Polymer Topology Driven Enzymatic Biodegradation in Polycaprolactone Block and Random Copolymer Architectures for Drug Delivery to Cancer Cells

Abstract

The present investigation reports polymer topology design principle for programming the enzymatic biodegradation and delivery of anticancer drugs at the intracellular compartments of breast and cervical cancers. To accomplish this goal, new classes of biodegradable amphiphilic block and random copolymers based on hydrophilic carboxylic-functionalized polycaprolactone (CPCL) and hydrophobic polycaprolactone (PCL) units were designed via ring-opening polymerization methodology. The interchain interactions and their packing were directly controlled by the topology of the polymers, and the block copolymers were found to be as semicrystalline materials. These amphiphilic block and random polymers were readily dispersible in water, and they self-assembled into <200 nm nanoparticles. These nanoparticles exhibited excellent capability for loading anticancer drug doxorubicin (DOX) in the hydrophobic pocket. In vitro drug release kinetics revealed that the polymer nanoscaffolds were stable under physiological conditions, and they exclusively ruptured in the presence of lysosomal esterase enzyme at the intracellular compartments to deliver DOX. The “burst” and “controlled” release of drugs from the polymer nanocarriers was directly controlled by length and chemical composition of block and random copolymers. In vitro cytotoxicity studies in breast cancer (MCF 7) and cervical cancer (HeLa) cells revealed that the nascent polymer nanoparticle was highly biocompatible and nontoxic to cells whereas their DOX-loaded nanoparticles accomplished >95% cell killing. Confocal microscopy reinstated the cellular uptake of the DOX-loaded polymer scaffold wherein the nanoparticle was highly concentrated at the nucleus and revealed that the drugs were predominantly delivered at the nucleus of the cells for apoptosis. Flow cytometry investigation confirmed the enhanced DOX delivering capability of block and random copolymer nanoparticles compared to free DOX. The newly designed fully biodegradable PCL-based block and random nanocarriers are excellent scaffolds for enzyme-mediated intracellular delivery of DOX, and the proof of concept was established in breast and cervical cancers.