Short-Chain and Long-Chain Fatty Acid-Containing Platinum–Acridine Anticancer Prodrugs: Exploiting Alternative Mechanisms of Cellular Internalization

Platinum-acridine hybrid agents (PAs) represent a mechanistically unique class of DNA-targeted anticancer compounds with superior potency compared to cisplatin, but systemic toxicity has limited their clinical utility. To address this, we have developed platinum(IV) prodrugs of PAs for controlled reductive activation in tumor tissues. Short-chain fatty acid (SCFA) containing derivatives demonstrated nanomolar cytotoxicity in cancer cells expressing human multidrug and toxin extrusion protein 1 (hMATE1), consistent with rapid transporter-dependent uptake. Long-chain fatty acid (LCFA)-modified derivatives were less potent than the SCFA-based prodrugs in hMATE1^high NCI-H460 (lung) and HepG2 (liver) cancer cells. Conversely, the LCFA derivatives, which target human serum albumin (HSA) and utilize the blood protein for cellular entry, showed an order of magnitude higher activity than the SCFA derivatives in hMATE1^low HCT116 colon cancer cells. Together, these prodrug strategies hold promise of extending treatment with PAs to hMATE1-deficient cancers and improving the therapeutic window of the hybrid agents.