A pH-responsive nanoparticle delivery system containing dihydralazine and doxorubicin-based prodrug for enhancing antitumor efficacy  

作　　者：Lianxue Zhang Jianxiang Huang Damiano Buratto Panli Han Zaixing Yang Ruhong Zhou 

机构地区：[1]Institute of Quantitative Biology,Shanghai Institute for Advanced Study,College of Life Sciences,Zhejiang University,Hangzhou,China [2]State Key Laboratory of Radiation Medicine and Protection,School for Radiological and Interdisciplinary Sciences(RAD-X),Soochow University,Suzhou,China [3]Cancer Center,Zhejiang University,Hangzhou,China [4]Department of Chemistry,Columbia University,New York,New York,USA

出　　处：《Aggregate》2024年第1期436-450,共15页聚集体（英文）

基　　金：National Key Research and Development Program of China,Grant/Award Numbers:2021YFA1201200,2021YFF1200404;National Natural Science Foundation of China,Grant/Award Numbers:U1967217,22176137;National Independent Innovation Demonstration Zone Shanghai Zhangjiang Major Projects,Grant/Award Number:ZJZX2020014;National Center of Technology Innovation for Biopharmaceuticals,Grant/Award Number:NCTIB2022HS02010;Shanghai Artificial Intelligence Lab,Grant/Award Number:P22KN00272;Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study,Grant/Award Number:SN-ZJU-SIAS-003;Natural Science Foundation of the Jiangsu Higher Education Institutions of China,Grant/Award Number:20KJA150010;Natural Science Foundation of Zhejiang Province,Grant/Award Number:2022LQ22H220001。

摘　　要：The efficacy of nanoparticle(NP)-based drug delivery technology is hampered by aberrant tumor stromal microenvironments(TSMs)that hinder NP transportation.Therefore,the promotion of NP permeation into deep tumor sites via the regulation of tumor microenvironments is of critical importance.Herein,we propose a potential solution using a dihydralazine(HDZ)-loaded nanoparticle drug delivery system containing a pH-responsive,cyclic RGD peptide-modified prodrug based on doxorubicin(cRGD-Dex-DOX).With a combined experimental and theoretical approach,we find that the designed NP system can recognize the acid tumor environments and precisely release the encapsulated HDZ into tumor tissues.HDZ can notably downregulate the expression levels of hypoxia-inducible factor 1α(HIF1α),α-smooth muscle actin,and fibronectin through the dilation of tumor blood vessels.These changes in the TSMs enhance the enrichment and penetration of NPs and also unexpectedly promote the infiltration of activated T cells into tumors,suggesting that such a system may offer an effective“multifunctional therapy”through both improving the chemotherapeutic effect and enhancing the immune response to tumors.In vivo experiments on 4T1 breast cancer bearing mice indeed validate that this therapy has the most outstanding antitumor effects over all the other tested control regimens,with the lowest side effects as well.

关 键 词：ANTITUMOR dihydralazine drug delivery system tumor stromal microenvironment VASCULATURE 

分 类 号：R730.5[医药卫生—肿瘤]