A Bioavailability-Enhanced Nobiletin Formulation Potentiates the Antitumor Efficacy of DM1 and a DM1-Based Antibody–Drug Conjugate

Background: Antibody–drug conjugates (ADCs) have emerged as an important class of targeted anticancer therapeutics; however, their efficacy can be limited by intrinsic or acquired resistance to their cytotoxic payloads. Pharmacological potentiation of payload activity may therefore provide a complementary strategy for improving ADC efficacy. Nobiletin, a polymethoxyflavone derived from citrus peel, has been reported to enhance the cytotoxic effects of microtubule-targeting agents, but its poor aqueous solubility and low bioavailability restrict its in vivo application. Objective: In this study, we investigated whether nobiletin and its bioavailability-enhanced formulation, Nob-MeHes ASD, an amorphous solid dispersion of nobiletin and methyl hesperidin, could potentiate the activity of the microtubule inhibitor DM1 and a DM1-containing ADC. Methods: The effects of nobiletin and Nob-MeHes ASD on DM1- and αEpCAM-DM1-induced cytotoxicity were evaluated using cell viability assays, cell cycle analysis, and mouse xenograft models. Findings: Nobiletin enhanced DM1-induced cytotoxicity in DLD1 colorectal cancer and BxPC-3 pancreatic cancer cells and increased the proportions of cells in the G2/M and Sub-G1 populations. Nob-MeHes ASD retained this potentiating activity in vitro and, when combined with DM1, significantly suppressed tumor growth in a BxPC-3 xenograft model. Nobiletin also enhanced the cytotoxic activity of αEpCAM-DM1, an EpCAM-targeting DM1-conjugated ADC, in EpCAM-positive cancer cells, although potentiation was also observed in HUVEC. In contrast, neither αEpCAM-DM1 alone nor its combination with nobiletin showed appreciable cytotoxicity in EpCAM-knockout DLD1 cells. Furthermore, Nob-MeHes ASD potentiated αEpCAM-DM1 activity in vitro and enhanced tumor growth suppression in a DLD1 xenograft model. Although changes in serum biochemical parameters were observed, further studies are required to establish the safety of the combination. Conclusions: These findings provide proof of concept that a bioavailability-enhanced phytochemical may serve as a pharmacological potentiator of DM1-containing ADC therapy, supporting further investigation of this combination strategy.