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

Ying Ji,Huan Meng,Xiangsheng Liu,Timothy Donahue,Jinhong Jiang,Max Huang,Yu-Pei Liao,Juan Li,Xiaodong Xie

doi:10.1038/s41467-020-17996-7

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.

Highlights

Aberrant cell cycle machinery and loss of the CDKN2A tumor suppressor locus make CDK4/6 a potential target in pancreatic ductal adenocarcinoma (PDAC)
In this study, we demonstrate the use of nano-enabled approach for implementing CDK4/6 inhibitor (CDK4/6i) combination therapy in PDAC
CDK4/6i have been tested for treating a list of solid tumor types, with particular success for certain breast cancer

Summary

Introduction

Aberrant cell cycle machinery and loss of the CDKN2A tumor suppressor locus make CDK4/6 a potential target in pancreatic ductal adenocarcinoma (PDAC). It has become popular to consider CDK4/6i combination therapy by introducing a second drug that impacts certain oncogenic pathway, such as mammalian target of rapamycin (mTOR) inhibitors[11,12], autophagy inhibitors[13], mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors[14], immunotherapeutics (anti-programmed cell death ligand 1)[15], transforming growth factor-β (TGF-β) inhibitors[16], and certain chemo-reagents[17]. These preclinical achievements serve as the basis of clinical trials in which

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