Center for Bionanoengineering and the State Key Laboratory of Chemical Engineering, Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.
Mol Pharm. 2012 Oct 1;9(10):2793-800. doi: 10.1021/mp200597r. Epub 2012 Sep 20.
Platinum(IV) prodrug diaminedichlorodihydroxyplatinum (ACHP) conjugated with a histone deacetylase (HDAC) inhibitor valproic acid (VA), VAAP, exhibited strong synergistic cytotoxicity, about 50-100 times more cytotoxic than ACHP or its simple mixture with VA, against various human carcinoma cell lines. VAAP could be quickly absorbed in the cell membrane and diffused into the cytosol. VAAP loaded in polyethylene glycol-polycaprolactone micelles (PEG-PCL) was taken up via endocytosis. The cytosolic VAAP was intracellular reduced to Pt(II) and released VA eliciting a HDAC inhibitory effect and subsequently induced cell cycle arrest at the S phase in 24 h and cell apoptosis in a time-dependent manner. The in vivo antitumor experiment on A549-xenograft tumor model showed that VAAP dispersed in Tween 80 or loaded in PEG-PCL nanoparticles had long blood circulation times and thereby high accumulation in tumors and exerted a significant in vivo inhibitory effect on tumor growth with low systemic toxicity. Therefore, this novel conjugate is very promising for cancer chemotherapy.
铂（IV）前药二胺二氯二羟铂（ACHP）与组蛋白去乙酰化酶（HDAC）抑制剂丙戊酸（VA）偶联形成的 VAAP，对各种人癌细胞系表现出强烈的协同细胞毒性，约比 ACHP 或其与 VA 的简单混合物高 50-100 倍。VAAP 可以快速被细胞膜吸收并扩散到细胞质中。负载在聚乙二醇-聚己内酯胶束（PEG-PCL）中的 VAAP 通过内吞作用被摄取。细胞质中的 VAAP 被细胞内还原为 Pt（II）并释放 VA，引发 HDAC 抑制作用，随后以时间依赖性方式诱导细胞周期停滞在 S 期并发生细胞凋亡。在 A549 异种移植肿瘤模型中的体内抗肿瘤实验表明，分散在 Tween 80 中的 VAAP 或负载在 PEG-PCL 纳米粒子中的 VAAP 具有较长的血液循环时间，从而在肿瘤中有高积累，并表现出对肿瘤生长的显著体内抑制作用，同时具有低系统毒性。因此，这种新型缀合物在癌症化疗中具有很大的应用前景。
