Redox-driven disassembly of polymer–chlorambucil polyprodrug: delivery of anticancer nitrogen mustard and dna alkylation.

Abstract

Utilization of nitrogen mustards as anticancer drugs opened the way for precise cancer chemotherapy owing to their ability to cross-link deoxyribonucleic acid (DNA). However, the non-specificity and lower water solubility limit their aptitude to behave as effective anticancer drugs. Herein we embed the clinically approved nitrogen mustard, chlorambucil (CBL), into a redox-responsive polymeric vector to overcome those bottlenecks as well as to achieve better efficacy. We have synthesized amphiphilic diblock copolymers (BCPs) consisting of polymerized segments of a pendent disulfide-labeled CBL prodrug monomer and hydrophilic 2-(dimethylamino)ethyl methacrylate monomer via reversible addition–fragmentation chain transfer polymerization. The well-defined polyprodrug amphiphiles with CBL loading content >40 wt% could form uniform micelles with an average diameter of 45–110 nm through a macromolecular self-assembly strategy. For the release of caged CBL, disassembly of the self-assembled micelles was attained under reducing conditions, confirmed through dynamic light scattering and field emission scanning electron microscopy. In vitro evaluation of CBL release showed that the percentage of drug release was profoundly enhanced up to >90% in the presence of 5 mM d,l-dithiothreitol. Cytotoxicity studies against a triple-negative breast cancer (MDA-MB-231) cell line revealed that the BCP has much better cytotoxicity than the free CBL. Furthermore, the alkylating activity of BCP was confirmed using a colorimetric indicator, 4-(4-nitrobenzyl)pyridine, and upon agarose gel electrophoresis with pUC19 plasmid DNA. Combining the features of redox-responsive drug release and DNA alkylation, BCPs provide insight into drug delivery and disrupt the thiol-rich environment of cancer cells.