Pt(IV) Prodrugs Bearing Sunitinib-Derived Ligands Display Exceptional Anticancer Activity against Renal Cell Carcinoma When Compared to Conventional Platinum Chemotherapy

The use of anticancer platinum chemotherapeutics is associated
with severe disadvantages, including cytotoxicity to healthy cells.
Sunitinib is an FDA-approved tyrosine kinase inhibitor that selectively
targets renal cell carcinoma due to the overexpression of its receptors,
such as vascular endothelial growth factor receptor (VEGFR) and platelet-derived
growth factor receptor (PDGFR). Here, three Pt(IV) prodrugs, based
on cisplatin, oxaliplatin, and carboplatin, bearing sunitinib-derived
axial ligands have been developed to overcome healthy cell toxicity.
This study highlights the first Pt(IV) complexes targeting renal carcinoma
tumors overexpressing VEGFR. In vitro cytotoxicity
and 3D spheroid assays demonstrated the superior activity of the cisplatin-based
prodrug over conventional cisplatin chemotherapy. The cisplatin-based
prodrug was tested in vivo against renal carcinoma
xenografts, revealing high efficacy superior to the cisplatin control.
These Pt(IV)–sunitinib conjugates have excellent potential
for the treatment of renal cell carcinoma, as they display significantly
enhanced tumor reduction and lower systemic toxicity when compared
to cisplatin chemotherapy.

铂类抗癌化疗药物的临床应用存在诸多严重弊端，其中包括对健康细胞产生细胞毒性。舒尼替尼（sunitinib）是经美国食品药品监督管理局（FDA）批准的酪氨酸激酶抑制剂，可通过靶向肾细胞癌表面过表达的受体（如血管内皮生长因子受体（VEGFR）与血小板衍生生长因子受体（PDGFR））实现选择性抗肿瘤作用。本研究设计并合成了三种分别基于顺铂（cisplatin）、奥沙利铂（oxaliplatin）与卡铂（carboplatin）的四价铂（Pt(IV)）前药，其轴向配体源自舒尼替尼，旨在克服铂类化疗药物对健康细胞的毒性问题。本研究首次报道了靶向VEGFR过表达肾细胞癌的四价铂配合物。体外细胞毒性实验与三维球体培养实验结果显示，该顺铂基前药的活性优于传统顺铂化疗方案。进一步针对肾细胞癌异种移植瘤的体内实验表明，该顺铂基前药的疗效优于顺铂对照组。与传统顺铂化疗相比，这类四价铂-舒尼替尼共轭物可显著增强肿瘤缩小效果并降低全身毒性，在肾细胞癌治疗中具有极佳的应用潜力。