Supramolecular combination chemotherapy: a pH-responsive co-encapsulation drug delivery system

Abstract

Most cancer chemotherapy regimens rely on the use of two or more chemotherapeutic agents. However, achieving the best possible dosing of the individual drugs can be challenging due to differences in metabolism, uptake, and clearance among other factors. Here we describe a supramolecular strategy for achieving drug delivery in which the loading ratio of two active components is easily defined. Specifically, we report the formation of aggregates comprised of self-assembled amphiphiles between carboxylatopillar[6]arene (CP6A) and an oxaliplatin (OX)-type Pt(IV) prodrug (PtC₁₀). The association constant (K_a) for the underlying host–guest interaction at pH 7.4 ((1.16 ± 0.03) × 10⁴ M⁻¹) is an order of magnitude higher than at pH 5.0 ((1.73 ± 0.15) × 10³ M⁻¹). A second chemotherapeutic, doxorubicin (DOX), may be encapsulated in the resulting vesicles (PtC₁₀⊂CP6A) to give a supramolecular combination chemotherapeutic system DOX@PtC₁₀⊂CP6A. Drug release studies served to confirm that PtC₁₀ and DOX are released in acidic environments. Support for a synergistic antiproliferative effect relative to PtC₁₀ + DOX came from cellular studies of DOX@PtC₁₀⊂CP6A using the human liver hepatocellular carcinoma (HepG-2) cell line. In vivo studies revealed that DOX@PtC₁₀⊂CP6A is not only able to retard tumor growth efficiently but also reduce drug-related toxic side effects in BALB/c nude mice bearing HepG-2 subcutaneous tumor xenografts. These favorable findings are attributed to the formation of a ternary complex that benefits from an enhanced permeability and retention (EPR) effect in vivo while allowing for the pH-based release of PtC₁₀ and DOX at the tumor site.