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.
Highlights
Clinical management of malignant tumors typically relies on the use of more than one chemotherapeutic agent
The zeta potential of PtC103CP6A was determined to be À30.6 mV (Fig. S13†), leading us to suggest that electrostatic repulsion could facilitate the stabilization of supramolecular vesicles when CP6A is combined with PtC10 at pH 1⁄4 7.4
We propose that the supramolecular drug delivery systems (DDSs) combination chemotherapy strategy embodied in DOX@PtC103CP6A can be used decrease the undesirable side effects of OX and DOX while maintaining good antitumor efficacy
Summary
Clinical management of malignant tumors typically relies on the use of more than one chemotherapeutic agent. Support for a synergistic antiproliferative effect relative to PtC10 + DOX came from cellular studies of DOX@PtC103CP6A using the human liver hepatocellular carcinoma (HepG-2) cell line. The resulting supramolecular combination chemotherapy system (DOX@PtC103CP6A) was found to target tumor tissues passively through an enhanced permeability and retention (EPR) effect.
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