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

Author

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  • Ying Ji

    (University of California
    University of California
    The Hong Kong Polytechnic University, Hunghom, Kowloon)

  • Xiangsheng Liu

    (University of California
    University of California)

  • Juan Li

    (University of California
    Chinese Academy of Science)

  • 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
    David Geffen School of Medicine at UCLA)

  • Huan Meng

    (University of California
    University of California)

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.

Suggested Citation

  • Ying Ji & Xiangsheng Liu & Juan Li & Xiaodong Xie & Max Huang & Jinhong Jiang & Yu-Pei Liao & Timothy Donahue & Huan Meng, 2020. "Use of ratiometrically designed nanocarrier targeting CDK4/6 and autophagy pathways for effective pancreatic cancer treatment," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17996-7
    DOI: 10.1038/s41467-020-17996-7
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