Stromal Homeostasis-Restoring Nanomedicine Enhances Pancreatic Cancer Chemotherapy
作者:
Yu, N (Yu, Na) [1] , [2] , [3] ;
Zhang, X (Zhang, Xi) [3] ;
Zhong, HP (Zhong, Haiping) [3] ;
Mu, JQ (Mu, Jingqing) [3] ;
Li, XW (Li, Xingwei) [3] ;
Liu, T (Liu, Tao) [3] ;
Shi, XG (Shi, Xiaoguang) [3] ;
Liang, XJ (Liang, Xing-Jie) [1] , [2] , [4] , [5] ;
Guo, ST (Guo, Shutao) [3]
NANO LETTERS, 2022
DOI
10.1021/acs.nanolett.2c03663
摘要
The desmoplastic stroma imposes a fatal physical delivery barrier in pancreatic ductal adenocarcinoma (PDAC) therapy. Decon-structing the stroma components hence predominates in stroma-targeting approaches, but conflicting outcomes have sometimes occurred due to the multifaceted nature of the stroma. Here, we constructed two sub-20-nm nanomedicines based on a so-called "next-wave" antifibrotic halofuginone (HF) and the tumoricidal paclitaxel (PTX) for enhanced PDAC chemotherapy. This was achieved by coassembling methoxy poly-(ethylene glycol)-b-poly(caprolactone) with ketal-linked HF-and PTX-derived prodrugs. HF nanomedicine and PTX nanomedicine had excellent prodrug-nanocarrier compatibility and exhibited greatly improved pharmacokinetic profiles and high tumor accumulation. HF nanomedicine pretreatment restored stromal homeostasis and consid-erably facilitated the distribution of PTX nanomedicine and its penetration into carcinoma cells, leading to positive modulation of the infiltration of cytotoxic T cells and significant regression of tumor growth in two PDAC models. Our nanomedicine-based stromal remodeling strategy appears promising for treating desmoplastic malignancies.