Use of ratiometrically designed nanocarrier targeting CDK4/6 and autophagy pathways for effective pancreatic cancer treatment

Ying Ji, Xiangsheng Liu, Juan Li, Xiaodong Xie, Max Huang, Jinhong Jiang, Yu-Pei Liao, Timothy Donahue and Huan Meng ()
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Ying Ji: University of California
Xiangsheng Liu: University of California
Juan Li: University of California
Xiaodong Xie: University of California
Max Huang: University of California
Jinhong Jiang: University of California
Yu-Pei Liao: University of California
Timothy Donahue: University of California
Huan Meng: University of California

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Aberrant cell cycle machinery and loss of the CDKN2A tumor suppressor locus make CDK4/6 a potential target in pancreatic ductal adenocarcinoma (PDAC). However, a vast majority of PDAC cases do not harbor a durable response to monotherapy of CDK4/6 inhibitor. Utilizing remote loading to co-encapsulate CDK4/6 inhibitor palbociclib (PAL) and an autophagy inhibitor hydroxychloroquine (HCQ), we demonstrate a ratiometrically designed mesoporous silica nanoformulation with synergistic efficacy in subcutaneous and orthotopic PDAC mouse models. The synergism is attributed to the effective intratumoral buildup of PAL/HCQ, which otherwise exhibit distinctly different circulatory and biodistribution profile. PAL/HCQ co-delivery nanoparticles lead to the most effective shrinkage of PDAC compared to various controls, including free drug mixture. Immunohistochemistry reveals that PAL/HCQ co-delivery nanoparticles trigger anti-apoptotic pathway after repetitive intravenous administrations in mice. When combined with a Bcl inhibitor, the performance of co-delivery nanoparticles is further improved, leading to a long-lasting anti-PDAC effect in vivo.

Date: 2020
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DOI: 10.1038/s41467-020-17996-7

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