Linear and Star Block Copolymer Nano-architectures for Drug Delivery

Abstract

Conventional chemotherapeutic clinical drugs are predominantly small molecules and they have many limitations such as poor biodistribution, lacking target specificity, short half-life and consequential side effects like cardiotoxicity, nephrotoxicity and neurotoxicity, etc. This obstacle in cancer treatment led to the development of “polymer therapeutics” that offer the advantage of passive selectively targeting the tumor tissue via the enhanced permeability and retention (EPR) effect. Herein, aliphatic polyesters seem to have gained impetus as polymeric drug delivery vehicles owing to their biodegradability facilitated by enzymes at the intracellular compartments, especially paving way for the environmentally stable and structurally tunable polycaprolactone (PCL) based scaffolds. The underlying principle of the thesis is to engineer amphiphilic fully biodegradable PCL nano-scaffolds and investigate the impact of polymer architecture on macromolecular self-assembly along with the ability to cross biological barriers. In this thesis work, new classes of amphiphilic linear block and random copolymers were developed via ring opening polymerization of ε-caprolactone and tailor-made ɣ-carboxylic substituted caprolactone. The difference in polymer topologies manifested in their solid-state assemblies, wherein the block copolymers were semi-crystalline in nature as opposed to the amorphous random copolymers. Their aqueous self-assemblies resulted in the formation of stable spherical nanoparticles with excellent loading capability of anticancer drug doxorubicin (DOX) in the hydrophobic pocket. These polymer scaffolds were found to be stable under physiological conditions and the in vitro release kinetics revealed selective rupturing in the presence of lysosomal esterase enzyme to deliver DOX at the intracellular compartment. The cytotoxicity study exhibited that the nascent polymers were highly biocompatible whereas the DOX-loaded nanoparticles resulted in > 90 % cell death. Further efforts have been taken to tweak the polymer architecture from linear to the highly branched star-shaped architectures to build single chain polymer nano-carriers, i.e. unimolecular micelles (UMs) whilst maintaining the same chemical composition and molecular weight. DOX-loaded unimolecular micelles were studied in vivo to understand the role played by polymer topology on the biodistribution, renal clearance, RES uptake of the star-shaped polymer UMs versus the linear polymer aggregated micelles. The UMs were able to selectively cross the impermeable blood brain barrier, evade RES uptake and result in reduced cardiotoxicity. The star-shaped architectures were further decorated with neutral, anionic and cationic charges and their respective UMs were studied to understand the role of surface charge on the ability of these single chain polymer nano-carriers to penetrate the cellular membrane and investigate the endocytosis mechanism.