ORCID Profile
0000-0002-9247-681X
Current Organisation
University of Queensland
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Proteins and Peptides | Medicinal and Biomolecular Chemistry | Biomaterials | Biologically Active Molecules |
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in Technology | Human Pharmaceutical Products not elsewhere classified
Publisher: MDPI AG
Date: 04-05-2022
DOI: 10.3390/PHARMACEUTICS14050986
Abstract: This study aimed to develop synergistic therapies to treat superbug infections through the encapsulation of sortase A inhibitors (SrtAIs trans-chalcone (TC), curcumin (CUR), quercetin (QC), or berberine chloride (BR)) into MCM-41 mesoporous silica nanoparticles (MSNs) or a phosphonate-modified analogue (MCM-41-PO3−) to overcome their poor aqueous solubility. A resazurin-modified minimum inhibitory concentration (MIC) and checkerboard assays, to measure SrtAI synergy in combination with leading antimicrobial peptides (AMPs pexiganan (PEX), indolicidin (INDO), and [I5, R8] mastoparan (MASTO)), were determined against methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. The results demonstrated that the MCM-41 and MCM-41-PO3− formulations significantly improved the aqueous solubility of each SrtAI. The MICs for SrtAI/MCM-41-PO3− formulations were lower compared to the SrtAI/MCM-41 formulations against tested bacterial strains, except for the cases of BR/MCM-41 and QC/MCM-41 against P. aeruginosa. Furthermore, the following combinations demonstrated synergy: PEX with TC/MCM-41 (against all strains) or TC/MCM-41-PO3− (against all strains except P. aeruginosa) PEX with BR/MCM-41 or BR/MCM-41-PO3− (against MSSA and MRSA) INDO with QC/MCM-41 or QC/MCM-41-PO3− (against MRSA) and MASTO with CUR/MCM-41 (against E. coli). These combinations also reduced each components’ toxicity against human embryonic kidney cells. In conclusion, MCM-41 MSNs provide a platform to enhance SrtAI solubility and demonstrated antimicrobial synergy with AMPs and reduced toxicity, providing novel superbug treatment opportunities.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.BMCL.2015.10.049
Abstract: Human papillomaviruses (HPVs) are associated with various cancers, with HPV16 linked to more than half of cervical cancer cases. Vaccines to prevent HPV infection and cancer development have proven effective, but are not useful in in iduals with prior HPV exposure. Treatment vaccines to eradicate or control HPV-associated lesions are therefore desirable for these patients. Herein we describe the development of a process to enable the production of semisynthetic vaccines based on the site-specific attachment of synthetic bacterial lipid analogs (e.g., Pam2Cys) to a non-oncogenic mutant HPV16 E7 protein to generate molecularly defined vaccines. Many cytotoxic lymphocyte (CTL) epitopes from E7 are delivered by this approach potentially ensuring that large numbers of immunized in iduals can generate CTLs to clear HPV infected cells. Delivery of this construct reduced the growth of HPV16-associated tumors in a TC1 mouse model, the effects of which were better than the potent CTL epitope HPV16 E7(44-57) administered with Montanide ISA51 adjuvant.
Publisher: Future Medicine Ltd
Date: 04-2016
DOI: 10.2217/NNM.16.27
Abstract: Aim: Endosome escape is essential for developing effective nonviral gene delivery systems. Herein, three endosome-disrupting peptides (HA2(1–20), GALA and KALA) were incorporated into a multicomponent oligonucleotide delivery system to identify which peptide imparted the most favorable endosome escape and toxicity profile. Materials & methods: Copper (I)-catalyzed azide-alkyne cycloaddition was used to construct multicomponent delivery vectors. The systems were evaluated for size, toxicity, cellular uptake and endosome escape activity. Results: Each system condensed plasmid DNA to form nanosized particles. The highest cellular uptake and endosome escape were associated with GALA and KALA containing systems, with KALA incorporation correlating with greater toxicity. Conclusion: GALA was selected as the most promising endosome-disrupting peptide for incorporation into the nanosized oligonucleotide delivery system.
Publisher: Wiley
Date: 2020
Abstract: Self-adjuvanting vaccines, consisting of recombinant protein antigens and covalently attached Toll-like receptor (TLR) agonists, have the ability to simultaneously and efficiently deliver antigen and TLR adjuvant to antigen presenting cells (APCs). Here, an enzyme-mediated ligation approach was used to overcome difficulties in producing homogeneous, molecularly defined self-adjuvanting vaccine products under native conditions. This process was optimized to allow the incorporation of the lipopeptide TLR2 agonist fibroblast-stimulating lipopeptide (FSL)-1 onto the N- or C-termini of recombinant protein antigens, employing the enzyme Staphylococcus aureus sortase A (SrtAsa) penta mutant. In addition, because SrtAsa-mediated ligations are reversible, a tryptophan zipper derived sequence was introduced into both reactants, which was demonstrated to improve ligation efficiency through the formation of a β-hairpin structure that hinders the reverse reaction. Finally, it was demonstrated that N- or C-terminal conjugation, and the incorporation of the β-hairpin structure, did not affect the TLR2-agonist activities of protein antigen TLR agonist conjugates. Overall, this SrtAsa-mediated ligation platform enabled production of antigen TLR2 agonist conjugates with enhanced ligation efficiency, with the conjugates demonstrating potent TLR2 signaling activation (EC
Publisher: American Chemical Society (ACS)
Date: 11-09-2018
DOI: 10.1021/ACS.BIOCONJCHEM.7B00478
Abstract: Traditional vaccines derived from attenuated or inactivated pathogens are effective at inducing antibody-based protective immune responses but tend to be highly reactogenic, causing notable adverse effects. Vaccines with superior safety profiles can be produced by subunit approaches, utilizing molecularly defined antigens (e.g., proteins and polysaccharides). These antigens, however, often elicit poor immunological responses, necessitating the use of adjuvants. Immunostimulatory adjuvants have the capacity to activate antigen presenting cells directly through specific receptors (e.g., Toll-like receptors (TLRs)), resulting in enhanced presentation of antigens as well as the secretion of proinflammatory chemokines and cytokines. Consequently, innate immune responses are lified and adaptive immunity is generated. Recently, site-specific conjugation of such immunostimulatory adjuvants (e.g., TLR ligands) onto defined antigens has shown superior efficacy over unconjugated mixtures, suggesting that the development of chemically characterized immunostimulatory adjuvants and optimized approaches for their conjugation with antigens may provide a better opportunity for the development of potent, novel vaccines. This review briefly summarizes various TLR agonists utilized as immunostimulatory adjuvants and focuses on the development of techniques (e.g., recombinant, synthetic, and semisynthetic) for generating adjuvant-antigen fusion vaccines incorporating peptide or protein antigens.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.BMC.2016.09.039
Abstract: Gastrin releasing peptide (GRP) receptor (GRPR), a bombesin family receptor, is overexpressed in many cancers including breast, prostate, pancreatic and lung. The targeting of therapeutics to GRPR can be achieved using the full-length (14 amino acid) GRP analogue Bombesin (BBN) or the truncated BBN(6-14) sequence, both of which bind GRPR with high affinity and specificity. In this study, we have investigated the level of GRPR expression in various cancerous (Caco-2, HeLa, LNCap, MDA-MB-231, and PC-3) and non-cancerous (WPMY-1) cell lines using a western blotting approach. Such information is currently lacking in the literature, and is therefore of importance for the in vitro assessment of GRPR targeted therapeutics. Of the cell lines assessed, the PC-3 (prostate cancer) and Caco-2 (colon cancer) cell lines demonstrated the highest and lowest levels of GRPR expression respectively. Using this information, we further investigated the cellular uptake of carboxyfluorescein-labelled BBN and BBN(6-14) peptides by flow cytometry and confocal microscopy using cell lines that express GRPR (Caco-2, HeLa, PC-3). The uptake of each of these peptides was similar, suggesting that the shorter BBN(6-14) peptide is sufficient for GRPR targeting. Further, the uptake of these peptides could be inhibited by competition with unlabelled BBN peptides, suggesting their cellular uptake is GRPR-mediated, while the level of BBN uptake (as measured by flow cytometry) was found to be directly proportional to the level of GRPR expression. Overall, the information obtained from these studies provides useful information for the in vitro assessment of GRPR targeted therapeutics.
Publisher: Wiley
Date: 28-02-2018
Abstract: Glucagon-like peptide-1 (GLP-1) is secreted by intestinal L-cells following food intake, and plays an important role in glucose homeostasis due to its stimulation of glucose-dependent insulin secretion. Further, GLP-1 is also associated with protective effects on pancreatic β-cells and the cardiovascular system, decreased appetite, and weight loss, making GLP-1 derivatives an exciting treatment for type 2 diabetes and obesity. Despite these benefits, wild-type GLP-1 exhibits a short circulation time due to its poor metabolic stability and rapid renal clearance, and must be administered by injection, making it a poor therapeutic agent. Many strategies have been used to improve the circulation time of GLP-1 (e.g., mutations, unnatural amino acids, depot formulations, use of exendin-4 sequences, and fusions with high-molecular-weight proteins or polymers), with its therapeutic utility further improved by adding agonist activity for gastric inhibitory peptide and glucagon receptors. This minireview focuses on strategies that have been used to improve the pharmacokinetics of GLP-1 and provides an overview of GLP-1-based therapeutics in the pipeline.
Publisher: American Chemical Society (ACS)
Date: 12-04-2021
Publisher: Springer New York
Date: 2006
Publisher: Elsevier BV
Date: 2008
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.BMC.2017.12.013
Abstract: The development of non-viral gene delivery systems, with the capacity to overcome most of the biological barriers facing gene delivery, is challenging. We have developed peptide-based, multicomponent, non-viral delivery systems, incorporating: a bombesin peptide ligand (BBN(6-14)), to selectively target the gastrin releasing peptide receptor (GRPR) oligoarginine peptides (hexa- (R
Publisher: Springer Science and Business Media LLC
Date: 09-2003
DOI: 10.1007/BF02442594
Publisher: Elsevier BV
Date: 12-2019
Publisher: American Chemical Society (ACS)
Date: 17-08-2007
DOI: 10.1021/JM070287B
Abstract: Four lipid-core peptide systems were synthesized using stepwise solid-phase peptide synthesis, incorporating a sequence from the human papillomavirus type-16 (HPV-16) E7 protein (E744-62), for the purpose of developing vaccines against HPV-16 associated cervical cancer. d-Mannose was conjugated to the vaccine in order to investigate whether the targeting of dendritic cell mannose receptors would improve vaccine efficacy. The ability of the vaccines to clear or reduce the size of HPV-16 associated tumors was assessed in C57BL/6 (H-2b) mice using the TC-1 HPV-16 tumor model. Overall, significant reductions in the size of TC-1 tumors were observed in the mouse model, with the conjugation of mannose to these vaccines demonstrated to clear or reduce the size of TC-1 tumors to a greater extent than non-mannose-containing vaccines (37 out of 40 versus 21 out of 30 tumors cleared, respectively).
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.BMC.2015.03.058
Abstract: Multicomponent gene delivery systems incorporating cell-penetrating peptides (CPP) from the human neurturin protein (NRTN-30, NRTN(132-161) NRTN-17, NRTN(145-161)) and a poly-l-lysine (PLL) dendron, were synthesized and characterized for plasmid DNA (pDNA) delivery. Acetylated NRTN peptides (Ac-CPP) and peptides conjugated to a PLL dendron (DEN-CPP) efficiently condensed and stabilized pDNA. Complexes between pDNA and DEN-CPP formed smaller and more stable nanoparticles. Flow cytometry experiments showed that pDNA-DEN-CPPs were taken up more efficiently into HeLa cells. There was also no significant difference between NRTN-30 and NRTN-17 for pDNA uptake, indicating that the truncated peptide alone is sufficient as a CPP for pDNA delivery.
Publisher: American Chemical Society (ACS)
Date: 26-09-2006
DOI: 10.1021/JM060475M
Abstract: We have developed a highly pure, self-adjuvanting, triepitopic Group A Streptococcal vaccine based on the lipid core peptide system, a vaccine delivery system incorporating lipidic adjuvant, carrier, and peptide epitopes into a single molecular entity. Vaccine synthesis was performed using native chemical ligation. Due to the attachment of a highly lipophilic adjuvant, addition of 1% (w/v) sodium dodecyl sulfate was necessary to enhance peptide solubility in order to enable ligation. The vaccine was synthesized in three steps to yield a highly pure product (97.7% purity) with an excellent overall yield. Subcutaneous immunization of B10.BR (H-2(k)) mice with the synthesized vaccine, with or without the addition of complete Freund's adjuvant, elicited high serum IgG antibody titers against each of the incorporated peptide epitopes.
Publisher: Springer Science and Business Media LLC
Date: 29-03-2023
Publisher: Springer Science and Business Media LLC
Date: 05-05-2006
Publisher: Wiley
Date: 2006
DOI: 10.1002/PSC.815
Abstract: Traditional vaccines consisting of whole attenuated microorganisms, killed microorganisms, or microbial components, administered with an adjuvant (e.g. alum), have been proved to be extremely successful. However, to develop new vaccines, or to improve upon current vaccines, new vaccine development techniques are required. Peptide vaccines offer the capacity to administer only the minimal microbial components necessary to elicit appropriate immune responses, minimizing the risk of vaccination associated adverse effects, and focusing the immune response toward important antigens. Peptide vaccines, however, are generally poorly immunogenic, necessitating administration with powerful, and potentially toxic adjuvants. The attachment of lipids to peptide antigens has been demonstrated as a potentially safe method for adjuvanting peptide epitopes. The lipid core peptide (LCP) system, which incorporates a lipidic adjuvant, carrier, and peptide epitopes into a single molecular entity, has been demonstrated to boost immunogenicity of attached peptide epitopes without the need for additional adjuvants. The synthesis of LCP systems normally yields a product that cannot be purified to homogeneity. The current study describes the development of methods for the synthesis of highly pure LCP analogs using native chemical ligation. Because of the highly lipophilic nature of the LCP lipid adjuvant, difficulties (e.g. poor solubility) were experienced with the ligation reactions. The addition of organic solvents to the ligation buffer solubilized lipidic species, but did not result in successful ligation reactions. In comparison, the addition of approximately 1% (w/v) sodium dodecyl sulfate (SDS) proved successful, enabling the synthesis of two highly pure, tri-epitopic Streptococcus pyogenes LCP analogs. Subcutaneous immunization of B10.BR (H-2(k)) mice with one of these vaccines, without the addition of any adjuvant, elicited high levels of systemic IgG antibodies against each of the incorporated peptides.
Publisher: American Chemical Society (ACS)
Date: 02-08-2006
DOI: 10.1021/JO060960P
Abstract: The aim of this study was to investigate methods for the synthesis of highly pure, well-characterized analogues of the lipid core peptide (LCP) system. Difficulties synthesizing and purifying conventional LCP systems have led to the requirement for a technique to produce highly pure, LCP-based vaccines for potential use in human clinical trials. The current study describes methods for the attachment of lipophilic adjuvants onto multi-epitopic peptide vaccines. Described is the synthesis, using native chemical ligation, of a highly pure, tri-epitopic, group A streptococcal (GAS) lipopeptide vaccine candidate. Intranasal immunization of the described tri-epitopic GAS lipopeptide with the mucosal adjuvant cholera toxin B subunit induced high serum IgG antibody titers specific for each of the incorporated peptide epitopes.
Publisher: American Society for Microbiology
Date: 30-04-2019
Abstract: GAS-related diseases disproportionally affect disadvantaged populations (e.g., indigenous populations), and development of a vaccine has been neglected. A recent strong advocacy c aign driven by the World Health Organization and the International Vaccine Institute has highlighted the urgent need for a GAS vaccine. One significant obstacle in GAS vaccine development is the lack of a widely used animal model to assess vaccine efficacy. Researchers in the field use a wide range of murine models of infection and in vitro assays, sometimes yielding conflicting results. Here we present the nonhuman primate pharyngeal infection model as a tool to assess vaccine-induced protection against colonization and clinical symptoms of pharyngitis and tonsillitis. We have tested the efficacy of an experimental vaccine candidate with promising results. We believe that the utilization of this valuable tool by the GAS vaccine research community could significantly accelerate the realization of a safe and effective GAS vaccine for humans.
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.IJPHARM.2019.03.053
Abstract: Liposomes are promising delivery vehicles and offer the added drawcard of being able to be made functional to target tissues such as cardiac muscle and cancerous cells. Current methods to manufacture liposomes need to be improved and supercritical fluid (SCF) technologies may offer a solution. Herein, the dispersibility of six different phospholipids (PLs) was determined in supercritical carbon dioxide (scCO
Publisher: Future Medicine Ltd
Date: 05-2019
Abstract: Aim: To develop a peptide hospholipid hybrid system for gastrin-releasing peptide receptor (GRPR)-targeted delivery of pDNA or siRNA. Materials & methods: A multifunctional GRPR-targeted peptide R 9 -K(GALA)-BBN(6-14) was combined with a phospholipid oligonucleotide delivery system (1:1 1,2-dioleoyl- sn-glycero-3-phosphoethanolamine and 1,2-dioleoyl-3-trimethylammonium-propane) and evaluated for pDNA and siRNA delivery in terms of complex size, toxicity, receptor-targeted delivery and gene expression or knockdown efficiency. Results: By combining peptide and phospholipid delivery systems, synergistic improvements in gene expression and knockdown were observed when compared with either system alone. The optimized formulation demonstrated high levels of EGFP expression and EGFP knockdown, GRPR-targeted delivery, enhanced endosomal release and minimal toxicity. Conclusion: The peptide hospholipid hybrid system provides efficient GRPR-targeted DNA/siRNA delivery.
Publisher: American Chemical Society (ACS)
Date: 12-12-2007
DOI: 10.1021/JM701091D
Abstract: The development of 16 self-adjuvanting group A streptococcal vaccine candidates, composed of (i) a universal helper T-cell epitope (P25), (ii) a target GAS B-cell epitope (J14), and (iii) a lipid moiety, is described. Systemic J14-specific IgG antibodies were detected following subcutaneous immunization of BALB/c (H-2 (d)) mice with each construct without the need for an additional adjuvant. The effect of changing the order of P25, J14, and lipid moiety attachment or incorporation of P25 and J14 into a lipid-core peptide system on antibody titers was assessed. The point of lipid moiety attachment had the greatest influence on systemic J14-specific IgG antibody titers. Overall, the best vaccines featured a C-terminal lipid moiety, conjugated through a lysine residue to P25 at the N-terminus, and J14 on the lysine side chain.
Publisher: Springer Science and Business Media LLC
Date: 15-06-2020
Publisher: Research Square Platform LLC
Date: 05-04-2023
DOI: 10.21203/RS.3.RS-2642181/V1
Abstract: Angiotensin-converting enzyme 2 (ACE2) is protective in cardiovascular disease, lung injury and diabetes yet paradoxically underlies our susceptibility to SARs-CoV2 infection and the fatal heart and lung disease it can induce. Furthermore, diabetic patients have chronic, systemic inflammation and altered ACE2 expression resulting in increased risk of severe COVID-19 and the associated mortality. A drug that could increase ACE2 activity and inhibit cellular uptake of severe acute respiratory syndrome coronavirus 2 (SARs-CoV2), thus decrease infection, would be of high relevance to cardiovascular disease, diabetes and SARs-CoV2 infection. While the need for such a drug lead was highlighted over a decade ago receiving over 600 citations, 1 to date, no such drugs are available. 2 Here, we report the development of a novel ACE2 stimulator, designated ‘2A’(international PCT filed), which is a 10 amino acid peptide derived from a snake venom, and demonstrate its in vitro and in vivo efficacy against SARs-CoV2 infection and associated lung inflammation. Peptide 2A also provides remarkable protection against glycaemic dysregulation, weight loss and disease severity in a mouse model of type 1 diabetes. No untoward effects of 2A were observed in these pre-clinical models suggesting its strong clinical translation potential.
Publisher: Wiley
Date: 2008
DOI: 10.1002/BIP.21002
Abstract: We applied native chemical ligation (NCL) method to the synthesis of highly pure lipid-core peptide (LCP) vaccines to attach various peptide epitopes. In the case of the synthesis of LCP vaccine with two different peptide epitopes, LCP moieties having two free Cys and two protected Cys derivatives (S-acetamidemethyl-Cys, (Cys(Acm)), N-methylsulfonylethyloxycarbonyl-Cys (Msc-Cys), or 1,3-thiazolidine-4-carboxylic acid (Thz)) on oligolysine branches were prepared in order to couple two different epitopes by stepwise NCL. It was found that the difficulty in NCL of first two peptide antigen was associated with the steric hindrance. Using Thz instead of Cys(Acm) and Msc-Cys was important to reduce the steric hindrance and improve NCL yield.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2016
Publisher: Future Medicine Ltd
Date: 2014
DOI: 10.2217/NNM.13.7
Abstract: Aim: To explore four-arm star poly(t-butyl)acrylate (P t BA)–peptide and linear P t BA–peptide conjugates as a vaccine-delivery system against Group A Streptococcus. Materials & methods: P t BA nanoparticles bearing J14 peptide epitopes were prepared via alkyne-azide 1,3-dipolar cycloaddition ‘click’ reaction. The conjugated products were self-assembled into small or large nanoparticles. These nanoparticle vaccine candidates were evaluated in vivo and J14-specific antibody titers were assessed. Results & discussion: Mice vaccinated with the nanoparticles were able to produce J14-specific IgG antibodies without the use of an external adjuvant after a single immunization. We have demonstrated for the first time that the immune responses against self-assembled P t BA nanoparticles are stronger for the smaller sized (˜20 nm) nanoparticles compared with the larger (˜500nm) P t BA nanoparticles. Conclusion: PtBA analogs have the potential to be developed as potent carrier systems for single-dose synthetic vaccines. Original submitted 29 August 2012 Revised submitted 6 December 2012 Published online 23 April 2013
Publisher: Elsevier BV
Date: 04-2006
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.ACTBIO.2017.06.032
Abstract: The development of carriers for the delivery of oligonucleotide therapeutics is essential for the successful translation of gene therapies to the clinic. In the present study, a delivery system, which combines the fusogenic lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) with a well-defined synthetic multifunctional peptide, was produced and optimized for gene delivery, with the aim to develop an efficient gene delivery platform for breast cancer cells. For this purpose, a breast cancer-specific cell targeting peptide (CTP) was incorporated into our leading peptide-based gene delivery system (to generate DEN-K(GALA)-TAT-K(STR)-CTP) to improve its cell-specific internalization, and investigated in combination with a formulation approach (DOPE/1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)). DEN-K(GALA)-TAT-K(STR)-CTP alone efficiently complexed with DNA or siRNA, and promoted efficient cellular uptake, but low levels of gene expression. By adding the formulation approach, synergistic improvements in gene expression and silencing were observed compared to the peptide or formulation approaches alone. Of significance, this current system demonstrated more efficient gene knockdown when compared to the leading commercial siRNA delivery agent Lipofectamine® RNAiMAX. The utility of this system was demonstrated through the delivery of BCL2 (B-cell lymphoma 2) siRNA to MCF-7 cells, which led to near complete knockdown of the Bcl-2 protein, and inhibition of MCF-7 cell migration in a wound healing assay. The present peptide/lipid hybrid system is an excellent candidate for the delivery of DNA or siRNA into breast cancer cells. The identification of safe and effective delivery systems for DNA and siRNA is of great importance. Herein, we developed a well-defined, multifunctional and cell-specific lipidic peptide DEN-K(GALA)-TAT-K(STR)-CTP as a breast cancer cell targeted gene delivery vector. When combined with a lipid component (DOTAP/DOPE), the peptide/lipid hybrid system demonstrated higher gene expression or knockdown levels compared to the peptide or lipid approach alone when used to deliver pDNA or siRNA respectively, indicating synergistic enhancement of gene delivery efficiency. Importantly, this delivery strategy achieved greater knockdown of the Bcl-2 protein when compared to the leading commercial siRNA delivery system Lipofectamine® RNAiMAX, suggesting its potential utility for the targeted treatment of Bcl-2 overexpressing breast cancers.
Publisher: Scientific Research Publishing, Inc.
Date: 2013
Publisher: Bentham Science Publishers Ltd.
Date: 08-2009
DOI: 10.2174/156720109789000537
Abstract: Although most commercial vaccines are delivered by injection, there is an increasing interest in needle-free vaccine delivery for reasons including the ability to elicit immune responses at mucosal surfaces, ease of administration, and the ability to administer vaccines without the need for trained medical professionals. This review summarizes strategies and technologies that are being used to improve oral vaccine absorption. Peptides and proteins, which comprise important vaccine components, exhibit unfavorable physicochemical properties including degradation in the gastrointestinal tract, and poor transport across the intestinal wall, which hinder oral vaccine development. Approaches to overcome these obstacles aim to provide new vaccines and delivery systems that are capable of eliciting protective immune responses, and are making an impact on current vaccine development.
Publisher: Bentham Science Publishers Ltd.
Date: 30-09-2015
DOI: 10.2174/0929867322666150825162941
Abstract: Gene therapy requires safe and effective vectors to deliver genes to their target site of action. Non-viral gene delivery systems have attracted growing attention due to their low toxicity, low immunogenicity and ease of production compared to viral vectors. Most non-viral gene delivery systems enter cells via endocytic pathways, and their escape from endosomes is therefore crucial for successful transfection. Several reagents have been developed to promote endosomal escape, including peptides, polymers and lipids. Among these, endosome-disrupting peptides have been used in many studies, and have proven to be one of the most promising approaches to overcome endosomal entrapment and lysosomal degradation. This review provides an up-to-date summary of strategies for enhancing endosomal escape, with a focus on the modification of endosome-disrupting peptides to further increase the efficient delivery of oligonucleotides.
Publisher: American Chemical Society (ACS)
Date: 16-02-2008
DOI: 10.1021/JM701410P
Abstract: Group A streptococcus (GAS) is associated with many human diseases, ranging in severity from benign to life-threatening. A promising strategy for developing vaccines against GAS involves the use of carbohydrates as carriers for peptide antigens. This study describes the optimized synthesis of d-glucose and d-galactose derived carriers, bearing an adipate linker and four tert-butoxycarbonyl protected aminopropyl groups. Prophylactic GAS vaccine candidates were synthesized by conjugating multiple copies of a single GAS M protein derived peptide antigen (either J8 or J14) onto the carbohydrate carriers. These antigens contain peptide sequences, which are highly conserved and offer the potential to prevent infections caused by up to 70% of GAS strains. Lipophilic amino acids were also conjugated to the d-glucose anomeric carbon to produce a self-adjuvanting liposaccharide vaccine. High serum IgG antibody titers against each of the incorporated peptide epitopes were detected following subcutaneous immunization of B10.BR (H-2 (k)) mice with the liposaccharide vaccine candidates.
Publisher: Wiley
Date: 21-12-2009
DOI: 10.1002/MED.20191
Abstract: Research related to peptide, vaccine, and gene delivery has grown exponentially over the last decade. In this review, we discuss the development of delivery systems for peptides, gene and vaccine products. Special focus is given to different lipidation and glycosylation strategies to improve the metabolic stability and membrane permeability of therapeutics, and their targeting to specific sites. The synthetic methods for preparation of the systems are also described.
Publisher: Elsevier BV
Date: 07-2007
Publisher: Elsevier BV
Date: 09-2021
DOI: 10.1016/J.DRUDIS.2021.03.019
Abstract: Virulence factor, sortase A (SrtA), has crucial roles in the pathogenesis of Gram-positive superbugs. SrtA is a bacterial cell membrane enzyme that anchors crucial virulence factors to the cell wall surface of Gram-positive bacteria. SrtA is not necessary for bacterial growth and viability and is conveniently accessible in the cell membrane therefore, it is an ideal target for antivirulence drug development. In this review, we focus on antimicrobial resistance (AMR)-expressing bacteria and SrtA as a potential target for overcoming AMR. The mechanism of action of SrtA and its inhibition by various types of inhibitors, such as synthetic small molecules, peptides, and natural products, are provided. Future SrtA research perspectives for alternative drug development to antibiotics are also proposed.
Publisher: Bentham Science Publishers Ltd.
Date: 10-2004
Abstract: The mucosal administration of vaccines is an area currently receiving a high level of interest due to potential advantages offered by this technique. These advantages include the ability to administer vaccines without need for needles, thus improving patient compliance with vaccination schedules, and the capacity to induce immune responses capable of preventing infections at the site of acquisition. Despite these advantages a number of limitations exist which currently inhibit our ability to successfully develop new mucosal vaccines. As such, much research is currently focused on developing new adjuvants and delivery systems to overcome these difficulties. However, despite high levels of interest in this area, relatively few mucosal vaccine candidates have successfully progressed to human clinical trials. In the review that follows, we aim to provide the reader with an overview of the immune system with respect to induction of mucosal immune responses. Furthermore, the review provides an overview of a number of microbial (bacterial toxins, CpG DNA, cytokines/chemokines, live vectors, and virus like particles) and synthetic (microspheres, liposomes, and lipopeptides) strategies that have been investigated as adjuvants or delivery systems for mucosal vaccine development, with a focus on the delivery of vaccines via the oral route.
Publisher: Future Medicine Ltd
Date: 06-2020
Abstract: Aim: To develop albendazole (ABZ)-loaded bombesin(6-14) (BBN(6-14)) functionalized liposomes for targeting GRPR to enhance delivery to cancer cells. Materials & methods: ABZ-loaded liposomes were formulated using supercritical CO 2 technology functionalized with a GRPR-targeted lipid-anchored BBN(6-14) peptide and evaluated for effects on cell viability, particle size and targeted cell uptake. Results: BBN(6-14)-coated ABZ liposomes decreased cell viability compared with nonfunctionalized ABZ liposomes. The level of GRPR expression positively correlated with intracellular uptake and decreased cell viability. The reduced cell viability, higher cell uptake and GRPR expression were observed in the order PC-3 Caco-2 HepG2 cells. Conclusion: BBN(6-14)-functionalized ABZ liposomes showed enhanced reduction in cell viability compared with nonfunctionalized ABZ liposomes.
Publisher: Informa UK Limited
Date: 12-11-2018
DOI: 10.1080/21691401.2018.1536059
Abstract: Supercritical fluid (SCF) technology offers a potential green alternative to organic solvent-based methods for drug formulation. Albendazole (ABZ) has promising anticancer activity when formulated to increase its cellular uptake. Herein, a static volume method was used to determine the solubility of ABZ in supercritical carbon dioxide (scCO
Publisher: MDPI AG
Date: 24-02-2023
DOI: 10.3390/MOLECULES28052114
Abstract: Sortase A (SrtA) is an enzyme which attaches proteins, including virulence factors, to bacterial cell walls. It is a potential target for developing anti-virulence agents against pathogenic and antimicrobial resistant bacteria. This study aimed to engineer 𝛽-lactoglobulin protein nanoparticles (PNPs) for encapsulating safe and inexpensive natural SrtA inhibitors (SrtAIs trans-chalcone (TC), curcumin (CUR), quercetin (QC), and berberine (BR)) to improve their poor aqueous dispersibility, to screen for synergy with antimicrobial peptides (AMPs), and to reduce the cost, dose, and toxicity of AMPs. Minimum inhibitory concentration (MIC), checkerboard synergy, and cell viability assays were performed for SrtAI PNPs against Gram-positive (methicillin-sensitive and -resistant S. aureus) and Gram-negative (E. coli, P. aeruginosa) bacteria alone and combined with leading AMPs (pexiganan, indolicidin, and a mastoparan derivative). Each SrtAI PNP inhibited Gram-positive (MIC: 62.5–125 µg/mL) and Gram-negative (MIC: 31.3–500 µg/mL) bacterial growth. TC PNPs with pexiganan demonstrated synergy against each bacteria, while BR PNPs with pexiganan or indolicidin provided synergy towards S. aureus. Each SrtAI PNP inhibited SrtA (IC50: 25.0–81.8 µg/mL), and did not affect HEK-293 cell viability at their MIC or optimal synergistic concentrations with AMPs. Overall, this study provides a safe nanoplatform for enhancing antimicrobial synergy to develop treatments for superbug infections.
Publisher: American Chemical Society (ACS)
Date: 14-05-2020
Publisher: Springer US
Date: 2009
Publisher: Wiley
Date: 11-01-2013
Abstract: Traditional vaccines, based on the administration of killed or attenuated microorganisms, have proven to be among the most effective methods for disease prevention. Safety issues related to administering these complex mixtures, however, prevent their universal application. Through identification of the microbial components responsible for protective immunity, vaccine formulations can be simplified, enabling molecular-level vaccine characterization, improved safety profiles, prospects to develop new high-priority vaccines (e.g. for HIV, tuberculosis, and malaria), and the opportunity for extensive vaccine component optimization. This subunit approach, however, comes at the expense of decreased immunity, requiring the addition of immunostimulatory agents (adjuvants). As few adjuvants are currently used in licensed vaccines, adjuvant development represents an exciting area for medicinal chemists to play a role in the future of vaccine development. In addition, immune responses can be further customized though optimization of delivery systems, tuning the size of particulate vaccines, targeting specific cells of the immune system (e.g. dendritic cells), and adding components to aid vaccine efficacy in whole immunized populations (e.g. promiscuous T-helper epitopes). Herein we review the current state of the art and future direction in subunit vaccine development, with a focus on the described components and their potential to steer the immune response toward a desired response.
Publisher: Bentham Science Publishers Ltd.
Date: 12-2007
DOI: 10.2174/092986707782794069
Abstract: Preclinical studies carried out over the last seven years by our group have focused on the development of a group A streptococcal (GAS) vaccine based on the antiphagocytic bacterial surface M protein using the Lipid-Core Peptide (LCP) system. This synthetic peptide vaccine delivery system has several advantages over other delivery systems including its self-adjuvanting properties and the ability to incorporate multiple peptide epitopes into a single vaccine. This review describes various vaccine delivery strategies including the LCP system, highlighting its functional properties and applications in vaccine research using data obtained from various LCP-based GAS vaccine candidates evaluated in murine models.
Publisher: American Chemical Society (ACS)
Date: 03-05-2019
DOI: 10.1021/ACS.MOLPHARMACEUT.9B00308
Abstract: Type 2 diabetes mellitus (T2DM) is increasing in global prevalence and is associated with serious health problems (e.g., cardiovascular disease). Various treatment options are available for T2DM, including the incretin hormone glucagon-like peptide-1 (GLP-1). GLP-1 is a therapeutic peptide secreted from the intestines following food intake, which stimulates the secretion of insulin from the pancreas. The native GLP-1 has a very short plasma half-life, owning to renal clearance and degradation by the enzyme dipeptidyl peptidase-4. To overcome this issue, various GLP-1 agonists with increased resistance to proteolytic degradation and reduced renal clearance have been developed, with several currently marketed. Strategies, such as controlled release delivery systems, methods to reduce renal clearance (e.g., PEGylation and conjugation to antibodies), and methods to improve proteolytic stability (e.g., stapling, cyclization, and glycosylation) provide means to further improve the ability of GLP-1 analogs. These will be discussed in this literature review.
Publisher: Bentham Science Publishers Ltd.
Date: 03-10-2019
DOI: 10.2174/1567201816666190529072914
Abstract: Gene therapy has the potential to treat both acquired and inherited genetic diseases. Generally, two types of gene delivery vectors are used - viral vectors and non-viral vectors. Non-viral gene delivery systems have attracted significant interest (e.g. 115 gene therapies approved for clinical trials in 2018 clinicaltrials.gov) due to their lower toxicity, lack of immunogenicity and ease of production compared to viral vectors. To achieve the goal of maximal therapeutic efficacy with minimal adverse effects, the cell-specific targeting of non-viral gene delivery systems has attracted research interest. Targeting through cell surface receptors the enhanced permeability and retention effect, or pH differences are potential means to target genes to specific organs, tissues, or cells. As for targeting moieties, receptorspecific ligand peptides, antibodies, aptamers and affibodies have been incorporated into synthetic nonviral gene delivery vectors to fulfill the requirement of active targeting. This review provides an overview of different potential targets and targeting moieties to target specific gene delivery systems.
Publisher: Elsevier BV
Date: 04-2006
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.SCITOTENV.2019.07.061
Abstract: Biotic interactions through diffusible and volatile organic compounds (VOCs) are frequent in nature. Soil bacteria are well-known producers of a wide range of volatile compounds (both organic and inorganic) with various biologically relevant activities. Since the last decade, they have been identified as natural biocontrol agents. Volatiles are airborne chemicals, which when released by bacteria, can trigger plant responses such as defence and growth promotion. In this study, we tested whether diffusible and volatile organic compounds (VOCs) produced by soil bacterial isolates exert anti-oomycete and plant growth-promoting effects. We also investigated the effects of inoculation with VOC-producing bacteria on the growth and development of Capsicum annuum and Arabidopsis thaliana seedlings. Our results demonstrate that organic VOCs emitted by bacterial antagonists negatively influence mycelial growth of the soil-borne phytopathogenic oomycete Phytophthora capsici by 35% in vitro. The bacteria showed plant growth promoting effects by stimulating biomass production, primary root growth and root hair development. Additionally, we provide evidence to suggest that these activities were deployed by the emission of either diffusible organic compounds or VOCs. Bacterial VOC profiles were obtained through solid phase microextraction (SPME) and analysis by gas chromatography coupled with mass spectrometry (GC-MS). This elucidated the main volatiles emitted by the isolates, which covered a wide range of aldehydes, alcohols, esters, carboxylic acids, and ketones. Collectively, twenty-five VOCs were identified to be produced by three bacteria some being species-specific. Our data show that bacterial volatiles inhibits P. capsici in vitro and modulate both plant growth promotion and root system development. These results confirm the significance of soil bacteria and highlights that ways of harnessing them to improve plant growth, and as a biocontrol agent for soil-borne oomycetes through their volatile emissions deserve further investigation.
Publisher: Future Medicine Ltd
Date: 02-2017
Abstract: Aim: To develop a new synthetic peptide-based nanoparticulate siRNA delivery system. Materials & methods: DEN-K(GALA)-TAT-K(STR) was generated by incorporating stearic acid into a multicomponent peptide (DEN-K(GALA)-TAT), containing a cationic poly-L-lysine dendron, an endosome-disrupting peptide GALA and a cell-penetrating peptide TAT(48–60). Its physicochemical characteristics, size, toxicity, cellular uptake and gene knockdown activity of the peptide/siRNA complexes were studied. Results: DEN-K(GALA)-TAT-K(STR) exhibited a pH-responsive behavior, which assists with endosomal escape. When siRNA was delivered by DEN-K(GALA)-TAT-K(STR), it showed a significantly enhanced cellular uptake, compared with the nonlipidic peptide. This system also displayed enhanced knockdown efficiency and reduced cytotoxicity over the widely used delivery system branched 25-kDa polyethyleneimine. Conclusion: Our stearylated multicomponent delivery system has great potential as an efficient siRNA delivery vector.
Publisher: American Chemical Society (ACS)
Date: 18-04-2014
DOI: 10.1021/BC500108B
Abstract: Subunit vaccines offer a means to produce safer, more defined vaccines compared to traditional whole microorganism approaches. Subunit antigens, however, exhibit weak immunity, which is normally overcome through coadministration with adjuvants. Enhanced vaccine properties (e.g., improved potency) can be obtained by linking antigen and adjuvant, as observed for synthetic peptide antigens and Toll-like receptor 2 (TLR2) ligands. As few protective peptide antigens have been reported, compared to protein antigens, we sought to extend the utility of this approach to recombinant proteins, while ensuring that conjugation reactions yielded a single, molecularly defined product. Herein we describe the development and optimization of techniques that enable the efficient, site-specific attachment of three synthetic TLR2 ligands (lipid core peptide (LCP), Pam2Cys, and Pam3Cys) onto engineered protein antigens, permitting the selection of optimal TLR2 agonists during the vaccine development process. Using this approach, broadly protective (J14) and population targeted (seven M protein N-terminal antigens) multiantigenic vaccines against group A streptococcus (GAS Streptococcus pyogenes) were produced and observed to self-assemble in PBS to yield nanoparticules (69, 101, and 123 nm, respectively). All nanoparticle formulations exhibited self-adjuvanting properties, with rapid, persistent, antigen-specific IgG antibody responses elicited toward each antigen in subcutaneously immunized C57BL/6J mice. These antibodies were demonstrated to strongly bind to the cell surface of five GAS serotypes that are not represented by vaccine M protein N-terminal antigens, are among the top 20 circulating strains in developed countries, and are associated with clinical disease, suggesting that these vaccines may elicit broadly protective immune responses.
Publisher: American Chemical Society (ACS)
Date: 16-06-2020
Publisher: Bentham Science Publishers Ltd.
Date: 02-2008
DOI: 10.2174/092986708783503249
Abstract: Despite the important role of adjuvants for vaccine development, relatively few adjuvants have been successfully incorporated into vaccines intended for human administration. This is in part due to the high toxicity associated with many experimental adjuvants. This lack of choice effectively hinders the ability to produce vaccines against many diseases, or to improve current vaccine formulations. The conjugation of immunostimulatory lipids to peptide antigens, to produce self-adjuvanting lipopeptide vaccines, has been tested in human clinical trials. These systems appear to have a number of advantages over more traditional adjuvants (e.g. alum salts) including the capacity for these vaccines to be administered via mucosal routes (e.g. orally or nasally) instead of by injection, elicitation of antigen-specific cytotoxic T-lymphocytes and mucosal immunity, as well as little-to-no observed toxicity. Several lipopeptide vaccine systems have been described in the literature, ranging from the conjugation of single fatty acid chains, to the conjugation of more complex lipids and glycolipids onto peptide antigens. The following review provides an overview of the most studied lipopeptide vaccine systems grouped into the following categories: 1) bacterial lipopeptides, including tri-palmitoyl-S-glyceryl cysteine (Pam3Cys) and di-palmitoyl-S--glyceryl cysteine (Pam2Cys) 2) the lipid-core peptide (LCP) and multiple antigen lipophilic adjuvant carrier (MALAC) systems 3) single-chain palmitoylated peptides and 4) glycolipids (e.g. monophosphoryl lipid A). The review also discusses the potential mechanisms of action for lipopeptide and glycolipopeptide vaccines, as well as structure activity relationships, and provides ex les of studies utilising each system.
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.BIOTECHADV.2017.03.005
Abstract: Traditional vaccination approaches (e.g. live attenuated or killed microorganisms) are among the most effective means to prevent the spread of infectious diseases. These approaches, nevertheless, have failed to yield successful vaccines against many important pathogens. To overcome this problem, methods have been developed to identify microbial components, against which protective immune responses can be elicited. Subunit antigens identified by these approaches enable the production of defined vaccines, with improved safety profiles. However, they are generally poorly immunogenic, necessitating their administration with potent immunostimulatory adjuvants. Since few safe and effective adjuvants are currently used in vaccines approved for human use, with those available displaying poor potency, or an inability to stimulate the types of immune responses required for vaccines against specific diseases (e.g. cytotoxic lymphocytes (CTLs) to treat cancers), the development of new vaccines will be aided by the availability of characterized platforms of new adjuvants, improving our capacity to rationally select adjuvants for different applications. One such approach, involves the addition of microbial components (pathogen-associated molecular patterns PAMPs), that can stimulate strong immune responses, into subunit vaccine formulations. The conjugation of PAMPs to subunit antigens provides a means to greatly increase vaccine potency, by targeting immunostimulation and antigen to the same antigen presenting cell. Thus, methods that enable the efficient, and inexpensive production of antigen-adjuvant fusions represent an exciting mean to improve immunity towards subunit antigens. Herein we review four protein-based adjuvants (flagellin, bacterial lipoproteins, the extra domain A of fibronectin (EDA), and heat shock proteins (Hsps)), which can be genetically fused to antigens to enable recombinant production of antigen-adjuvant fusion proteins, with a focus on their mechanisms of action, structural or sequence requirements for activity, sequence modifications to enhance their activity or simplify production, adverse effects, and ex les of vaccines in preclinical or human clinical trials.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C5SC03859F
Abstract: Conjugation of multiple peptides by their N-termini is a promising technique to produce branched multiantigenic vaccines.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Springer New York
Date: 2009
Publisher: Springer New York
Date: 2009
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.JCONREL.2019.11.018
Abstract: Protein antigens are, in general, weakly immunogenic, and therefore require co-delivery with adjuvants to stimulate potent immune responses. The fusion of (poly)peptide antigens to immunostimulatory adjuvants (e.g. Toll-like receptor (TLR) agonists) has been demonstrated to greatly improve vaccine potency compared to mixtures of antigen and adjuvant. Chemical approaches, to enable the rapid, site-specific and high-yielding linkage of TLR2 ligands to recombinant protein antigens, have been previously optimized. These approaches require the use of denaturing conditions to ensure high reaction yields, which limits their application, as maintenance of native protein folding is necessary to elicit antibodies against conformational epitopes. Here, this work aimed to optimize an alternative method, to ensure the efficient bioconjugation of TLR2 ligands onto folded protein antigens. An enzyme-mediated approach, using Staphylococcus aureus sortase A (or a penta mutant with enhanced efficiency), was optimized for reaction yield and time, as well as enzyme type and amount. This approach enabled the site-specific conjugation of the TLR2-agonist fibroblast-stimulating lipopeptide-1 (FSL-1) onto a model group A Streptococcus (GAS) recombinant polytope antigen under conditions that maintain protein folding, yielding a homogeneous, molecularly-defined product, with ligation yields as high as 90%. Following intramuscular (IM) administration of the ligation product to humanized plasminogen AlbPLG1 mice, high-titer, antigen-specific IgG antibodies were observed, which conferred protection against subcutaneous challenge with GAS strain 5448. In comparison, mixtures of the GAS antigen with aluminum hydroxide or FSL-1 failed to provide protection, with the FSL-1 mixture yielding ~1000-fold lower antigen-specific IgG antibody titers, and the mixture with alum yielding a Th2-biased response compared to the more balanced Th1/Th2 responses observed with the FSL-1 conjugate. Overall, a FSL-1 bioconjugation method for the efficient production of antigen-TLR2 agonist conjugates, which maintain protein folding, was produced, with broad utility for the development of self-adjuvanting vaccines against subunit protein antigens.
Publisher: Wiley
Date: 02-2015
DOI: 10.1002/9780471729259.MC1801S36
Abstract: Vaccination has a proven record as one of the most effective medical approaches to prevent the spread of infectious diseases. Traditional vaccine approaches involve the administration of whole killed or weakened microorganisms to stimulate protective immune responses. Such approaches deliver many microbial components, some of which contribute to protective immunity, and assist in guiding the type of immune response that is elicited. Despite their impeccable record, these approaches have failed to yield vaccines for many important infectious organisms. This has prompted a move towards more defined vaccines (‘subunit vaccines’), where in idual protective components are administered. This unit provides an overview of the components that are used for the development of modern vaccines including: an introduction to different vaccine types (whole organism, protein eptide, polysaccharide, conjugate, and DNA vaccines) techniques for identifying subunit antigens vaccine delivery systems and immunostimulatory agents (‘adjuvants’), which are fundamental for the development of effective subunit vaccines.
Publisher: IOP Publishing
Date: 29-07-2019
Abstract: The development of polymer-based nanoparticulate delivery systems for siRNA is important for the clinical success of gene therapy. However, there are some major drawbacks that need to be overcome. Short interfering RNA (siRNA) has been investigated as a potential therapeutic drug to silence disease-associated genes, but its usage is limited due to the lack of effective and safe nanocarriers. In this study, DOPE-PEI, a nanoparticle consisting of the fusogenic lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) conjugated with low-molecular-weight, 600 Da, branched polyethylenimine (PEI) was produced and optimized for siRNA delivery. This delivery system was modified with other components such as 1,2-dioleoyl-sn-glycerol-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)2000] (DOPE-PEG2K), DOPE-PEG3.4K-bombesin and 1,2-dioleoyl-sn-glycerol-3-phosphoethanolamine/1,2-dioleoyl-3-trimethylammonium-propane (DOPE/DOTAP) and tested on PC-3 cells. The conjugation of DOPE to PEI polymer (DOPE-PEI) improved the efficiency of PEI to deliver siRNA into the cytosol and knockdown genes, but demonstrated high toxicity. The addition of DOPE-PEG2K reduced cellular toxicity by masking the surface positive charge of the DOPE-PEI/siRNA complex, with the incorporation of a gastrin-releasing peptide receptor (GRPR) targeting peptide and DOPE/DOTAP components improving the cellular uptake of siRNA into targeted cells and the siRNA knockdown efficiency.
Publisher: American Chemical Society (ACS)
Date: 22-10-2010
DOI: 10.1021/JA1064312
Publisher: Future Medicine Ltd
Date: 12-2014
DOI: 10.2217/NNM.14.190
Abstract: Aim: Utilize lipopeptide vaccine delivery system to develop a vaccine candidate against Group A Streptococcus. Materials & methods: Lipopeptides synthesized by solid-phase peptide synthesis-bearing carboxyl (C)-terminal and amino (N)-terminal Group A Streptococcus peptide epitopes. Nanoparticles formed were evaluated in vivo. Results: Immune responses were induced in mice without additional adjuvant. We demonstrated for the first time that incorporation of the C-terminal epitope significantly enhanced the N-terminal epitope-specific antibody response and correlated with forming smaller nanoparticles. Antigen-presenting cells had increased uptake and maturation by smaller, more immunogenic nanoparticles. Antibodies raised by vaccination recognized isolates. Conclusion: Demonstrated the lipopeptidic nanoparticles to induce an immune response which can be influenced by the combined effect of epitope choice and size.
Start Date: 2020
End Date: 2023
Funder: Australian Research Council
View Funded ActivityStart Date: 2013
End Date: 12-2016
Amount: $370,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 06-2020
End Date: 12-2024
Amount: $514,000.00
Funder: Australian Research Council
View Funded Activity