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 hMATE1high 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 hMATE1low 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.