Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Sector 67, Mohali 160062, Punjab, India.
Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Vidya Vihar, Pilani 333031, Rajasthan, India.
ACS Biomater Sci Eng. 2022 Jun 13;8(6):2349-2362. doi: 10.1021/acsbiomaterials.1c01582. Epub 2022 May 6.
Triple-negative breast cancer (TNBC) cells show improved sensitivity for cisplatin therapy due to their defective DNA damage repair system. However, the clinical utilization of cisplatin is limited by dose-dependent systemic toxicities and chemoresistance. Cisplatin Pt(IV) derivatives having kinetically inert octahedral geometry provide an effective strategy to overcome these limitations. Upon cellular reduction, these derivatives release cisplatin and axial ligands, acting as dual-action prodrugs. Hereby, we have developed three cisplatin(IV) conjugates using distinct bioactive axial moieties (valproate, tocopherol, and chlorambucil), which can synergistically complement cisplatin activity and attack multiple cellular targets. The designed derivatives showcased enhanced antiproliferative activity and improved therapeutic synergism along with a noteworthy cisplatin dose reduction index in a panel of six cancer cells. These Pt(IV) derivatives remarkably improved cellular drug uptake and showed lower dependency on copper transporter 1 (Ctr1) for uptake than cisplatin. The results of enhanced in vitro activity were well corroborated by in vivo efficacy testing in the 4T1 cell-based TNBC model, showcasing ∼2-7-folds higher tumor volume reduction for Pt(IV) derivatives than cisplatin. In addition, the designed derivatives significantly reduced the nephrotoxicity risk involved in cisplatin therapy, indicated by systemic toxicity biomarkers and organ histopathology. The results indicated that cisplatin(IV) derivatives could open new avenues for safer synergistic chemotherapy in TNBC.
三阴性乳腺癌（TNBC）细胞由于其 DNA 损伤修复系统缺陷，对顺铂治疗表现出更高的敏感性。然而，顺铂的临床应用受到剂量依赖性全身毒性和化疗耐药性的限制。具有动力学惰性八面体几何形状的顺铂 Pt(IV)衍生物为克服这些限制提供了一种有效的策略。在细胞还原后，这些衍生物释放顺铂和轴向配体，作为双重作用前药发挥作用。在此，我们使用不同的生物活性轴向基团（丙戊酸、生育酚和苯丁酸氮芥）开发了三种顺铂（IV）缀合物，它们可以协同补充顺铂的活性并攻击多个细胞靶标。设计的衍生物在一组六种癌细胞中表现出增强的增殖抑制活性和改善的治疗协同作用，以及显著降低的顺铂剂量减少指数。这些 Pt(IV)衍生物显著增加了细胞内药物摄取，并且与顺铂相比，对铜转运蛋白 1（Ctr1）的摄取依赖性更低。体外活性增强的结果在基于 4T1 细胞的 TNBC 模型中的体内疗效测试中得到了很好的证实，与顺铂相比，Pt(IV)衍生物使肿瘤体积减少了约 2-7 倍。此外，这些设计的衍生物显著降低了顺铂治疗相关的肾毒性风险，这可通过系统毒性生物标志物和器官组织病理学来指示。结果表明，顺铂（IV）衍生物可能为 TNBC 的更安全协同化疗开辟新途径。
