Pharmaceutically Relevant Amphiphilic Copolymers and Their Applications: Crystal Inhibition and Membrane Stabilization
2022-06
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Pharmaceutically Relevant Amphiphilic Copolymers and Their Applications: Crystal Inhibition and Membrane Stabilization
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2022-06
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Polymeric materials have realized a broad range of applications in the biomedical world due to their customizability, innocuity, and their ability to mimic biomacromolecules. Amphiphilic copolymers are especially useful because they can associate with hydrophobic motifs while remaining soluble in aqueous solution. Thus, they have been useful in applications including drug delivery, therapeutics, and biomimetic materials. Herein, we investigate the structure-property relationship of polymers in two applications: (i) Promoting the aqueous supersaturation of hydrophobic drug molecules to enhance their bioavailability, and (ii) stabilization of cell membranes to protect them from a variety of stresses. Amorphous solid dispersions (ASDs), consisting of a mixture of a polymer excipient and a hydrophobic drug, are an attractive means to enhance the concentration and bioavailability of hydrophobic drug molecules. In this work, the solution behavior of poly(N-isopropylacrylamide-co-N,N-dimethyl acrylamide) (PND) and poly(vinylpyrrolidone-co-vinylacetate) (PVPVA), as polymer excipients, and phenytoin (PHY), nilutamide (NLT) and itraconazole (ITN), as drug models, were monitored using an in-vitro dissolution assay, cryogenic transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), and polarized optical microscopy (POM). Amorphous nanoparticles were coincident with periods of drug supersaturation in each system. In this study, we propose that the kinetic stability of the nanoparticles is based on whether the polymer excipient interacts more strongly with water or the particle’s drug-rich phase. Achieving a better understanding of how polymer excipients interact with drug-rich phases in aqueous solution will help inform the design of future ASD systems. Poloxamers are a class of block copolymers composed of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) segments. They have been used pharmaceutically to restore cell membrane integrity and to treat conditions such as Duchenne’s muscular dystrophy and ischemia reperfusion injury. In this project, we investigated the mechanism with which poloxamers stabilize cell membranes by studying (a) the effect of polymer hydrophobicity on polymer/membrane binding and cell protection efficacy, and (b) the effect of poloxamers on the elasticity and toughness of model lipid membranes. In (a) we compared a series of poly(1,2-butylene oxide)-b-PEO (PBO-b-PEO) copolymers to PPO/PEO analogues using a combination of pulsed-field-gradient NMR experiments and a lactate dehydrogenase (LDH) cell assay. We found that PBO-b-PEO copolymers bound significantly more to model liposomes composed of 1-palmitoyl-2-oleoyl-glycero-3- phosphocholine (POPC) compared to PPO/PEO copolymers. However, both classes of polymers performed similarly when compared by an LDH assay. In (b) we used micropipette aspiration to measure the effect of poloxamer molar mass, hydrophobicity and concentration on the mechanical properties of POPC membranes. We found that at poloxamers increase the elasticity of POPC membranes through a decrease in their stretching modulus, while having minimal effect on their bending modulus. Additionally, poloxamers can slightly increase or decrease membrane toughness, based on their PPO/PEO composition. Studies (a) and (b) provide important insights into the protection mechanism of poloxamers by attempting to directly relate polymer-membrane binding to properties such as cellular resistance to osmotic stress and membrane elasticity.
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University of Minnesota Ph.D. dissertation. June 2022. Major: Chemistry. Advisors: Timothy Lodge, Marc Hillmyer. 1 computer file (PDF); xiii, 210 pages.
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Van Zee, Nicholas. (2022). Pharmaceutically Relevant Amphiphilic Copolymers and Their Applications: Crystal Inhibition and Membrane Stabilization. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/258678.
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