Biohybrid and Biomimetic Platforms for Programmable Therapeutic Delivery
Type of DegreeDissertation
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Drug and gene delivery carriers such as hydrogels and metallic nanoparticles have shown remarkable promise as programmable platforms in the targeted delivery of their payload. In this work, the fundamental principles of biomimesis have been applied for the synthesis of recognitive hydrogels from monomers of diverse chemical functionalities. We exploit the configurational biomimetic imprinting process, which creates macromolecular memory for the drug within the network and delays the transport of drug from the matrix via interactions with the functional groups organized within the structure. The most biomimetic network, which was synthesized from four functional monomers, demonstrated 6 times enhanced loading over the non-imprinted network and 3 times enhanced loading over the networks containing two or three functional monomers. Delayed release kinetics of therapeutically relevant concentrations of drug was observed over 5 days. All imprinted networks had significantly lower diffusion coefficients than non-imprinted networks, in spite of comparable mesh sizes (21-31 Å) and equilibrium polymer volume fractions in the swollen state (0.634±0.025). Furthermore, the most biomimetic network had a diffusion coefficient which was lesser by factors of 15, 76, 49, and 113 from the networks synthesized from two or three functional monomers. In this work, we show the controlled release of nucleic acid therapeutics loaded into hydrogels, via enzymatic and physical triggers such as specific and non-specific endonucleases and temperature. The physiological relevance of the platform was demonstrated by the in-vitro down regulation of a HIV Tat/Rev gene by the specific release of an anti-HIV deoxyribozyme from the hydrogel. Furthermore, the crosslinking densities of the hydrogels were varied in order to obtain tunable release profiles of DNA. Substrate non-specific (DNase I) enzymes were used to trigger the release of fluorescent neomycin immobilized onto gold nanoparticles. Surface coverage densities of the DNA were quantified and optimized by varying buffer ionic strengths, reaction times and sonication. Such novel schemes could be used for the intracellular delivery of multiple drugs from the same platform, as injectable systems targeted to specific cells using functionalized ligands such as folic acid. We anticipate that our study will spur further inquiry into nucleic acid based programmable on-demand switches and modulatory mechanisms, with exquisite control and sensitivity.