A pH responsive complexation-based drug delivery system for oxaliplatin† †Electronic supplementary information (ESI) available: General experimental details, variable-temperature 1H NMR spectra, mole ratio plot, ITC titration curves, and in vitro cytotoxicity assay. See DOI: 10.1039/c7sc01438d Click here for additional data file.

A responsive drug delivery system (DDS) for oxaliplatin (OX) has been designed with a view to overcoming several drawbacks associated with this anticancer agent, including fast degradation/deactivation in the blood stream, lack of tumor selectivity, and low bioavailability. The present approach is based on the direct host–guest encapsulation of OX by a pH-responsive receptor, carboxylatopillar[6]arene (CP6A). The binding affinities of CP6A for OX were found to be pH-sensitive at biologically relevant pH. For example, the association constant (Ka) at pH 7.4 [Ka 1⁄4 (1.02 0.05) 10 M ] is 24 times larger than that at pH 5.4 [Ka 1⁄4 (4.21 0.06) 10 M ]. Encapsulation of OX within the CP6A cavity did not affect its in vitro cytotoxicity as inferred from comparison studies carried out in several cancer cells (e.g., the HepG-2, MCF-7, and A549 cell lines). On the other hand, complexation by CP6A serves to increase the inherent stability of OX in plasma by 2.8-fold over a 24 h incubation period. The formation of a CP6AIOX host– guest complex served to enhance in a statistically significant way the ability of OX to inhibit the regrowth of sarcoma 180 (S180) tumors in Kunming (KM) mice xenografts. The improved anticancer activity observed in vivo for CP6AIOX is attributed to the combined effects of enhanced stability of the host– guest complex and the pH-responsive release of OX. Specifically, it is proposed that OX is protected as the result of complex formation and then released effectively in the acidic tumor environment.