Development and Optimization of Functionalized Self-Assembling Polymeric NanobiomaterialsPublic
Nanocarriers as structures with at least one dimension in the nanometer scale are capable of loading small molecule therapeutics that would otherwise have poor bioavailability, non- specific uptake, and off target effects. Polymeric nanocarriers can be modified to tune their chemical and biological behavior to better suit the intended application. This work investigates the development of two such examples of polymeric nanocarriers, poly(ethylene glycol)-block- poly(propylene sulfide) (PEG-b-PPS) and the class of poly(amino acid)-block-poly(propylene sulfide) (PAA-b-PPS), that can be modified to incorporate a range of unique functionalities. The purpose of these efforts is to demonstrate the versatility of these two diblock copolymer classes of material to be used in a range of biomedical applications.The optimized synthesis of PEG-b-PPS is described to reduce complexities and enhance product quality, followed by two applications that showcase the tuning of PEG-b-PPS properties to enhance uptake into non-phagocytic cells, and to deliver a small molecule therapeutic for modulating the inflammasome. Extensive work details the development and optimization of the completely novel PAA-b-PPS class of biomimetic self-assembling diblock copolymers that have a vast potential for forming multiple stable morphologies and incorporating modular functionality based on general sequence control of the monomer units. I found that the synthesis of PEG-b-PPS can be significantly improved to produce material of high quality in very high yields while requiring less time and resources compared to previous protocols. I demonstrated that uptake of PEG-b-PPS nanocarriers into non-phagocytic DAOY and ASZ cells can be enhanced by selecting the correct morphology, size, and introducing a cationic surface charge. I show that micelles make an effective delivery vehicle for the encapsulation and delivery of the small hydrophobic FiVe1 drug, which may have a number of relative biomedical applications. I designed an effective strategy to rapidly synthesize PAA-b-PPS diblock copolymers in a range of weight ratios using a rationally selected linker for unrestricted combinatorial paring of polymer blocks. I assembled and characterized representative formulations via three orthogonal techniques to show that this material is capable of forming unique morphologies at defined weight ratios. I then expanded these PAA backbones to more complex functional amino acid units to demonstrate the versatility of this delivery system. Finally, I present an approach to use experimental results and computational analysis to exert general sequence control and synthesize a copolymer with a statistically random order of monomers. I conclude that these two PEG-b-PPS and PAA-b-PPS materials are effective platforms for designing nanocarrier therapeutics for biomedical applications with specifically tuned physiochemical characteristics. Additionally, I present the novel PAA-b-PPS material as a platform with significant potential as a biomimetic nanocarrier platform worth further investigation.
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