ORCID Profile
0000-0003-0676-1444
Current Organisation
Genentech
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Publisher: American Chemical Society (ACS)
Date: 05-11-2020
Abstract: Porous colloids have been shown to exert unique bioactivities for mediating lipid (fat) metabolism and thereby offer significant potential as anti-obesity therapies. In this study, we compare the capacity for two classes of colloids, that is, smectite clays (Laponite XLG, LAP montmorillonite, MMT) and mesoporous silica (SBA-15 ordered silica MPS), to impede intestinal lipid hydrolysis and provoke lipid and carbohydrate excretion through adsorption within their particle matrices. A two-stage
Publisher: American Society of Civil Engineers (ASCE)
Date: 10-2018
Publisher: Wiley
Date: 17-11-2017
Publisher: American Chemical Society (ACS)
Date: 13-07-2021
DOI: 10.1021/ACS.MOLPHARMACEUT.1C00309
Abstract: Peptide drugs face several barriers to oral delivery, including enzymatic degradation in the gastrointestinal tract and low membrane permeability. Importantly, the direct interaction between various biorelevant colloids (i.e., bile salt micelles and bile salt-phospholipid mixed micelles) present in the aqueous gastrointestinal environment and peptide drug molecules has not been studied. In this work, we systematically characterized interactions between a water-soluble model peptide drug, octreotide, and a range of physiologically relevant bile salts in solution. Octreotide membrane flux in pure bile salt solutions and commercially available biorelevant media, i.e., fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF), was evaluated using a side-by-side diffusion cell equipped with a cellulose dialysis membrane. All seven micellar bile salt solutions as well as FaSSIF and FeSSIF decreased octreotide membrane flux, and dihydroxy bile salts were found to have a much larger effect than trihydroxy bile salts. An inverse relationship between octreotide membrane flux and pancreatic enzymatic stability was also observed bile salt micelles and bile salt-phospholipid mixed micelles provided a protective effect toward enzymatic degradation and prolonged octreotide half-life in vitro. Diffusion ordered nuclear magnetic resonance (DOSY NMR) spectroscopy and dynamic light scattering (DLS) were used as complementary experimental techniques to confirm peptide-micelle interactions in solution. Experiments were also performed using desmopressin as a second model peptide drug desmopressin interacted with bile salts in solution, albeit to a lower extent relative to octreotide. The findings described herein demonstrate that hiphilic, water-soluble peptide drugs do interact with bile salts and phospholipids in solution, with an effect on peptide membrane flux and enzymatic stability. Correspondingly, oral peptide drug absorption and bioavailability may be impacted.
No related grants have been discovered for Tahnee Dening.