Short-Chain and Long-Chain Fatty Acid-Containing Platinum-Acridine Anticancer Prodrugs: Exploiting Alternative...

Area of Science:

• Medicinal Chemistry
• Cancer Therapeutics
• Drug Delivery

Background:

• Platinum-acridine hybrid agents (PAs) are potent DNA-targeting anticancer compounds but face clinical limitations due to systemic toxicity.
• Cisplatin is a widely used platinum-based chemotherapy agent, but PAs offer superior potency.
• Developing strategies to control PA activation and delivery is crucial for improving their therapeutic index.

Purpose of the Study:

• To develop platinum(IV) prodrugs of PAs for controlled reductive activation in tumor tissues.
• To investigate the differential efficacy of short-chain fatty acid (SCFA) and long-chain fatty acid (LCFA) modified PA prodrugs.
• To explore the role of human multidrug and toxin extrusion protein 1 (hMATE1) and human serum albumin (HSA) in PA prodrug delivery and efficacy.

Main Methods:

• Synthesis of platinum(IV) prodrugs of platinum-acridine hybrid agents (PAs) with SCFA and LCFA modifications.
• In vitro cytotoxicity assays in cancer cell lines with varying expression levels of hMATE1 (NCI-H460, HepG2, HCT116).
• Evaluation of transporter-dependent uptake (hMATE1) and albumin-mediated delivery (HSA) for different PA prodrug derivatives.

Main Results:

• SCFA-modified PA prodrugs exhibited nanomolar cytotoxicity in hMATE1-expressing cancer cells, indicating efficient transporter-mediated uptake.
• LCFA-modified PA prodrugs showed lower potency in hMATE1-high cells but significantly enhanced activity in hMATE1-low colon cancer cells via HSA targeting.
• The differential activity highlights the distinct cellular entry mechanisms influenced by fatty acid chain length and transporter expression.

Conclusions:

• Fatty acid-modified platinum(IV) prodrugs of PAs offer tunable delivery and activation strategies.
• Targeting hMATE1 and HSA provides distinct routes for PA prodrug delivery, enabling treatment of hMATE1-deficient cancers.
• These prodrug approaches hold promise for improving the therapeutic window and clinical utility of platinum-acridine hybrid agents.