TY - JOUR
T1 - Use of ratiometrically designed nanocarrier targeting CDK4/6 and autophagy pathways for effective pancreatic cancer treatment
AU - Ji, Ying
AU - Liu, Xiangsheng
AU - Li, Juan
AU - Xie, Xiaodong
AU - Huang, Max
AU - Jiang, Jinhong
AU - Liao, Yu Pei
AU - Donahue, Timothy
AU - Meng, Huan
N1 - Funding Information:
This study was supported by the U.S. Public Health Service Grant, 1U01CA198846. This study was partially supported by a research grant, DISC2-08824, funded by California Institute for Regenerative Medicine. We acknowledge use of the IVIS imaging facilities in the Preclinical Imaging Technology Center, the Translational Pathology Core Laboratory for histology H&E and IHC staining, the Electron Imaging Center for Nanomachines for CryoEM, the Molecular Instrumentation Center for UPLC-MS, and the CNSI Advanced Light Microscopy/Spectroscopy Shared Facility for confocal fluorescent microscopy at UCLA.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85089907143&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-17996-7
DO - 10.1038/s41467-020-17996-7
M3 - Journal article
C2 - 32843618
AN - SCOPUS:85089907143
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4249
ER -
