Sharma Arpit, Al Amin Md, Kshetri Man B, Alqarni Suha, Jogadi Wjdan, Solmen Jordan, Lin Zexin, Akter Shirin, Zheng Yao-Rong
Department of Chemistry and Biochemistry, Kent State University, 236 Integrated Sciences Building, Kent, OH 44242, USA.
Department of Chemistry, University of Bisha, Bisha 67714, Saudi Arabia.
Pharmaceutics. 2025 Mar 29;17(4):440. doi: 10.3390/pharmaceutics17040440.
The utilization of amphiphilic Pt(IV) complexes as prodrugs offers a promising strategy to revolutionize Pt-based cancer therapy by enhancing drug delivery and activation. While PEGylation is widely used to optimize drug properties, its impact on the biological behavior of amphiphilic Pt(IV) complexes remains unclear. This study systematically investigates how the PEGylation of varying molecular weights influences their cytotoxicity, cellular uptake, and activation. Pt(IV) complexes were synthesized with PEG chains of different molecular weights using HATU-catalyzed amide bond formation and copper-free click chemistry. Their biological properties were assessed through cell-based analyses, focusing on cytotoxicity, cellular uptake, and activation by biological reductants. Small PEG modifications retained the potent cytotoxicity of amphiphilic Pt(IV) prodrugs, whereas large PEG chains significantly reduced efficacy. The decrease in potency was linked to impaired cellular uptake and mitochondrial accumulation. Additionally, large PEG modifications slowed the reduction and activation of Pt(IV) prodrugs by biological reductants, further limiting their anticancer activities. These findings underscore the critical role of PEGylation in metallodrug design and provide key insights into optimizing PEGylation strategies for enhancing platinum-based cancer therapies.
利用两亲性铂（IV）配合物作为前药，为通过增强药物递送和激活来彻底改变基于铂的癌症治疗提供了一种有前景的策略。虽然聚乙二醇化被广泛用于优化药物性质，但其对两亲性铂（IV）配合物生物学行为的影响仍不清楚。本研究系统地研究了不同分子量的聚乙二醇化如何影响其细胞毒性、细胞摄取和激活。使用HATU催化的酰胺键形成和无铜点击化学合成了具有不同分子量聚乙二醇链的铂（IV）配合物。通过基于细胞的分析评估其生物学性质，重点关注细胞毒性、细胞摄取以及生物还原剂的激活作用。小的聚乙二醇修饰保留了两亲性铂（IV）前药的强大细胞毒性，而大的聚乙二醇链显著降低了疗效。效力的降低与细胞摄取受损和线粒体积累有关。此外，大的聚乙二醇修饰减缓了生物还原剂对铂（IV）前药的还原和激活，进一步限制了它们的抗癌活性。这些发现强调了聚乙二醇化在金属药物设计中的关键作用，并为优化聚乙二醇化策略以增强基于铂的癌症治疗提供了关键见解。
