Development and Mechanistic Investigation of Nucleus-targeting Platinum(IV) Prodrugs for Improved Anticancer Activity
DescriptionThe issues of toxicity and drug resistance associated with platinum-based antineoplasticagents such as cisplatin and oxaliplatin have encouraged researchers to seek novelmetal-based complexes, and platinum(IV) anticancer prodrugs have shown greatpromise in chemotherapeutic applications. Although platinum drugs are DNA-damagingagents, only a small fraction of the drug finally reaches the nuclear area to damageDNA. A new generation of platinum(IV) complexes with a targeting property andimproved anticancer activity would be highly desirable. On the other hand, althoughoxaliplatin’s mechanism of action has been studied, the details have not been fullyrevealed, which limits the further development of oxaliplatin-based platinum complexes.The proposed study will contribute to these research directions based on our uniquedesign and approaches. We plan to obtain nucleus-targeting platinum(IV) anticancerprodrugs that can be controllably activated after they reach the desired target. Severalprodrugs will be designed, synthesized, and characterized. Their stability and activationproperties will be studied, and their nuclear accumulation properties will be evaluated.The cytotoxicity of the complexes against various human cancer cells, includingplatinum-resistant cells, will be tested. We will also conduct a detailed study on themechanism of the nucleus-targeting platinum(IV) prodrugs. The proposed study willgrant nucleus-targeting properties to platinum-based anticancer agents in an attemptto shift their subcellular distribution, with the promise that the new complexes will bearincreased antitumor activity and reduced systematic toxicity, and it may also shed lighton the detailed mechanism of oxaliplatin and oxaliplatin(IV) prodrugs. This informationwill guide the rational design and synthesis of the next generation of platinum-basedprodrugs.
|Effective start/end date||1/08/19 → …|