Supramolecular Engineering of Molecular Inhibitors in an Adaptive Cytotoxic Nanoparticle for Synergistic Cancer Therapy

Combinatorial regimens that rationally pair molecular inhibitors with standard cytotoxic chemotherapeutics are used to improve therapeutic outcomes. Simultaneously engineering these therapies within a single nanocarrier that spans cytotoxic, antiangiogenic, and anti-invasive mechanisms and that enables the delivery of unique drug combinations remains a technical challenge. In this study, we developed a simple and broadly applicable strategy in which ultrastable cytotoxic nanoparticles with an established excellent antitumor efficacy and pi-rich inner core structure supramolecularly stabilized the antiangiogenic molecular inhibitor apatinib to create a synergistic drug delivery system (termed sTKI-pSN38). This small-sized nanoparticle accomplished the sequential release of both encapsulated drugs to exert antimetastatic, antivascular, and cytotoxic activities simultaneously. In xenograft models of hepatocellular carcinoma, a single intravenous administration of sTKI-pSN38 elicited robust and durable tumor reduction and suppressed metastasis to lymph nodes. Interestingly, sTKI-pSN38 treatment alleviated intratumoral hypoxia, which could contribute to impaired tumor metastasis and reduced drug resistance. Collectively, this nanotherapeutic platform offers a new strategy for cancer therapy by simply engineering a drug cocktail in conventional nanoparticles and by enabling the spatiotemporal modulation of drug release to enhance the synergy of the combined drugs.