Synthetic copolymer conjugates of docetaxel and in vitro assessment of anticancer efficacy

Abstract

Docetaxel (DTX) is a widely used chemotherapy drug that is associated with numerous side effects and limited bioavailability. Macromolecular conjugates of DTX may improve drug targeting, solubility, reduce off-target toxicity, and overcome mechanisms of multidrug resistance. However, most polymer conjugates of DTX investigated to date make use of biopolymers, which are of fixed structure and are not well suited to optimisation and subsequent reaction to introduce further functionality. Here, we show the preparation of synthetic copolymer conjugates of DTX with drug loading of up to 20% w/w that also has potential for tuning backbone hydrophilicity and the number of reactive sites for conjugation. The intermediates produced are comprehensively characterised, as are the macromolecular conjugates, which are tested in the MCF-7 human breast adenocarcinoma cell line to assess toxicity and anticancer efficacy. The conjugates produced have IC₅₀ values within one order of magnitude of DTX, as expected for slow release of DTX by ester hydrolysis. The results suggest that the system is promising for delivery of DTX and future work may examine conjugates of a wider molecular weight range, optimisation of DTX and PEG conjugation efficiency, and in vivo biodistribution.