A Platinum(IV) Anticancer Prodrug Targeting Nucleotide Excision Repair To Overcome Cisplatin Resistance

Abstract

DNA damage response plays a key role not only in maintaining genome integrity but also in mediating the antitumor efficacy of DNA‐damaging antineoplastic drugs. Herein, we report the rational design and evaluation of a PtIV anticancer prodrug inhibiting nucleotide excision repair (NER), one of the most pivotal processes after the formation of cisplatin‐induced DNA damage that deactivates the drug and leads to drug resistance in the clinic. This dual‐action prodrug enters cells efficiently and causes DNA damage while simultaneously inhibiting NER to promote apoptotic response. The prodrug is strongly active against the proliferation of cisplatin‐resistant human cancer cells with an up to 88‐fold increase in growth inhibition compared with cisplatin, and the prodrug is much more active than a mixture of cisplatin and an NER inhibitor. Our study highlights the importance of targeting downstream pathways after the formation of Pt‐induced DNA damage as a novel strategy to conquer cisplatin resistance.

Tailoring Platinum(IV) Amphiphiles for Self-Targeting All-in-One Assemblies as Precise Multimodal Theranostic Nanomedicine

“…The three key elements in a theranostic nanoparticle-based drug delivery system include the drug, − targeting ligand, − and imaging agent. − Current approaches typically integrate these components in a stepwise manner into various organic or inorganic drug carriers. − Although there are numerous ways of introducing these three key elements to a certain carrier system, there are still concerns about uncontrollable composition, , inevitable toxicity of carrier materials, batch-to-batch variation of drug content, incomplete monitoring of drug metabolism/pharmacokinetics, etc ., which is far from satisfactory for precise therapeutics. These drawbacks limit the clinical use of the currently developed nanomedicine.…”