A pH responsive complexation-based drug delivery system for oxaliplatin

Abstract

A responsive drug delivery system (DDS) for oxaliplatin (<b>OX</b>) 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 <b>OX</b> by a pH-responsive receptor, carboxylatopillar[6]arene (<b>CP6A</b>). The binding affinities of <b>CP6A</b> for <b>OX</b> were found to be pH-sensitive at biologically relevant pH. For example, the association constant (<i>K</i>_a) at pH 7.4 [<i>K</i>_a = (1.02 ± 0.05) × 10⁴ M^-1] is 24 times larger than that at pH 5.4 [<i>K</i>_a = (4.21 ± 0.06) × 10² M^-1]. Encapsulation of <b>OX</b> within the <b>CP6A</b> cavity did not affect its <i>in vitro</i> cytotoxicity as inferred from comparison studies carried out in several cancer cells (<i>e.g.</i>, the HepG-2, MCF-7, and A549 cell lines). On the other hand, complexation by <b>CP6A</b> serves to increase the inherent stability of <b>OX</b> in plasma by 2.8-fold over a 24 h incubation period. The formation of a <b>CP6A</b>⊃<b>OX</b> host-guest complex served to enhance in a statistically significant way the ability of <b>OX</b> to inhibit the regrowth of sarcoma 180 (S180) tumors in Kunming (KM) mice xenografts. The improved anticancer activity observed <i>in vivo</i> for <b>CP6A</b>⊃<b>OX</b> is attributed to the combined effects of enhanced stability of the host-guest complex and the pH-responsive release of <b>OX</b>. Specifically, it is proposed that <b>OX</b> is protected as the result of complex formation and then released effectively in the acidic tumor environment.