Design, synthesis, and evaluation of poly(1,2-glycerol carbonate)-paclitaxel conjugate nanoparticles for the tunable delivery of paclitaxel
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Since their initial conceptualization, polymer-drug conjugate nanocarriers have been a mainstay of the drug delivery field. The conjugation of therapeutic agents to polymeric carriers offers several critical advantages including improved drug solubilization, controlled release, and enhanced safety. Accordingly, polymer-drug conjugate nanocarriers are uniquely positioned to remedy some of the limitations of conventional small molecule chemotherapeutics, namely their narrow window of therapeutic efficacy, rapid clearance, and limited tumor exposure. This dissertation describes the design, synthesis, and evaluation of a novel sustained release, biodegradable polymeric nanocarrier as a single administration replacement of multi-dose paclitaxel (PTX) treatment regimens. The synthesis of poly(1,2-glycerol carbonate)-graft-succinic acid-paclitaxel (PGC-PTX) is presented, and its use enables high, controlled PTX loadings. Moreover, the polymer backbone is composed of biocompatible building blocks—glycerol and carbon dioxide. When formulated as nanoparticles (NPs), PGC-PTX NPs exhibit high aqueous PTX concentrations, sub-100 nm diameters, narrow dispersity, prolonged storage stability, and sustained and controlled PTX release kinetics. In murine models of peritoneal carcinomatosis, in which the clinical implementation of multi-dose intraperitoneal (IP) treatment regimens is limited by catheter-related complications, PGC-PTX NPs exhibit improved safety at high doses, tumor localization, and efficacy even after a single IP injection, with comparable therapeutic effect to multi-dose IP PTX treatment regimens. The PGC-PTX NP platform is additionally amenable to optimization via modulation of nanocarrier properties. Specifically, the dual conjugation and physical entrapment of PTX in the NPs harnesses the physicochemical interactions between free and conjugated PTX to achieve unprecedented ultra-high drug loadings as well as facile control of nanomechanical properties and release kinetics. Optimization of these programmable carriers consequently enables the safe delivery of high drug doses as well as sustained therapeutic efficacy. In a murine model of peritoneal carcinomatosis, a single high dose of dual-loaded PGC-PTX nanocarriers affords significantly improved survival compared to weekly, multi-dose PTX treatment. Modulation of nanocarrier properties via the incorporation of poly(lactide-co-glycolide) (PLGA) is additionally explored. Although the integration of PLGA does not significantly alter NP physical properties, the polymer blend nanocarriers exhibit improved in vitro potency relative to PGC-PTX NPs, warranting the continued evaluation of the mechanism by which PLGA modulates nanocarrier efficacy.