Zwitterionic polymeric nanoparticles for drug delivery

Abstract

Bottlebrush block copolymers, characterized by their densely grafted side chains stemming from a highly persistent backbone, offer unique advantages for drug delivery, including enhanced micellar stability, reduced critical micelle concentration, and controlled surface topography, setting them apart from traditional linear polymers. This dissertation focuses on zwitterionic bottlebrush block copolymers (ZBCPs) composed of poly(D, L-lactide) (PLA) and poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) side chains, synthesized via a combination of ring-opening and controlled radical polymerization using a grafting-from approach. ZBCPs were self-assembled into uniform spherical micelles and nanoparticles through direct dissolution and rapid mixing methods, and these self-assembled nanostructures were systematically evaluated. Compared to non-ionic PEG micelles (standard), zwitterionic bottlebrush micelles (ZBM) demonstrated superior stability under high salt conditions, elevated temperatures cycles, and in the presence of fetal bovine serum, whereas kinetically assembled nanoparticles (ZBNP) exhibited greater drug loading capacity. Both ZBM and ZBNP also showed excellent hemocompatibility, with ZBM displaying exceptional redispersibility in the absence of cryoprotectants. In parallel, this dissertation investigates boronic acid-functionalized zwitterionic polymers for drug delivery. A linear ABC-type amphiphilic copolymer containing poly(3-aminophenylboronic acid) as the central block was synthesized and compared to its non-functional counterpart. The boronic acid-containing nanoparticles exhibited pH- and oxidation-responsive behavior, enabling controlled drug release. Expanding this concept to a bottlebrush architecture, boronic acid-functionalized bottlebrush triblock copolymers were developed to further enhance nanoparticle performance. The inclusion of a boronic acid interlayer in the bottlebrushes significantly improved redispersibility of drug-loaded nanoparticles while maintaining high drug loading capacity, superior stability, and excellent hemocompatibility. This dissertation provides fundamental insights into solution-based self-assembled nanostructures derived from ZBCPs and boronic acid-functionalized polymers, establishing them as promising advanced drug delivery platforms. These systems offer tunable release kinetics, robust colloidal stability in harsh biological environments, excellent hemocompatibility, and superior redispersibility, thereby enhancing their translational potential in the field of nanomedicine.