisher: American Chemical Society (ACS)
Date: 15-03-2023
Responsive self-assembled nanostructured lipid systems for drug delivery and diagnostics
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.JCIS.2016.08.077
Abstract: While stimuli-responsive polymers have received a huge amount of attention in the literature, responsive lipid-based mesophase systems offer unique opportunities in biomedical applications such as drug delivery and biosensing. The different mesophase equilibrium structures enables dynamic switching between nanostructures to facilitate drug release or as a transducer for recognition events. In drug delivery, this behavior offers researchers the means to deliver a therapeutic payload at a specific rate and time i.e. 'on-demand'. This review summarizes the distinctive features of these multifaceted materials and aggregates the current state of the art research from our groups and others into the use of these materials as bulk gels and nanostructured dispersions for drug delivery, biosensing and diagnostics.
Bulk and Dispersed Aqueous Phase Behavior of Phytantriol: Effect of Vitamin E Acetate and F127 Polymer on Liquid Crystal Nanostructure
Publisher: American Chemical Society (ACS)
Date: 17-10-2006
DOI: 10.1021/LA061706V
Buccal mucosal delivery of a potent peptide leads to therapeutically-relevant plasma concentrations for the treatment of autoimmune diseases
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.JCONREL.2014.12.001
Abstract: Stichodactyla helianthus neurotoxin (ShK) is an immunomodulatory peptide currently under development for the treatment of autoimmune diseases, including multiple sclerosis and rheumatoid arthritis by parenteral administration. To overcome the low patient compliance of conventional self-injections, we have investigated the potential of the buccal mucosa as an alternative delivery route for ShK both in vitro and in vivo. After application of fluorescent 5-Fam-ShK to untreated porcine buccal mucosa, there was no detectable peptide in the receptor chamber using an in vitro Ussing chamber model. However, the addition of the surfactants sodium taurodeoxycholate hydrate or cetrimide, and formulation of ShK in a chitosan mucoadhesive gel, led to 0.05-0.13% and 1.1% of the applied dose, respectively, appearing in the receptor chamber over 5h. Moreover, confocal microscopic studies demonstrated significantly enhanced buccal mucosal retention of the peptide (measured by mucosal fluorescence associated with 5-Fam-ShK) when enhancement strategies were employed. Administration of 5-Fam-ShK to mice (10mg/kg in a mucoadhesive chitosan-based gel (3%, w/v) with or without cetrimide (5%, w/w)) resulted in average plasma concentrations of 2.6-16.2nM between 2 and 6h, which were substantially higher than the pM concentrations required for therapeutic activity. This study demonstrated that the buccal mucosa is a promising administration route for the systemic delivery of ShK for the treatment of autoimmune diseases.
Examination of the impact of a range of Pluronic surfactants on the in-vitro solubilisation behaviour and oral bioavailability of lipidic formulations of atovaquone
Publisher: Oxford University Press (OUP)
Date: 06-2006
Abstract: Exogenous surfactants are increasingly used to enhance the dispersion properties of lipid-based formulations of poorly water-soluble drugs, yet their possible effects on formulation digestion and oral bioavailability in-vivo are not well documented. In this study, in-vitro dispersion and digestion experiments were conducted using formulations comprising a blend of long-chain glycerides, ethanol, a model poorly water-soluble drug (atovaquone), and a series of surfactants including Cremophor EL and a range of Pluronic surfactants (Pluronics L121, L61, L72, L43 and F68). Inclusion of Cremophor EL, a surfactant with a high hydrophilic-lipophilic balance (HLB), promoted complete digestion of the formulation and effective dispersion and solubilisation of the lipolytic products and co-administered drug. Surprisingly, formulations containing the Pluronic (L121) with the lowest HLB (0.5) equally effectively promoted digestion and drug solubilisation and a trend towards decreased digestion and drug solubilisation was observed with Pluronics of increasing HLB values. All formulations effectively prevented drug precipitation, suggesting possible utility in-vivo, and no correlation was evident between the ability of the formulations to self-emulsify on dispersion and to promote drug solubilisation on digestion. Subsequent assessment of the oral bioavailability of atovaquone after administration of formulations containing Cremophor EL or Pluronic L121 or a simple solution of atovaquone in long-chain glycerides confirmed the utility of lipid-based formulations for enhancing the oral bioavailability of poorly water-soluble drugs such as atovaquone, but also indicated that in some cases microemulsion preconcentrate formulations may not provide additional bioavail-ability benefits beyond that achievable using simple lipid solutions.
Nitric oxide-sensing actuators for modulating structure in lipid-based liquid crystalline drug delivery systems
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.JCIS.2017.08.079
Abstract: Herein we report on the development of a nitric oxide-sensing lipid-based liquid crystalline (LLC) system specifically designed to release encapsulated drugs on exposure to NO through a stimulated phase change. A series of nitric oxide (NO)-sensing lipids compatible with phytantriol and GMO cubic phases were designed and synthesized, and utilized in enabling nitric oxide-sensing LLC systems. The nitric oxide (NO)-sensing lipids react with nitric oxide, resulting in hydrolysis of these lipids and phase transition of the LLC system. Specifically, the N-3-aminopyridinyl myristylamine (NAPyM)+phytantriol mixture formed a lamellar phase in excess aqueous environment. The NAPyM+phytantriol LLC responded to the nitric oxide gas as a chemical stimulus which triggers a phase transition from lamellar phase to inverse cubic and hexagonal phase. The nitric oxide-triggered phase transition of the LLC accelerated the release of encapsulated model drug from the LLC bulk phase, resulting in a 15-fold increase in the diffusion coefficient compared to the starting lamellar structure. The nitric oxide-sensing LLC system has potential application in the development of smart medicines to treat nitric oxide implicated diseases.
Isolating the interface of an emulsion using X-ray scattering and tensiometry to understand protein-modulated alkylglyceride crystallisation
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.JCIS.2022.10.069
Abstract: Dairy proteins and mono- and diglycerides (MDG) are often used in unison to tailor the properties of dairy-based emulsions. However, there are significant gaps in our understanding of how proteins affect lipid crystallisation at the oil-water interface. We have used a unique combination of interfacially-sensitive techniques to elucidate the impact of dairy proteins on interfacial MDG crystal formation. The formation temperature of interfacial MDG crystals was assessed through interfacial tension studies via drop shape analysis. Small and Wide-Angle X-ray Scattering measurements were performed on isolated oil-water interfaces, allowing for in-situ interrogation of MDG crystal structure and concentration at and near the interface. Dairy proteins are seen to reduce the temperature at which MDG crystals form at the oil-water interface. The displacement of proteins upon interfacial crystal formation was also clearly observed in interfacial tension measurements. For the first time, lipid crystals formed at the oil-water interface have been characterised using X-ray scattering. All scattering studies showed no change to the MDG crystal structures at the oil-water interface in the presence of adsorbed proteins. The results demonstrate that informed selection of emulsifier components is critical to controlling interfacial crystallisation with concomitant impact on emulsion stability.
Controlling the Nanostructure of Gold Nanorod–Lyotropic Liquid-Crystalline Hybrid Materials Using Near-Infrared Laser Irradiation
Publisher: American Chemical Society (ACS)
Date: 24-09-2012
DOI: 10.1021/LA302901Q
Abstract: Lipid-based liquid-crystalline matrixes provide a unique prospect for stimuli-responsive nanomaterials, attributed to the ability to effect self-assembly of the lipids at the molecular level. Differences in liquid crystal nanostructure have previously been shown to change drug diffusion and hence release, with research progressing toward the use of in situ changes to nanostructure to control drug release. Toward this goal, we have previously communicated the ability to switch between nonlamellar structures using gold nanorod (GNR)-phytantriol-based liquid-crystalline hybrid nanomaterials as near-infrared light responsive systems (Fong et al. Langmuir 2010, 26, 6136-6139). In this study, the effect of laser activation on matrix nanostructure with changes in a number of system variables including lipid composition, GNR aspect ratio, GNR concentration, and laser pulse time were investigated. The nanostructure of the matrix was followed using small-angle X-ray scattering, while both cryoFESEM and cryoTEM were used to visualize the effect of GNR incorporation into the liquid crystal nanostructure. The system response was found to be dependent on all variables, thus demonstrating the potential of these nanocomposite materials as reversible "on-demand" drug delivery applications.
A comparison of changes to doxorubicin pharmacokinetics, antitumor activity, and toxicity mediated by PEGylated dendrimer and PEGylated liposome drug delivery systems
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.NANO.2011.05.013
Abstract: The pharmacokinetics, biodistribution, and antitumor efficacy of three doxorubicin formulations (doxorubicin in saline, conjugated to a polylysine dendrimer, and encapsulated within a stealth liposome) were investigated in Walker 256 tumor-bearing rats. Liposomal and dendrimer-based delivery systems resulted in more prolonged plasma exposure of total doxorubicin when compared to administration of doxorubicin in saline, although concentrations of free doxorubicin remained low in both cases. Biodistribution profiles revealed enhanced accumulation of dendrimer- and liposome-associated doxorubicin in tumors when compared to doxorubicin alone, although all three doxorubicin formulations reduced tumor growth to a similar extent. Markers of systemic toxicity (spleen weight, white blood cell counts, body weight, and cardiotoxicity) were more pronounced in rats that received doxorubicin and liposomal doxorubicin when compared to dendrimer-doxorubicin. The data provide preliminary evidence that dendrimer-doxorubicin displays similar antitumor efficacy to PEGylated liposomal doxorubicin, but with lower systemic toxicity (resulting from reduced drug exposure to nontarget organs). In this manuscript, three different doxorubicin preparations are compared and preliminary evidence suggests that dendrimer-doxorubicin displays similar antitumor efficacy to PEGylated liposomal doxorubicin, but with lower systemic toxicity.
Correction to: Lessons learned in the development of sustained release penicillin drug delivery systems for the prophylactic treatment of rheumatic heart disease (RHD)
Publisher: Springer Science and Business Media LLC
Date: 15-03-2018
DOI: 10.1007/S13346-018-0511-Y
Abstract: Jürgen B. Bulitta's name was misspelled in the original version of the article. It is correct as reflected here. The original article has been revised.
Adsorption of nonlamellar nanostructured liquid-crystalline particles to biorelevant surfaces for improved delivery of bioactive compounds
Publisher: American Chemical Society (ACS)
Date: 09-05-2011
DOI: 10.1021/AM2003069
Abstract: The adsorption of nanostructured lyotropic liquid-crystal particles, cubosomes and hexosomes, at surfaces was investigated for potential use in surface-specific agrochemical delivery. Adsorption of phytantriol (PHYT) and glyceryl monooleate (GMO)-based cubosomes and hexosomes, stabilized using Pluronic F127, at tristearin-coated (model leaf surface) and uncoated zinc selenide surfaces was studied using attenuated total reflectance Fourier transform IR (ATR-FTIR) spectroscopy, by quantifying the IR absorbance due to the lipid components of the particles over time. The delivery of an encapsulated hydrophobic model herbicide [dichlorodiphenyldichloroethylene (DDE)] was also examined on the model and real leaf surfaces. The adsorption behavior of the particles by ATR-FTIR was dependent on the internal nanostructure and lipid composition, with PHYT cubosomes adsorbing more avidly at tristearin surfaces than GMO-based cubosomes or hexosomes. There was a direct correlation between DDE associated with the surfaces and the particle adsorption observed in the ATR-FTIR study, strongly implicating particle adsorption with the delivery efficiency. Differences between the mode of interaction of the Pluronic stabilizer with the different lipids and particle nanostructures were proposed to lead to differences in the particle adsorption behavior.
Garlic-inspired trisulfide linkers for thiol-stimulated H2S release
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7CC03820H
Abstract: Garlic-inspired cholesterol-mPEG conjugates incorporating a trisulfide linkage have the ability to cleave upon exposure to thiols with a concomitant release of H 2 S.
Graphene as a photothermal actuator for control of lipid mesophase structure
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C6NR08185A
Abstract: The optical density of pristine graphene is high and broad in the near infrared region of the electromagnetic spectrum positioning this material as a highly efficient photothermal agent for in vivo applications. In this study, surfactant assisted exfoliated graphene was incorporated within bulk lipid s les of varying lipid types: glyceryl monoether, glyceryl monooleate and phytantriol. The pristine graphene sheets did not disrupt the packing of the liquid crystals while being in sufficiently intimate contact to provide localized heating and induce phase transitions. The phase progressions induced through heating using NIR irradiation of the entrained graphene particles within the bulk liquid crystal were studied using SAXS and confirmed using polarized optical microscopy. Increases in apparent temperature experienced by the matrix of up to 50 °C were observed by establishing a SAXS versus bulk temperature calibration curve allowing in situ measurements. The studies demonstrate the potential for use of graphene as a photothermal actuator across a range of lipid based systems of interest in controlled drug delivery.
Revisiting dispersible milk-drug tablets as a solid lipid formulation in the context of digestion
Publisher: Elsevier BV
Date: 2019
Microfluidic preparation of drug-loaded PEGylated liposomes, and the impact of liposome size on tumour retention and penetration
Publisher: Informa UK Limited
Date: 20-11-2017
DOI: 10.1080/08982104.2017.1391285
Abstract: Understanding the effect of liposome size on tendency for accumulation in tumour tissue requires preparation of defined populations of different sized particles. However, controlling the size distributions without changing the lipid composition is difficult, and differences in compositions itself modify distribution behaviour. Here, a commercial microfluidic format as well as traditional methods was used to prepare doxorubicin-loaded liposomes of different size distributions but with the same lipid composition, and drug retention, biodistribution and localization in tumour tissues were evaluated. The small (∼50 nm diameter) liposomes prepared by microfluidics and large (∼75 nm diameter) liposomes displayed similar drug retention in in vitro release studies, and similar biodistribution patterns in tumour-bearing mice. However, the extent of extravasation was clearly dependent on size of the liposomes, with the small liposomes showing tissue distribution beyond the vascular area compared to the large liposomes. The use of microfluidics to prepare smaller size distribution liposomes compared to sonication methods is demonstrated, and allowed preparation of different size distribution drug carriers from the same lipid composition to enable new understanding of tissue distribution in compositionally consistent materials is demonstrated.
Photoswitchable Molecules in Long-Wavelength Light-Responsive Drug Delivery: From Molecular Design to Applications
Publisher: American Chemical Society (ACS)
Date: 09-04-2018
Aqueous ROPISA of α-amino acid N-carboxyanhydrides: polypeptide block secondary structure controls nanoparticle shape anisotropy
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1PY00995H
Abstract: Ring-Opening Polymerization-Induced Self-Assembly (ROPISA) of N -carboxyanhydride is an efficient one-step process to obtain nanomaterials made of polypeptides.
Proceedings of the Drug Delivery Australia 2012 symposium
Publisher: Springer Science and Business Media LLC
Date: 25-01-2014
Colloidal aspects of dispersion and digestion of self-dispersing lipid-based formulations for poorly water-soluble drugs
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.ADDR.2019.01.008
Abstract: Self-dispersing lipid-based formulations, particularly self-microemulsifying drug delivery systems (SMEDDS) have gained an increased interest in recent times as a means to enhance the oral bioavailability of poorly water-soluble lipophilic drugs. Upon dilution, SMEDDS self-emulsify in an aqueous fluid and usually form a kinetically stable oil-in-water emulsion or in some rare cases a true thermodynamically stable microemulsion. The digestion of the formulation leads to the production of hiphilic digestion products that interact with endogenous hiphilic components and form self-assembled colloidal phases in the aqueous environment of the intestine. The formed colloidal phases play a pivotal role in maintaining the lipophilic drug in the solubilised state during gastrointestinal transit prior to absorption. Thus, this review describes the structural characterisation techniques employed for SMEDDS and the recent literature studies that elucidated the colloidal aspects during dispersion and digestion of SMEDDS and solid SMEDDS. Possible future studies are proposed to gain better understanding on the colloidal aspects of SMEDDS and solid SMEDDS.
Revisiting the Dissolution of Praziquantel in Biorelevant Media and the Impact of Digestion of Milk on Drug Dissolution
Publisher: MDPI AG
Date: 19-10-2022
DOI: 10.3390/PHARMACEUTICS14102228
Abstract: Praziquantel is a poorly water-soluble drug used to treat parasitic infections. Previous studies have suggested that its rate and extent of dissolution in milk and biorelevant media are slow and limited compared to dissolution in the pharmacopoeial-recommended medium, despite being reported as displaying a positive food effect upon administration. This study aimed to revisit the dissolution of praziquantel in biorelevant media and milk to better understand this apparent dichotomy. The context of digestion was introduced to better understand drug solubilisation under more relevant gastrointestinal conditions. The amount of praziquantel solubilised in the various media during digestion was quantified using high performance liquid chromatography (HPLC) and the kinetics of dissolution were confirmed by tracking the disappearance of solid crystalline drug using in situ small angle X-ray scattering (SAXS). For the dissolution media, where sodium lauryl sulfate (SLS) is typically included as a wetting agent, a prominent effect of SLS on drug dissolution was also apparent where .5 fold more drug was solubilised in SLS-containing dissolution medium compared to that without (0.1 M HCl only). In milk, significant dissolution of praziquantel was observed only during digestion and not during dispersion, hence suggesting that (1) milk can be potentially administered with praziquantel to improve oral bioavailability and (2) incorporating a digestion step into existing in vitro dissolution testing can better reflect the potential for a positive food effect when lipids are present.
Human milk composition and the effects of pasteurisation on the activity of its components
Publisher: Elsevier BV
Date: 05-2021
Nonequilibrium Effects in Self-Assembled Mesophase Materials: Unexpected Supercooling Effects for Cubosomes and Hexosomes
Publisher: American Chemical Society (ACS)
Date: 05-04-2010
DOI: 10.1021/LA904803C
Abstract: Polar lipids often exhibit equilibrium liquid crystalline structures in excess water, such as the bicontinuous cubic phases (Q(II)) at low temperatures and inverse hexagonal phase (H(II)) at higher temperatures. In this study, the equilibrium and nonequilibrium phase behavior of glyceryl monooleate (GMO) and phytantriol (PHYT) systems in excess water were investigated using both continuous heating and cooling cycles, and rapid temperature changes. Evolution of the phase structure was followed using small-angle X-ray scattering (SAXS). During cooling, not only was supercooling of the liquid crystalline systems by up to 25 degrees C observed, but evidence for nonequilibrium phase structures (not present on heating such as the gyroid cubic phase only present at low water content in equilibrium) was also apparent. The nonequilibrium phases were surprisingly stable, with return to equilibrium structure for dispersed submicrometer sized particle systems taking more than 13 h in some cases. Inhibition of phase nucleation was the key to greater supercooling effects observed for the dispersed particles compared to the bulk systems. These findings highlight the need for continued study into the nonequilibrium phase structures for these types of systems, as this may influence performance in applications such as drug delivery.
Drug nanocrystallisation within liposomes
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.JCONREL.2018.09.001
Abstract: Liposomes are phospholipid bilayer vesicles that have been explored in pharmaceutical research as drug delivery systems for >50 years. Despite being important to their morphology and drug release pattern, the physical state of the drug within liposomes (liquid, solid, crystalline form) is often overlooked. This review focuses on precipitation of drug within liposomes, which can result in the formation of confined nanocrystals, and consequent changes in liposome morphology and drug release patterns. The type of drugs that form nanocrystals within liposomes, preparation and characterisation of liposomal drug nanocrystals, and the in vitro drug release behaviour from these systems are communicated, with a discussion of their potential as drug delivery systems.
Selective deuteration for molecular insights into the digestion of medium chain triglycerides
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.CHEMPHYSLIP.2015.06.007
Abstract: Medium chain triglycerides (MCTs) are a unique form of dietary fat that have a wide range of health benefits. They are molecules with a glycerol backbone esterified with medium chain (6-12 carbon atoms) fatty acids on the two outer (sn-1 and sn-3) and the middle (sn-2) positions. During lipid digestion in the gastrointestinal tract, pancreatic lipase stereoselectively hydrolyses the ester bonds of these triglycerides on the sn-1 and sn-3 positions resulting in sn-2 monoglyceride and fatty acids as major products. However, the sn-2 monoglycerides are thermodynamically less stable than their sn-1/3 counterparts. Isomerization or fatty acid migration from the sn-2 monoglyceride to sn-1/3 monoglyceride may occur spontaneously and would lead to glycerol and fatty acid as final products. Here, tricaprin (C10) with selectively deuterated fatty acid chains was used for the first time to monitor chain migration and the stereoselectivity of the pancreatic lipase-catalyzed hydrolysis of ester bonds. The intermediate and final digestion products were studied using NMR and mass spectrometry under biologically relevant conditions. The hydrolysis of the sn-2 monocaprin to glycerol and capric acid did not occur within biologically relevant timescales and fatty acid migration occurs only in limited amounts as a result of the presence of undigested diglyceride species over long periods of time in the digestion medium. The slow kinetics for the exchange of the sn-2 fatty acid chain and the stereoselectivity of pancreatic lipase on MCTs is relevant for industrial processes that involve enzymatic interesterification and the production of high-value products such as specific structured triacylglycerols, confectionery fats and nutritional products.
Influence of Casein and Milk Phospholipid Emulsifiers on the Digestion and Self-Assembled Structures of Milk Lipids
Publisher: MDPI AG
Date: 28-08-2023
Abstract: Interfacial compositions of fat globules modulate the digestion behaviour of milk triglycerides in the gastrointestinal tract, thereby affecting lipid metabolism and delivery of nutrients. In this study, we aim to understand the impact of emulsifiers on lipid digestibility and the self-assembled liquid crystal structures formed by anhydrous milk fat (AMF) during digestion. AMF was emulsified with casein and milk phospholipids, and digestion was performed in both gastric and small intestinal conditions to account for changes at the oil/water interface following enzymatic digestion in the gastric phase. Small angle X-ray scattering was used to characterise the self-assembled structures of the digestion products, while coherent anti-Stokes Raman scattering microscopy was utilised to probe changes in lipid distribution at the single droplet level during digestion. Our findings confirmed that emulsifiers play a key role in the digestion of AMF. Milk phospholipids exhibited a protective effect on milk triglycerides against pancreatic lipase digestion by slowing digestion, but this effect was slightly negated in emulsions pre-digested under gastric conditions. The overall types of liquid crystal structures formed after digestion of casein- and milk phospholipids-emulsified AMF were comparable to commercial bovine milk irrespective of gastric pre-treatment. However, emulsification of AMF with milk phospholipids resulted in changes in the microstructures of the liquid crystal phases, suggesting potential interactions between the digested products of the fat globules and milk phospholipids. This study highlights the importance of emulsifiers in regulating lipid digestion behaviour and lipid self-assembly during digestion.
Understanding the Interfacial Properties of Nanostructured Liquid Crystalline Materials for Surface-Specific Delivery Applications
Publisher: American Chemical Society (ACS)
Date: 31-08-2012
DOI: 10.1021/LA302435G
Abstract: Nonlamellar liquid crystalline dispersions such as cubosomes and hexosomes have great potential as novel surface-targeted active delivery systems. In this study, the influence of internal nanostructure, chemical composition, and the presence of Pluronic F127 as a stabilizer, on the surface and interfacial properties of different liquid crystalline particles and surfaces, was investigated. The interfacial properties of the bulk liquid crystalline systems with coexisting excess water were dependent on the internal liquid crystalline nanostructure. In particular, the surfaces of the inverse cubic systems were more hydrophilic than that of the inverse hexagonal phase. The interaction between F127 and the bulk liquid crystalline systems depended on the internal liquid crystalline structure and chemical composition. For ex le, F127 adsorbed to the surface of the bulk phytantriol cubic phase, while for monoolein cubic phase, F127 was integrated into the liquid crystalline structure. Last, the interfacial adsorption behavior of the dispersed liquid crystalline particles also depended on both the internal nanostructure and the chemical composition, despite the dispersions all being stabilized using F127. The findings highlight the need to understand the specific surface characteristics and the nature of the interaction with colloidal stabilizer for understanding and optimizing the behavior of nonlamellar liquid crystalline systems in surface delivery applications.
Local inflammation alters the lung disposition of a drug loaded pegylated liposome after pulmonary dosing to rats
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.JCONREL.2019.05.043
Abstract: The development of inhalable 'nanomedicines' based on biocompatible lipids and polymers is attracting increasing interest worldwide. Our understanding of how pulmonary inflammation impacts on lung distribution and clearance kinetics however, is limited. Similarly, there is limited information on how the inhaled delivery of biocompatible nanomaterials affects existing respiratory disease. We have addressed these knowledge gaps by describing and comparing the pulmonary pharmacokinetic behaviour of a
Impact of Ferroquine on the Solubilization of Artefenomel (OZ439) during in Vitro Lipolysis in Milk and Implications for Oral Combination Therapy for Malaria
Publisher: American Chemical Society (ACS)
Date: 04-03-2019
Solid-State Behavior and Solubilization of Flash Nanoprecipitated Clofazimine Particles during the Dispersion and Digestion of Milk-Based Formulations
Publisher: American Chemical Society (ACS)
Date: 30-04-2019
Controlling the Mesostructure Formation within the Shell of Novel Cubic/Hexagonal Phase Cetyltrimethylammonium Bromide–Poly(acrylamide-acrylic acid) Capsules for pH Stimulated Release
Publisher: American Chemical Society (ACS)
Date: 27-10-2015
Abstract: The self-assembly of ordered structures in mixtures of oppositely charged surfactant and polymer systems has been exploited in various cleaning and pharmaceutical applications and continue to attract much interest since their discovery in the late twentieth century. The ability to control the electrostatic and hydrophobic interactions that dictate the formation of liquid crystalline phases in these systems is advantageous in manipulation of structure and rendering them responsive to external stimuli. Nanostructured capsules comprised of the cationic surfactant, cetyltrimethylammonium bromide (CTAB), and the diblock copolymer poly(acrylamide-acrylic acid) (PAAm-AA) were prepared to assess their potential as pH responsive nanomaterials. Crossed-polarizing light microscopy (CPLM) and small-angle X-ray scattering (SAXS) identified coexisting Pm3n cubic and hexagonal phases at the surfactant-polymer interface. The hydrophobic and electrostatic interactions between the oppositely charged components were studied by varying temperature and solution pH, respectively, and were found to influence the liquid crystalline nanostructure formed. The lattice parameter of the mesophases and the fraction of cubic phase in the system decreased upon heating. Acidic conditions resulted in the loss of the highly ordered structures due to protonation of the carboxylic acid group, and subsequent reduction of attractive forces previously present between the oppositely charged molecules. The rate of release of the model hydrophilic drug, Rhodamine B (RhB), from nanostructured macro-sized capsules significantly increased when the pH of the solution was adjusted from pH 7 to pH 2. This allowed for immediate release of the compound of interest "on demand", opening new options for structured materials with increased functionality over typical layer-by-layer capsules.
Stimuli responsive liquid crystals provide ‘on-demand’ drug delivery in vitro and in vivo
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.JCONREL.2009.01.009
Abstract: Lipid-based liquid crystalline materials have been proposed as controlled drug delivery systems. Differences in liquid crystal nanostructure have previously been shown to change drug diffusion and hence release, however there has been little progress towards the use of in situ changes to nanostructure to control drug release. In this study, phytantriol and glyceryl monooleate-based bicontinuous cubic (Q2) and inverse hexagonal (H2) nanostructures have been designed to allow change to the nanostructure in response to external change in temperature, with a view to controlling drug release rates in vivo. Changes to nanostructure with temperature were confirmed by crossed polarised optical microscopy and small angle X-ray scattering. Phytantriol containing 3% (w/w) vitamin E acetate provided the necessary phase transition behaviour to progress this system to in vitro release and in vivo proof of concept studies. Using glucose as a model hydrophilic drug, drug diffusion was shown to be reversible on switching between the H2 and Q2 nanostructures at temperatures above and below physiological temperature respectively. An in vivo proof of concept study in rats showed that after subcutaneous administration of these materials, the changes in nanostructure induced by application of a heat or cool pack at the injection site stimulated changes in drug release from the matrix anticipated from in vitro release behaviour, thereby demonstrating the potential utility of these systems as 'on demand' drug release delivery vehicles.
Partly-PEGylated Poly-L-lysine Dendrimers Have Reduced Plasma Stability and Circulation Times Compared With Fully PEGylated Dendrimers
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1002/JPS.21692
Novel Spiropyran Amphiphiles and Their Application as Light-Responsive Liquid Crystalline Components
Publisher: American Chemical Society (ACS)
Date: 22-08-2013
DOI: 10.1021/JP403840M
Abstract: Light-responsive materials formed by liquid crystalline lipids in water have potential application to drug delivery through inclusion of photochromic additives such as spiropyran. A series of novel analogues of spiropyran (SP) have been synthesized with an SP headgroup that possess a C8 (SP-OC), C12 (SP-L), and C16 (SP-P) tail to probe the influence of the length of the hydrophobic tail on their physicochemical properties and effect on behavior in liquid crystal matrices with a view to application as stimulus-responsive elements on ultraviolet irradiation. In addition, compounds possessing an oleyl (SP-OL) and phytanyl (SP-PHYT) tail, to mimic those of the "parent" reverse bicontinuous cubic (V2) phase forming lipids, glyceryl monooleate (GMO) and phytantriol, were also prepared. The photochromic compounds were characterized by their melting points and photophysical behavior in solution using techniques including hot stage microscopy (HSM), differential scanning calorimetry (DSC), and UV-visible spectroscopy. Their effect on the equilibrium nanostructure of bulk V2 phases and phase-switching kinetics after exposure to UV light was assessed using small-angle X-ray scattering (SAXS). The melting point of the SP derivatives decreased linearly with increasing chain length, which suggests that interactions between the head groups governed their melting point, rather than the van der Waals interactions between the tails. Changing the R group did not influence the equilibrium rate constants for the isomerization of SP. Phase transition temperatures of liquid crystalline (LC) matrices were influenced significantly by incorporation of the SP derivatives and were greatest when the photochromic compound possessed an intermediate tail length substituent compared to the short alkyl or bulkier moieties. The level of disruption of lipid packing, and hence phase structure, were dependent on the duration of UV exposure.
Cationic Poly-l -lysine Dendrimers: Pharmacokinetics, Biodistribution, and Evidence for Metabolism and Bioresorption after Intravenous Administration to Rats
Publisher: American Chemical Society (ACS)
Date: 04-08-2006
DOI: 10.1021/MP060032E
Abstract: Cationic poly-L-lysine 3H-dendrimers with either 16 or 32 surface amine groups (BHALys [Lys]4 [3H-Lys]8 [NH2]16 and BHALys [Lys]8 [3H-Lys]16 [NH2]32, generation 3 and 4, respectively) have been synthesized and their pharmacokinetics and biodistribution investigated after intravenous administration to rats. The species in plasma with which radiolabel was associated was also investigated by size exclusion chromatography (SEC). Rapid initial removal of radiolabel from plasma was evident for both dendrimers (t(1/2) < 5 min). Approximately 1 h postdose, however, radiolabel reappeared in plasma in the form of free lysine and larger (but nondendrimer) species that coeluted with albumin by SEC. Plasma and whole blood pharmacokinetics were similar, precluding interaction with blood components as a causative factor in either the rapid removal or reappearance of radioactivity in plasma. Administration of monomeric 3H L-lysine also resulted in the appearance in plasma of a radiolabeled macromolecular species that coeluted with albumin by SEC, suggesting that biodegradation of the dendrimer to L-lysine and subsequent bioresorption may explain the pharmacokinetic profiles. Capping the Lys8 dendrimer with D-lysine to form BHALys [Lys]4 [3H-Lys]8 [D-Lys]16 [NH2]32 resulted in similar, and very rapid, initial disappearance kinetics from plasma when compared to the L-lysine capped dendrimer. Since significant extravasation of these large hydrophilic molecules seems unlikely, this most likely reflects both elimination and extensive binding to vascular surfaces. Capping with "non-natural" D-lysine also appeared to render the dendrimer essentially inert to the biodegradation process. For the L-lysine capped dendrimers, radiolabel was widely distributed throughout the major organs, with no apparent selectivity for organs of the reticuloendothelial system. In contrast, a greater proportion of the administered radiolabel was recovered in the organs of the reticuloendothelial system for the D-lysine capped system, as might be expected for a nondegrading circulating foreign colloid. To our knowledge this is the first data to demonstrate the biodegradation/bioresorption of poly-L-lysine dendrimers and has significant implications for the utility of these systems as drugs or drug delivery systems.
Novel self-assembling conjugates as vectors for agrochemical delivery
Publisher: Springer Science and Business Media LLC
Date: 21-11-2018
Characterization of Solubilizing Nanoaggregates Present in Different Versions of Simulated Intestinal Fluid
Publisher: American Chemical Society (ACS)
Date: 11-2017
Structural Transformation in Vesicles upon Hydrolysis of Phosphatidylethanolamine and Phosphatidylcholine with Phospholipase C
Publisher: American Chemical Society (ACS)
Date: 23-10-2019
DOI: 10.1021/ACS.LANGMUIR.9B02288
Abstract: This study provides insights into dynamic nanostructural changes in phospholipid systems during hydrolysis with phospholipase C, the fate of the hydrolysis products, and the kinetics of lipolysis. The effect of lipid restructuring of the vesicle was investigated using small-angle X-ray scattering and cryogenic scanning electron microscopy. The rate and extent of phospholipid hydrolysis were quantified using nuclear magnetic resonance. Hydrolysis of two phospholipids, phosphatidylethanolamine (PE) and phosphatidylcholine (PC), results in the cleavage of the molecular headgroup, causing two strikingly different changes in lipid self-assembly. The diacylglycerol product of PC escapes the lipid bilayer, whereas the diacylglycerol product adopts a different configuration within the lipid bilayer of the PE vesicles. These results are then discussed concerning the change of the lipid configuration upon the lipid membrane and its potential implications in vivo, which is of significant importance for the detailed understanding of the fate of lipidic particles and the rational design of enzyme-responsive lipid-based drug delivery systems.
Capping Methotrexate α-Carboxyl Groups Enhances Systemic Exposure and Retains the Cytotoxicity of Drug Conjugated PEGylated Polylysine Dendrimers
Publisher: American Chemical Society (ACS)
Date: 21-01-2011
DOI: 10.1021/MP1001872
Abstract: A generation 5 PEGylated (PEG 1100) polylysine dendrimer, conjugated via a stable amide linker to OtBu protected methotrexate (MTX), was previously shown to have a circulatory half-life of 2 days and to target solid tumors in both rats and mice. Here, we show that deprotection of MTX and substitution of the stable linker with a matrix metalloproteinase (MMP) 2 and 9 cleavable linker (PVGLIG) dramatically increased plasma clearance and promoted deposition in the liver and spleen (50-80% of the dose recovered in the liver 3 days post dose). Similar rapid clearance was also seen using a scrambled peptide suggesting that clearance was not dependent on the cleavable nature of the linker. Surprisingly, dendrimers where OtBu capped MTX was linked to the dendrimer surface via the hexapeptide linker showed equivalent in vitro cytotoxicity against HT1080 cells when compared to the uncapped dendrimer and also retained the long circulating characteristics of the stable constructs. The OtBu capped MTX conjugated dendrimer was subsequently shown to significantly reduce tumor growth in HT1080 tumor bearing mice compared to control. In contrast the equivalent dendrimer comprising uncapped MTX conjugated to the dendrimer via the same hexapeptide linker did not reduce tumor growth, presumably reflecting very rapid clearance of the construct. The results are consistent with the suggestion that protection of the α-carboxyl group of methotrexate may be used to improve the circulatory half-life and reduce the liver accumulation of similar MTX-conjugated dendrimers, while still retaining antitumor activity in vivo.
Deuterated phytantriol – A versatile compound for probing material distribution in liquid crystalline lipid phases using neutron scattering
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.JCIS.2018.09.022
Abstract: Phytantriol is an interfacially-active lipid that is chemically robust, non-digestible and forms particles with internal bicontinuous cubic phase structures (cubosomes) when dispersed with non-ionic surfactants at ambient and physiological temperatures. The liquid crystalline internal structure of phytantriol-based cubosomes can be changed to alter the interfacial contact area/topology with the aqueous dispersant to trigger bioactive payload release or to alter the local membrane curvature around bound or embedded proteins. To enable the study of payload distribution, structure and transformation kinetics within phytantriol particles by neutron scattering techniques it is desirable to have access to a deuterated version of this molecule but to date a synthetic route has not been available. The first successful synthesis of phytantriol-d
Examining the gastrointestinal transit of lipid-based liquid crystalline systems using whole-animal imaging
Publisher: Springer Science and Business Media LLC
Date: 02-09-2015
DOI: 10.1007/S13346-015-0253-Z
Abstract: Lipid-based liquid crystalline (LC) systems have the potential to sustain the oral absorption of poorly water-soluble drugs in vivo, facilitating slow drug release from their complex internal structure. To further evaluate the dynamic relationship between gastric retention and sustained drug absorption for these systems, this study aimed to explore non-invasive X-ray micro-CT imaging as an approach to assess gastric retention. Pharmacokinetic studies were also conducted with cinnarizine-loaded LC formulations to correlate gastric retention of the formulation to drug absorption. The in vivo studies demonstrated the interplay between gastric retention and drug absorption based on the digestibility of the LC structures. An increase in non-digestible phytantriol (PHY) composition in the formulation relative to digestible glyceryl monooleate (GMO) increased the gastric retention, with 68 ± 4 % of formulation intensity remaining at 8 h for 85 % w/w PHY, and 26 ± 9 % for 60 % w/w PHY. Interestingly, it was found that PHY 30 % w/w in GMO provided the highest bioavailability for cinnarizine (CZ) amongst the other combinations, including GMO alone. The studies demonstrated that combining digestible and non-digestible lipids into LC systems allowed for an optimal balance between sustaining drug absorption whilst increasing plasma concentration (C max) over time, leading to enhanced oral bioavailability. The results demonstrate the potential for utilising non-invasive X-ray micro-CT imaging to dynamically assess the GI transit of orally administered liquid crystal-forming formulations.
Sensitivity of Nanostructure in Charged Cubosomes to Phase Changes Triggered by Ionic Species in Solution
Publisher: American Chemical Society (ACS)
Date: 07-11-2013
DOI: 10.1021/LA402426Y
Abstract: The phase behavior of dispersions comprising mixed ionic surfactant and phytantriol was precisely controlled by varying the ionic surfactant content in the mixed lipid and the ionic strength in the system. Two important trends in the phase transition of the mixed lipid systems were identified: (1) An increase in the ionic surfactant content increased the curvature of the self-assembled system toward the hydrophobic region, resulting in the phase transition from cubic phase to lamellar phase. (2) An increase in ionic strength decreased repulsion between the headgroups of the ionic surfactant, resulting in a phase transition from lamellar phase to cubic phase. The phase transitions were confirmed using small-angle X-ray scattering and cryo-TEM and were strongly correlated with the visual turbidity of the dispersions. The lipid mixture with anionic surfactant showed high sensitivity to multivalent cations for triggering the phase transition, which may be a potential strategy to develop a detection/treatment system for toxic multivalent metallic cations such as chromium.
Overcoming biological barriers to in vivo efficacy of antisense oligonucleotides
Publisher: Cambridge University Press (CUP)
Date: 03-2009
DOI: 10.1017/S1462399409001021
Abstract: Antisense oligonucleotides as a therapeutic platform have been slow to progress since the approval of the first antisense drug in 1998. Recently, there have been several ex les of convincing antisense interventions in animal models and promising clinical trial data. This review considers the factors determining the success of antisense oligonucleotides as therapeutic agents. In order to produce target knockdown after systemic delivery, antisense oligonucleotides must avoid nuclease degradation, reticuloendothelial-system uptake and rapid renal excretion, and extravasate to the target cell type outside the vasculature. They then must enter the target cell, and escape the endosome–lysosome pathway so as to be free to interact with the target mRNA. We consider the significance of these limiting factors based on the literature and our own experience using systemic administration of antisense oligonucleotides.
Probing cell–nanoparticle (cubosome) interactions at the endothelial interface: do tissue dimension and flow matter?
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9BM00243J
Abstract: Nanostructured lipid-based particles interacted differently with human endothelial cells in classical 2D versus dynamic 3D vasculature bio-nano testing platforms.
Surface changes and polymyxin interactions with a resistant strain of Klebsiella pneumoniae
Publisher: SAGE Publications
Date: 25-07-2013
Abstract: This study examines the interaction of polymyxin B and colistin with the surface and outer membrane components of a susceptible and resistant strain of Klebsiella pneumoniae. The interaction between polymyxins and bacterial membrane and isolated LPS from paired wild type and polymyxin-resistant strains of K. pneumoniae were examined with N-phenyl-1-naphthylamine (NPN) uptake, fluorometric binding and thermal shift assays, lysozyme and deoxycholate sensitivity assays, and by 1 H NMR. LPS from the polymyxin-resistant strain displayed a reduced binding affinity for polymyxins B and colistin in comparison with the wild type LPS. The outer membrane NPN permeability of the resistant strain was greater compared with the susceptible strain. Polymyxin exposure enhanced the permeability of the outer membrane of the wild type strain to lysozyme and deoxycholate, whereas polymyxin concentrations up to 32 mg/ml failed to permeabilize the outer membrane of the resistant strain. Zeta potential measurements revealed that mid-logarithmic phase wild type cells exhibited a greater negative charge than the mid-logarithmic phase-resistant cells. Taken together, our findings suggest that the resistant derivative of K. pneumoniae can block the electrostatically driven first stage of polymyxin action, which thereby renders the hydrophobically driven second tier of polymyxin action on the outer membrane inconsequential.
Investigation of Donor–Acceptor Stenhouse Adducts as New Visible Wavelength-Responsive Switching Elements for Lipid-Based Liquid Crystalline Systems
Publisher: American Chemical Society (ACS)
Date: 20-02-2017
DOI: 10.1021/ACS.LANGMUIR.6B03726
Abstract: The ability of donor-acceptor Stenhouse adducts (DASAs) to function as a green light responsive switch for lipid-based liquid crystalline drug delivery systems was investigated. The host matrix comprising phytantriol cubic phase was selected due to its high sensitivity toward changes in lipid packing. Small-angle X-ray scattering demonstrated that the matrix undergoes rapid and fully reversible order-order phase transitions upon irradiation with 532 nm light, converting between the bicontinuous cubic phase and reversed hexagonal phases. This approach shows promise for use as an actuator for the development of visible wavelength light-activated, "on-demand" drug delivery systems.
Alkylation of Spiropyran Moiety Provides Reversible Photo-Control over Nanostructured Soft Materials
Publisher: American Vacuum Society
Date: 09-02-2012
DOI: 10.1007/S13758-011-0003-9
Abstract: The purpose of this study was to create a light responsive nanostructured liquid crystalline matrix using a novel alkylated spiropyran photochromic molecule (spiropyran laurate, SPL) as a light activated drug delivery system. The liquid crystal matrix, prepared from phytantriol, responds reversibly to changes in photoisomerism of SPL on irradiation, switching between the bicontinuous cubic and the reversed hexagonal liquid crystal structures, a change previously shown to dramatically alter drug release rate. In contrast, the non-derivatized spiropyran and spirooxazine photochromic compounds do not sufficiently disrupt the matrix on isomerization to induce the phase change. Thus, novel alkylated spiropyran has the potential to be an effective agent for use in liquid crystalline systems for reversible ‘on-demand’ drug delivery applications.
Plasmonic Nanorods Provide Reversible Control over Nanostructure of Self-Assembled Drug Delivery Materials
Publisher: American Chemical Society (ACS)
Date: 04-2010
DOI: 10.1021/LA100644S
Abstract: The nanostructure of mesophase liquid crystals prepared from hiphilic lipids controls the rate of release of incorporated agents from the material, such as drug molecules, and reversible transition between different nanostructures essentially provides an "on-off" switch for release (Fong, W.-K. Hanley, T. Boyd, B. J. J. Controlled Release 2009, 135, 218-226). In this study, the incorporation of plasmonic hydrophobized gold nanorods (GNRs) permits reversible manipulation of nanostructure on-demand, by irradiation of the matrix using a near-infrared laser. Synchrotron small-angle X-ray scattering was used to probe the kinetics of the response of nanostructure to laser irradiation, and the specificity of the approach is shown by the lack of response in the absence of nanorods, or for GNR whose dimensions are not matched to the specific wavelength of the incident light.
Commercially Supplied Amine-Modified siRNAs May Require Ultrafiltration prior to Conjugation with Amine-Reactive Compounds
Publisher: Hindawi Limited
Date: 2011
DOI: 10.4061/2011/154609
Abstract: Conjugation of siRNA to macromolecules such as serum albumin has multiple potential benefits, including enhanced extravasation via albumin-mediated transcytosis across endothelial cells and reduced renal clearance. In attempting to conjugate siRNA to albumin, we used commercially sourced amine-modified siRNA and reacted it with the heterobifunctional linker succinimidyl 4-[ N -maleimidomethyl]cyclohexane-1-carboxylate (SMCC) to introduce a maleimide group suitable for conjugation to the thiol group of the surface-exposed cysteine residue (Cys 34) within albumin. We found the conjugation of the SMCC-treated siRNA to bovine serum albumin (BSA) to be very inefficient and investigated the cause of the low yield of conjugate. Ultrafiltration with phosphate-buffered saline prior to activation with SMCC dramatically increased the yield of siRNA-albumin conjugate (~15-fold). Communication with the commercial supplier revealed that ammonium acetate buffer was used in a desalting step as part of the siRNA purification process prior to supply, likely resulting in ammonium counterions to the siRNA polyanion, which would interfere with conjugation by consuming the SMCC. After ultrafiltration, a greatly reduced amount of SMCC could be used to affect conjugation, without significant reduction in yield. These data indicate that amine-modified siRNA sourced commercially may require ultrafiltration or dialysis prior to use in conjugation reactions.
Silica-lipid hybrid (SLH) formulations enhance the oral bioavailability and efficacy of celecoxib: an in vivo evaluation
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.JCONREL.2013.01.012
Abstract: This study is the first to demonstrate in canines the ability of silica-lipid hybrid (SLH) microparticles to enhance the bioavailability and efficacy of a poorly water-soluble drug after oral administration. Spray-dried SLH microparticles comprising Capmul MCM (mono-diglycerides of C8/C12 fatty acids) and silica nanoparticles (Aerosil® 380) were shown to significantly enhance the fasted state oral bioavailability of celecoxib (CEL) (6.5 fold, relative to an aqueous suspension and more than 2-fold higher relative to the fed state) after oral administration to beagle dogs. Comparable bioavailability was observed between the SLH microparticle formulation and a conventional Capmul lipid solution, however, plasma concentrations were observed to be higher (Cmax, 1.1±0.06 vs. 0.8±0.03μg/mL) (p≤0.05) with the SLH microparticle system. The enhanced bioavailability of CEL observed with the SLH microparticles was reflected in a subsequent efficacy study conducted in an adjuvant-induced arthritis model in the rat. Reduced clinical and histological severity was observed at a dose of 3mg/kg/day, with the progression of arthritic symptoms and tissue damage reduced to a similar degree to that of a higher dose administered at 5mg/kg/day and prepared in an aqueous suspension., The enhanced bioavailability and improved efficacy observed with the SLH microparticles were attributed to the maintenance of CEL in a solubilised form during digestion of the lipid vehicle. We hypothesise that the presence of silica in the formulation may have contributed to the prevention of drug precipitation in the intestinal lumen by providing an alternative binding site for CEL to adsorb to prior to re-solubilisation and absorption. The study highlights the potential utility of novel SLH microparticle formulations as stable dry powders that possess the properties of a lipid-based formulation for the enhanced delivery and efficacy of poorly water-soluble drugs.
Understanding selectivity of metabolic labelling and click-targeting in multicellular environments as a route to tissue selective drug delivery
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1TB00721A
Abstract: The efficiency of metabolic labelling and click-chemistry to attach nanoparticles to cell surfaces is different between different cell populations in co-culture formats.
Correction: Comparison of bulk and microfluidic methods to monitor the phase behaviour of nanoparticles during digestion of lipid-based drug formulations using in situ X-ray scattering
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/C9SM90251A
Abstract: Correction for ‘Comparison of bulk and microfluidic methods to monitor the phase behaviour of nanoparticles during digestion of lipid-based drug formulations using in situ X-ray scattering’ by Ben J. Boyd et al. , Soft Matter , 2019, 15 , 9565–9578.
Inclusion of Digestible Surfactants in Solid SMEDDS Formulation Removes Lag Time and Influences the Formation of Structured Particles During Digestion
Publisher: Springer Science and Business Media LLC
Date: 23-01-2017
DOI: 10.1208/S12248-016-0036-6
Abstract: Solid self-microemulsifying drug delivery systems (SMEDDS) have received considerable attention in recent times attempting to overcome the drawbacks of liquid SMEDDS. Earlier literature reports on solid SMEDDS have focussed on formulation development however, the digestibility and propensity for self-assembly of the digested components with endogenous bile salts and phospholipids are unknown. Therefore, as a starting point, previously reported solid SMEDDS containing Gelucire® 44/14 (GEL) and the non-digestible surfactants, Vitamin E TPGS (TPGS) and Lutrol® F 127 (F 127), were prepared, and their dispersion and digestion behaviours were studied using an in vitro lipolysis model, coupled with small-angle X-ray scattering (SAXS) to determine the formed colloidal structures during digestion in real time. GEL alone was digested (89%) and formed a lamellar phase (Lα). When surfactants were added at a 40:60% w/w lipid to surfactants ratio, digestion was inhibited with a significant lag time being evident. However, increasing the fraction of GEL to 50% w/w enabled digestion with reduced lag time. The substitution of the non-digestible surfactants with digestible surfactants, sucrose esters S-1670 (S-1670) and Span® 60 (S-60), eliminated the digestion lag time, and the formation of colloidal structures was more similar to that of GEL alone.
Liquid Crystalline Systems of Phytantriol and Glyceryl Monooleate Containing a Hydrophilic Protein: Characterisation, Swelling and Release Kinetics
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1002/JPS.21724
Probing the amphiphile micellar to hexagonal phase transition using Positron Annihilation Lifetime Spectroscopy
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.JCIS.2013.03.039
Abstract: Positron Annihilation Lifetime Spectroscopy (PALS) has been utilised only sparingly for structural characterisation in self assembled materials. Inconsistencies in approaches to experimental configuration and data analysis between studies has complicated comparisons between studies, meaning that the technique has not provided a cohesive data set across the study of different self assembled systems that advance the technique towards an important tool in soft matter research. In the current work a systematic study was conducted using ionic and non-ionic micellar systems with increasing surfactant concentration to probe positron behaviour on changes between micellar phase structures, and data analysed using contemporary approaches to fit four component spectra. A characteristic orthopositronium lifetime (in the organic regions) of 3.5±0.2 ns was obtained for the hexagonal phase for surfactants with C12 alkyl chains. Chemical quenching of the positron species was also observed for systems with ionic hiphiles. The application of PALS has also highlighted an inconsistency in the published phase diagram for the octa(ethylene oxide) monododecyl ether (C12EO8) system. These results provide new insight into how the physical properties of micellar systems can be related to PALS parameters and means that the PALS technique can be applied to other more complex self-assembled hiphile systems.
Revisiting β-Casein as a Stabilizer for Lipid Liquid Crystalline Nanostructured Particles
Publisher: American Chemical Society (ACS)
Date: 18-11-2011
DOI: 10.1021/LA203061F
Abstract: Lipid liquid crystalline nanoparticles such as cubosomes and hexosomes have unique internal nanostructures that have shown great potential in drug and nutrient delivery applications. The triblock copolymer, Pluronic F127, is usually employed as a steric stabilizer in dispersions of lipid nanostructured particles. In this study, we investigated the formation, colloidal stability and internal nanostructure and morphology of glyceryl monooleate (GMO) and phytantriol (PHYT) cubosome dispersions on substituting β-casein with F127 in increasing proportion as the stabilizer. Internal structure and particle morphology were evaluated using small-angle X-ray scattering (SAXS) and cryo-transmission electron microscopy (cryo-TEM), while protein secondary structure was studied using synchrotron radiation circular dichroism (SRCD). The GMO cubosome dispersion stabilized by β-casein alone displayed a V(2) (Pn3m) phase structure and a V(2) to H(2) phase transition at 60 °C. In comparison, F127-stabilized GMO dispersion had a V(2) (Im3m) phase structure and the H(2) phase only appeared at higher temperature, that is, 70 °C. In the case of PHYT dispersions, only the V(2) (Pn3m) phase structure was observed irrespective of the type and concentration of stabilizers. However, β-casein-stabilized PHYT dispersion displayed a V(2) to H(2) to L(2) transition behavior upon heating, whereas F127-stabilized PHYT dispersion displayed only a direct V(2) to L(2) transition. The protein secondary structure was not disturbed by interaction with GMO or PHYT cubosomes. The results demonstrate that β-casein provides steric stabilization to dispersions of lipid nanostructured particles and avoids the transition to Im3m structure in GMO cubosomes, but also favors the formation of the H(2) phase, which has implications in drug formulation and delivery applications.
Impurities in Commercial Phytantriol Significantly Alter Its Lyotropic Liquid-Crystalline Phase Behavior
Publisher: American Chemical Society (ACS)
Date: 04-06-2008
DOI: 10.1021/LA8005579
Abstract: The lyotropic liquid-crystalline phase behavior of phytantriol is receiving increasing interest in the literature as a result of similarities with glyceryl monooleate, despite its very different molecular structure. Some differences in the phase-transition temperature for the bicontinuous cubic to reverse hexagonal phase have been reported in the literature. In this study, we have investigated the influence that the commercial source and hence the purity has on the lyotropic phase behavior of phytantriol. Suppression of the phase-transition temperatures (by up to 15 degrees C for the bicontinuous cubic to reverse hexagonal phase transition) is apparent with lower-purity phytantriol. In addition, the composition boundaries were also found to depend significantly on the source and purity of phytantriol, with the bicontinuous cubic phase + excess water boundary occurring at a water content above that reported previously (i.e., >5% higher). Both the temperature and compositional changes in phase boundaries have significant implications on the use of these materials and highlight the impact that subtle levels of impurities can play in the phase behavior of these types of materials.
Magnetically-stimulated transformations in nanostructure of lipid mesophases: Effect of structure of iron oxide nanoparticles
Publisher: Elsevier BV
Date: 07-2020
Conducting polymers with defined micro- or nanostructures for drug delivery
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.BIOMATERIALS.2016.09.021
Abstract: Conducting polymers (CPs) are redox active materials with tunable electronic and physical properties. The charge of the CP backbone can be manipulated through redox processes, with accompanied movement of ions into and out of the polymer to maintain electrostatic neutrality. CPs with defined micro- or nanostructures have greatly enhanced surface areas, compared to conventionally prepared CPs. The resulting high surface area interface between polymer and liquid media facilities ion exchange and can lead to larger and more rapid responses to redox cycling. CP systems are maturing as platforms for electrically tunable drug delivery. CPs with defined micro- or nanostructures offer the ability to increase the amount of drug that can be delivered whilst enabling systems to be finely tuned to control the extent and rate of drug release. In this review, fabrication approaches to achieve CPs with micro- or nanostructure are outlined followed by a detailed review and discussion of recent advances in the application of the materials for drug delivery.
Nanostructured liquid crystalline particles provide long duration sustained-release effect for a poorly water soluble drug after oral administration
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.JCONREL.2011.03.033
Abstract: This study is the first to demonstrate the ability of nanostructured liquid crystal particles to sustain the absorption of a poorly water soluble drug after oral administration. Cubic (V(2)) liquid crystalline nanostructured particles (cubosomes) formed from phytantriol (PHY) were shown to sustain the absorption of cinnarizine (CZ) beyond 48h after oral administration to rats. Plasma concentrations were sustained within the range of 21.5±1.5ng/mL from 12 to 48h. In stark contrast, cubosomes prepared using glyceryl monooleate (GMO) did not sustain the absorption of CZ and drug concentrations fell below quantifiable levels after 24h. Sustained absorption of CZ from PHY cubosomes lead to a significant enhancement (p 24h) leading to the conclusion that in the case of non-digestible PHY cubosomes, the stomach may act as a non-sink reservoir that facilitates the slow release of poorly water soluble drugs, highlighting the potential use of non-digestible LC nanostructured particles as novel sustained oral drug delivery systems.
Submicron Dispersions of Hexosomes Based on Novel Glycerate Surfactants
Publisher: CSIRO Publishing
Date: 2005
DOI: 10.1071/CH05173
Abstract: Glycerate-based surfactants are a new class of swelling hiphiles which swell to a finite degree with water. Among this class of surfactants, oleyl (cis-octadec-9-enyl) glycerate is very similar in structure to a well characterized mesophase-forming lipid, glyceryl monooleate (GMO). Despite the similar structural characteristics, a subtle change in connectivity of the ester bond substantially alters the binary surfactant–water phase behaviour. Whereas the phase behaviour of GMO is erse and dominated by cubic phases, the phase behaviour of oleyl glycerate and a terpenoid analogue phytanyl (3,7,11,15-tetramethyl-hexadecane) glycerate is much simplified. Both exhibit an inverse hexagonal phase (HII), which is stable to dilution with excess water, and an inverse micellar phase (LII) at ambient temperatures. The inverse hexagonal phases formed by oleyl glycerate and phytanyl glycerate have been characterized using SAXS. Analogous to GMO cubosomes, the inverse hexagonal phase of phytanyl glycerate has been dispersed to form hexagonally facetted particles, termed hexosomes, whose structure has been verified using cryo-TEM.
Soft polyhedral particles based on cubic liquid crystalline emulsion droplets
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7SM01521F
Abstract: Soft polyhedral particles based on variations of the cubic symmetry group are produced from a precursor emulsion by extracting solvent to grow facets on the droplets.
Gastric Pre-Processing Is an Important Determinant of the Ability of Medium-Chain Lipid Solution Formulations to Enhance Oral Bioavailability in Rats
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1002/JPS.23690
Stimuli‐Responsive Lipid‐Based Self‐Assembled Systems
Publisher: Wiley
Date: 14-09-2012
Probing drug solubilization patterns in the gastrointestinal tract after administration of lipid‐based delivery systems: A phase diagram approach
Publisher: Elsevier BV
Date: 02-2004
DOI: 10.1002/JPS.10554
Comparison across three hybrid lipid-based drug delivery systems for improving the oral absorption of the poorly water-soluble weak base cinnarizine
Publisher: American Chemical Society (ACS)
Date: 04-10-2017
DOI: 10.1021/ACS.MOLPHARMACEUT.7B00676
Abstract: Three state-of-the-art drug delivery vehicles engineered by nanostructuring lipid colloids within solid particle matrices were fabricated for the oral delivery of the poorly water-soluble, weak base, cinnarizine (CIN). The lipid and solid phase of each formulation was varied to systematically analyze the impact of key material characteristics, such as nanostructure and surface chemistry, on the in vitro and in vivo fate of CIN. The three systems formulated were: silica-stabilized lipid cubosomes (SSLC), silica-solid lipid hybrid (SSLH), and polymer-lipid hybrid (PLH) particles. Significant biopharmaceutical advantages were presented for CIN when solubilized in the polymer (poly(lactic-co-glycolic) acid PLGA) and lipid phase of PLH particles compared to the lipid phases of SSLC and SSLH particles. In vitro dissolution in simulated intestinal conditions highlighted reduced precipitation of CIN when administered within PLH particles, given by a 4-5-fold improvement in the extent of CIN dissolution compared to the other delivery vehicles. Furthermore, CIN solubilization was enhanced 1.5-fold and 6-fold under simulated fasted state lipid digestion conditions when formulated with PLH particles compared to SSLH and SSLC particles, respectively. In vivo pharmacokinetics correlated well with in vitro solubilization data, whereby oral CIN bioavailability in rats, when encapsulated in the corresponding formulations, increased from SSLC < SSLH < PLH. The pharmacokinetic data obtained throughout this study indicated a synergistic effect between PLGA nanoparticles and lipid droplets in preventing CIN precipitation and thus, enhancing oral absorption. This synergy can be harnessed to efficiently deliver challenging poorly water-soluble, weak bases through oral administration.
The distribution of cell-penetrating peptides on polymeric nanoparticles prepared using microfluidics and elucidated with small angle X-ray scattering
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.JCIS.2019.08.007
Abstract: The distribution of three cell-penetrating peptides (CPPs) with different architectures (short, long linear and branched) on poly(lactic-co-glycolic) acid (PLGA) nanoparticles depends on the conjugation approach. Here, we explore the utilization of a zero-length crosslinking reaction for the covalent attachment of CPPs to PLGA nanoparticles and the translation of the reaction into a microfluidic platform. A microfluidic device with a staggered herringbone mixer was used for the formulation of CPP-tagged PLGA nanoparticles. CPP-tagged PLGA nanoparticles were labeled with gold nanoparticles (AuNPs) and transmission electron microscopy (TEM) and small angle X-ray scattering (SAXS) were used to elucidate the distribution of CPPs. The SAXS scattering profiles for the CPP-tagged PLGA nanoparticles prepared with the in situ microfluidics conjugation approach indicated a distribution of the Au-labeled CPPs throughout the PLGA nanoparticles. For the post-microfluidics conjugation approach, the SAXS scattering profiles did not show the feature of the Au-labeled CPPs distributed throughout the PLGA nanoparticles and an arrangement of the Au-labeled CPP on the surface was support by TEM micrographs. The distribution of the CPPs was highly dependent on the conjugation approach and was not influenced by the architecture of the CPPs. The results provided insight for the rational design of CPP-tagged PLGA nanoparticles using microfluidics.
Characterisation and tumour targeting of PEGylated polylysine dendrimers bearing doxorubicin via a pH labile linker
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.JCONREL.2011.02.005
Abstract: Polylysine dendrimers have potential as biodegradable vectors for the delivery of cytotoxic drugs to solid tumours. Here, the cytotoxicity, drug release and tumour targeting properties of Generation 5 PEGylated polylysine dendrimers comprising an outer generation of l-lysine or succinimyldipropyldiamine (SPN) and containing doxorubicin (DOX) linked through an acid labile 4-(hydrazinosulfonyl) benzoic acid (HSBA) linker have been characterised. Less than 10% of the DOX load was released from LYS or SPN dendrimers in pH 7.4 buffer over 3 days. In contrast approximately 100% release was evident at pH 5. The DOX-conjugated dendrimers also retained similar cytotoxic properties to free DOX in in vitro cell culture studies (presumably as a result of in situ liberation of free DOX). The clearance patterns of the DOX conjugated SPN and all-lysine dendrimers were similar to the equivalent non-DOX conjugated systems, however the SPN dendrimers showed reduced metabolic lability and increased uptake into RES organs when compared to the equivalent all-lysine dendrimers. In vivo assessment of the DOX-conjugated, PEGylated polylysine dendrimers (both SPN and LYS constructs) in rats bearing Walker 256 tumours revealed higher uptake into tumour tissue when compared with control tissue such as muscle (~8 fold) and heart (~3 fold). The data suggest that polylysine dendrimers containing DOX conjugated via an acid labile HSBA linker may provide a mechanism to target the delivery of DOX to tumours.
A lipid-based liquid crystalline matrix that provides sustained release and enhanced oral bioavailability for a model poorly water soluble drug in rats
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/J.IJPHARM.2007.03.020
Abstract: Liquid crystalline phases that are stable in excess water, formed using lipids such as glyceryl monooleate (GMO) and oleyl glycerate (OG), are known to provide a sustained release matrix for poorly water soluble drugs in vitro, yet there has been no report of the use of these materials to impart oral sustained release behaviour in vivo. In the first part of this study, in vitro lipolysis experiments were used to compare the digestibility of GMO with a second structurally related lipid, oleyl glycerate, which was found to be less susceptible to hydrolysis by pancreatic lipase than GMO. Subsequent oral bioavailability studies were conducted in rats, in which a model poorly water soluble drug, cinnarizine (CIN), was administered orally as an aqueous suspension, or as a solution in GMO or OG. In the first bioavailability study, plasma s les were taken over a 30 h period and CIN concentrations determined by HPLC. Plasma CIN concentrations after administration in the GMO formulation were only sustained for a few hours after administration while for the OG formulation, the plasma concentration of cinnarizine was at its highest level 30 h after dosing, and appeared to be increasing. A second study in which CIN was again administered in OG, and plasma s les taken for 120 h, revealed a Tmax for CIN in rats of 36 h and a relative oral bioavailability of 344% when compared to the GMO formulation (117%) and the aqueous suspension formulation (assigned a nominal bioavailability of 100%). The results indicate that lipids that form liquid crystalline structures in excess water, may have application as an oral sustained release delivery system, providing they are not digested rapidly on administration.
Lipid Liquid-Crystal Phase Change Induced through near-Infrared Irradiation of Entrained Graphene Particles
Publisher: American Chemical Society (ACS)
Date: 11-06-2015
DOI: 10.1021/ACS.LANGMUIR.5B01308
Abstract: Lipid packing is intimately related to the geometry of the lipids and the forces that drive self-assembly. Here, the photothermal response of a cubic liquid-crystalline phase formed using phytantriol in the presence of low concentrations of pristine graphene was evaluated. Small-angle X-ray scattering showed the reversible phase changes from cubic to hexagonal to micellar due to localized heating through irradiation with near-infrared (NIR) light and back to cubic after cooling.
Interactions of Artefenomel (OZ439) with Milk during Digestion: Insights into Digestion-Driven Solubilization and Polymorphic Transformations
Publisher: American Chemical Society (ACS)
Date: 22-06-2018
DOI: 10.1021/ACS.MOLPHARMACEUT.8B00541
Abstract: Milk has been used as a vehicle for the delivery of antimalarial drugs during clinical trials to test for a food effect and artefenomel (OZ439) showed enhanced oral bioavailability with milk. However, the nature of the interaction between milk and OZ439 in the gastrointestinal tract remains poorly understood. To understand the role of milk digestion on the solubilization of OZ439 and polymorphism, we conducted real-time monitoring of crystalline drug in suspension during in vitro intestinal lipolysis of milk containing OZ439 using synchrotron X-ray scattering. OZ439 formed an unstable solid-state intermediate free base form (OZ439-FB form 1) at intestinal pH and was partially solubilized by milk fat globules prior to lipolysis. Dissolution of the free base form 1 and recrystallization of OZ439 in a more stable polymorphic form (OZ439-FB form 2) occurred during in vitro lipolysis in milk. Simply stirring the milk/drug suspension in the absence of lipase or addition of lipase to OZ439 in a lipid-free buffer did not induce this polymorphic transformation. The formation of OZ439-FB form 2 was therefore accelerated by the solubilization of OZ439-FB form 1 during the digestion of milk. Our findings confirmed that although crystalline precipitates of OZ439-FB form 2 could still be detected after in vitro digestion, milk-based lipid formulations provided a significant reduction in crystalline OZ439 compared to lipid-free formulations, which we attribute to the formation of colloidal structures by the digested milk lipids. Milk may therefore be particularly suited as a form of lipid-based formulation (LBF) for coadministration with OZ439, from which both an enhancement in OZ439 oral bioavailability and the delivery of essential nutrients should result.
Impact of Surface Derivatization of Poly-l -lysine Dendrimers with Anionic Arylsulfonate or Succinate Groups on Intravenous Pharmacokinetics and Disposition
Publisher: American Chemical Society (ACS)
Date: 23-10-2007
DOI: 10.1021/MP070047S
Abstract: Tritium-labeled poly- l-lysine dendrimers displaying 8 or 16 surface lysines have been capped with benzene sulfonate (BS), benzene disulfonate (BDS), or succinate (Succ) groups, and the intravenous pharmacokinetics and disposition profiles of the resulting dendrimers (Lys(8)(BS)(16), Lys(16)(BS)(32), Lys(16)(BDS)(32), Lys(16)(Succ)(32)) have been evaluated. Lys(16)(Succ)(32) was rapidly removed from the plasma primarily via renal elimination. Lys(16)(BS)(32) and Lys(16)(BDS)(32) were opsonized, resulting in more prolonged plasma elimination kinetics and increased uptake by the liver. Data obtained at higher doses suggested some evidence of nonlinear pharmacokinetics. Lys(8)(BS)(16) had reduced affinity for plasma proteins and was cleared more rapidly than the larger Lys(16)(BS)(32) or Lys(16)(BDS)(32) dendrimers. Lys(8)(BS)(16) and Lys(16)(BS)(32) were metabolized in vivo, resulting in the production of a low molecular weight species (possibly the cleavage product Lys(BS) (2)) that was extensively renally eliminated and accounted for almost all of the radioactivity recovered in urine ( approximately 20-45% of administered (3)H). In contrast, only 3-5% of the administered (3)H was recovered in the urine of rats administered Lys(16)(BDS)(32), suggesting increased resistance to in vivo degradation. The plasma clearance, distribution, and metabolic profiles of lysine dendrimers are therefore significantly influenced by the structure and charge of the capping groups. In particular, larger arylsulfonate-capped lysine dendrimers are rapidly opsonized and initially cleared from the plasma by the reticuloendothelial organs. The degree of metabolism is subsequently dictated by the nature of the surface capping group with BDS surfaces seemingly more resistant to breakdown. In contrast, smaller arylsulfonate-capped dendrimers are less readily opsonized and phagocytozed but are metabolically labile, and succinate-capped dendrimers are rapidly eliminated by the kidneys.
Using the Polymer Partitioning Method to Probe the Thermodynamic Activity of Poorly Water‐soluble Drugs Solubilized in Model Lipid Digestion Products
Publisher: Elsevier BV
Date: 06-2003
DOI: 10.1002/JPS.10390
Metallic implant drug/device combinations for controlled drug release in orthopaedic applications
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.JCONREL.2014.01.026
Abstract: The study of metallic drug/device combinations for controlled drug release in orthopaedic applications has gained significant momentum in the past decade, particularly for the prevention and reduction of implant associated infection. Such combinations are commonly based upon a permanent metallic implant (such as stainless steel or titanium) and are then coated with a drug-eluting polymer or ceramic system. Drug elution is also possible from the implant itself by utilising metallic foams, porous architectures and bioresorbable metals. This review will explore the current research into metallic implant drug/device combinations via a critical review of the relevant literature.
Solid State Characterization of Ciprofloxacin Liposome Nanocrystals
Publisher: American Chemical Society (ACS)
Date: 29-11-2018
DOI: 10.1021/ACS.MOLPHARMACEUT.8B00940
Abstract: Liposomes have been widely researched as drug delivery systems however, the solid state form of drug inside the liposome, whether it is in solution or in a solid state, is often not studied. The solid state properties of the drug inside the liposomes are important, as they dictate the drug release behavior when the liposomes come into contact with physiological fluid. Recently, a new approach of making liposomal ciprofloxacin nanocrystals was proposed by the use of an additional freeze-thawing step in the liposomal preparation method. This paper aims to determine the solid state properties of ciprofloxacin inside the liposomes after this additional freeze-thawing cycle using cryo-TEM, small-angle X-ray scattering (SAXS), and cross-polarized light microscopy (CPLM). Ciprofloxacin precipitated in the ciprofloxacin hydrate crystal form with a unit cell dimension of 16.7 Å. The nanocrystals also showed a phase transition at 93 °C, which represents dehydration of the hydrate crystals to the anhydrate form of ciprofloxacin, verified by temperature-dependent SAXS measurements. Furthermore, the dependence of the solid state form of the nanocrystals on pH was investigated in situ, and it was shown that the liposomal ciprofloxacin nanocrystals retained their crystalline form at pH 6-10. Understanding the solid state attributes of nanocrystals inside liposomes provides improved understanding of drug dissolution and release as well as opening avenues to new applications where the nanosized crystals can provide a dissolution benefit.
Generic construction of single component particles that elicit humoural and cellular immune responses without the need for adjuvants
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.VACCINE.2008.09.087
Abstract: Insoluble, pure protein particles could be advantageous as single-entity vaccines or as carriers for small peptide epitopes. Dense gas anti-solvent precipitation was employed to produce pure protein particles which were found to be insoluble in water. As particulate and multimerized antigens are more immunogenic and hence more advantageous for vaccination, particles were produced via this method using ovalbumin as a model antigen. The particles produced had a mean diameter of approximately 300nm, and remained as discrete particles at low pH. At neutral pH or in the presence of electrolyte, the particles exhibited predictable flocculation behaviour to produce aggregates 1-5microm in diameter. Immunisation of mice with these flocculates elicited specific ovalbumin antibody production, T-cell proliferation and a cytotoxic T-cell response, all in the absence of adjuvant. Thus, dense gas processing could be used as a generic method to produce pure protein particulate vaccines.
Pluronic-functionalized silica-lipid hybrid microparticles: improving the oral delivery of poorly water-soluble weak bases
Publisher: American Chemical Society (ACS)
Date: 12-11-2015
DOI: 10.1021/ACS.MOLPHARMACEUT.5B00622
Abstract: A Pluronic-functionalized silica-lipid hybrid (Plu-SLH) microparticle system for the oral delivery of poorly water-soluble, weak base drugs is reported for the first time. A highly effective Plu-SLH microparticle system was composed of Labrasol as the lipid phase, Pluronic F127 as the polymeric precipitation inhibitor (PPI), and silica nanoparticles as the solid carrier. For the model drug cinnarizine (CIN), the Plu-SLH delivery system was shown to offer significant biopharmaceutical advantages in comparison with unformulated drug and drug in the silica-lipid hybrid (SLH) system. In vitro two-phase dissolution studies illustrated significantly reduced pH provoked CIN precipitation and an 8- to 14-fold improvement in the extent of dissolution in intestinal conditions. In addition, under simulated intestinal digesting conditions, the Plu-SLH provided approximately three times more drug solubilization than the SLH. Oral administration in rats resulted in superior bioavailability for Plu-SLH microparticles, i.e., 1.6- and 2.1-fold greater than the SLH and the unformulated CIN, respectively. A physical mixture of Pluronic and SLH (Plu&SLH), having the same composition as Plu-SLH, was also evaluated, but showed no significant increase in CIN absorption when compared to unmodified CIN or SLH. This work represents the first study where different methods of incorporating PPI to formulate solid-state lipid-based formulations were compared for the impact on the biopharmaceutical performance. The data suggest that the novel physicochemical properties and structure of the fabricated Plu-SLH microparticle delivery system play an important role in facilitating the synergistic advantage of Labrasol and Pluronic F127 in preventing drug precipitation, and the Plu-SLH provides efficient oral delivery of poorly water-soluble weak bases.
PEGylation and surface functionalization of liposomes containing drug nanocrystals for cell-targeted delivery
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.COLSURFB.2019.110362
Abstract: Liposomal formulations have important therapeutic applications in anti-cancer treatments but current formulations suffer from serious side effects, high dosage requirements and prolonged treatment. In this study, PEGylated azide-functionalized liposomes containing drug nanocrystals were investigated with the aim of increasing the drug payload and achieving functionalization for targeted delivery. Liposomes were characterized using cryogenic transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS), small and ultra-small angle neutron scattering (SANS/USANS) and small and wide angle X-ray scattering (SAXS/WAXS). Cryo-TEM experiments revealed the dimensions of the nanocrystal-loaded liposomes and the change of shape from spherical to elongated after the formation of nanocrystals. Results from SANS/USANS experiments confirmed the asymmetric particle shape. SAXS/WAXS experiments confirmed that the crystalline drug only occurred in freeze-thawed s les and correlated with a new unidentified polymorphic form of ciprofloxacin. Using a small molecule dye, dibenzocyclooctyne (DBCO)-cy5, specific conjugation between DBCO groups and surface azide groups on the liposomes was confirmed this indicates the promise of this system for tumour-targeted delivery.
Thiol-responsive lyotropic liquid crystals exhibit triggered phase re-arrangement and hydrogen sulfide (H2S) release
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.JCIS.2021.12.180
Abstract: Hydrogen sulfide (H
Tristearin as a Model Cuticle for High-Throughput Screening of Agricultural Adjuvant Systems
Publisher: American Chemical Society (ACS)
Date: 05-12-2018
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