PH-labile and photochemically cross-linkable polymer vesicles from coumarin based random copolymer for cancer therapy

Abstract

The stability of a drug payload inside a nanocarrier at physiological environment and the release of the said drug at specific tumor cells in a sustainable manner are the two most important factors that determine the efficiency of a smart targeted drug-delivery system. In this work, 2-hydroxyethyl methacrylate and a coumarin-based methacrylate monomer containing β-thiopropionate moiety were copolymerized via reversible addition-fragmentation chain transfer (RAFT) process, followed by characterization using NMR and GPC. The said copolymer self-assembled at physiological pH to form vesicular nano-aggregates which was confirmed using DLS, TEM and by fluorescence measurements. These vesicles were further stabilized by photochemical crosslinking via coumarin (2π + 2π) cycloaddition reaction. These cross-linked vesicles (CVs) exhibited a 38% reduction in premature drug leakage as compared to the uncross-linked vesicles (UCVs) at physiological pH. Additionally, a slow hydrolysis of the β-thiopropionate moieties under mildly acidic conditions prevalent in tumor cells resulted in disassembly of the vesicles, thereby releasing the loaded drug in a sustainable manner. Studies related to in vitro toxicity, efficiency of cellular uptake and pH-responsive antineoplastic activity of doxorubicin (DOX) loaded in the cross-linked vesicles (CVs) toward cancer cell lines were undertaken. A significant reduction in IC50 was noticed for DOX-loaded CVs in comparison to free DOX toward MG63 cancer cell lines, making these vesicles as potent nanocarrier systems for cancer therapy.