Novel Nanococktail of a Dual PI3K/mTOR Inhibitor and Cabazitaxel for Castration-Resistant Prostate Cancer
文献类型： 外文期刊
作者： Huang, Yee 1 ; Xue, Xiangdong 2 ; Li, Xiaocen 2 ; Jia, Bei 2 ; Pan, Chong-Xian 3 ; Li, Yuanpei 2 ; Lin, Tzu-Yin 3 ;
作者机构： 1.Zhejiang Acad Agr Sci, Inst Anim Husb & Vet Sci, Hangzhou 310021, Zhejiang, Peoples R China
2.Univ Calif Davis, Dept Biochem & Mol Med, 2700 Stockton Blvd, Sacramento, CA 95817 USA
3.Univ Calif Davis, Sch Med, Dept Internal Med, 2700 Stockton Blvd, Sacramento, CA 95817 USA
4.VA Northern Calif Hlth Care Syst, Dept Med, Mather, CA 95655 USA
关键词： disulfide cross-linked micelles; gedatolisib; PI3K pathways; synergistic antitumor effects
期刊名称：ADVANCED THERAPEUTICS （ 影响因子：5.003； 五年影响因子：5.445 ）
ISSN：
年卷期： 2020 年 3 卷 10 期
页码：
收录情况： SCI
摘要： Prognosis for castration-resistant prostate cancer (CRPC) is poor, and no effective therapeutic regimen is yet known. The PI3K/Akt/mTOR pathway plays a predominant role and may be a promising molecular target for CRPC. However, the toxicity of the dual PI3K inhibitors in clinical trials limits their clinical efficacy for CRPC. To solve this problem, a highly integrated precision nanomedicine strategy is employed to molecularly and physically target CRPC through enhanced targeted drug delivery efficiency and reduced unwanted side-effects. Gedatolisib (Ge), a potent inhibitor of PI3K/mTOR, is formulated into disulfide cross-linked micelle platform (NanoGe), which exhibits excellent water solubility, small size, excellent stability with redox stimulus-responsive disintegration, and preferential uptake at tumor sites. NanoGe improves the anti-neoplastic effect of free Ge by 53 times in PC-3M cells and 13 times in C4-2B cells, through its enhanced uptake via caveolae- and clathrin-mediated endocytic pathways and the subsequent inhibition of the PI3K/mTOR pathway, resulting in Bax/BcI-2-dependent apoptosis. In vivo, NanoGe shows superior efficacy than free Ge, and synergizes with nanoformulated cabazitaxel (NanoCa) as a nanococktail format to achieve a cure rate of 83%. Taken together, the results of this study demonstrate the potency of NanoGe in combination with NanoCa against CRPC.
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