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Novel Nanococktail of a Dual PI3K/mTOR Inhibitor and Cabazitaxel for Castration‐Resistant Prostate Cancer
Author(s) -
Huang Yee,
Xue Xiangdong,
Li Xiaocen,
Jia Bei,
Pan ChongXian,
Li Yuanpei,
Lin TzuYin
Publication year - 2020
Publication title -
advanced therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
0ISSN - 2366-3987
DOI - 10.1002/adtp.202000075
Subject(s) - pi3k/akt/mtor pathway , prostate cancer , cabazitaxel , cancer research , chemistry , pharmacology , protein kinase b , endocytic cycle , taxane , medicine , apoptosis , cancer , androgen deprivation therapy , endocytosis , receptor , breast cancer , biochemistry
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/Bcl‐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.