Enhanced Antitumor Efficacy and Reduced Myelosuppression by a Supramolecular Complex Composed of Azocalix[4]arene and Sunitinib

Antiangiogenic therapy, which inhibits tumor growth by blocking oxygen and nutrition supply, represents a promising strategy for antineoplastic therapy. However, the widespread biodistribution of antiangiogenic agents often leads to off-target toxicities, including hematotoxicity and myelosuppression. In this study, we demonstrated that the sunitinib@mannose-modified azocalix[4]arene (ST@ManAC4A) complex exhibited favorable tumor-targeting capabilities, hypoxia-responsive drug release, and effective accumulation at the tumor site, thus enhancing antiproliferative efficacy while alleviating thrombocytopenia and myelosuppression. The complex exhibited robust antitumor activity in both cellular and in vivo assays. Additionally, histopathological, immunohistochemical, and bone marrow analyses demonstrated that ST@ManAC4A enhanced antiproliferation, apoptosis, and antiangiogenesis while alleviating thrombocytopenia and platelet-related myelosuppression. These findings underscore the potential of the mannose-modified supramolecular host–guest complex as a versatile form for improving chemotherapy outcomes. By enabling efficient drug loading and precision targeting, this approach offers a promising strategy to enhance therapeutic efficacy while minimizing off-target toxicities, addressing a critical challenge in cancer treatment.