Click Nanogels from pH-Labile Dextran Prodrugs for Robust Solid Tumor Chemotherapy

作者：Rong Jin, Minqiang Wang, Liefu Zhou, Zhengshi Yang, Qing Chang, Aoneng Cao · 发表于：ACS Applied Polymer Materials · 年份：2021 · DOI：10.1021/acsapm.1c01272 · 被引用次数：13 · 研究领域：Nanoparticle-Based Drug Delivery、Cancer Research and Treatments、Nanoplatforms for cancer theranostics

Bioresponsive prodrug nanogels are promising drug delivery systems for cancer chemotherapy due to their advantages such as a high drug-loading content (DLC) and colloidal stability. Herein, a group of polymeric nanogels from clickable dextran prodrugs (CDPs) were designed for pH-responsive drug release against solid tumors. The CDP nanogels were prepared by metal-free click-crosslinking between two clickable dextran-hydrazone-doxorubicin (DOX) prodrugs having azadibenzocyclooctyne and azide residues, respectively, also being termed as DDB/DOX and DAZ/DOX. By adjusting the amounts of these clickable residues and DOX, an equivalent molar amount of DDB/DOX and DAZ/DOX prodrugs containing five of clickable residues and three of DOX, respectively, were applied to produce the CDP5/DOX3 nanogels showing the smallest size (∼130 nm), a nearly neutral surface charge (+3.1 mV), and a high DLC (12.8%). In vitro accumulative drug release testing indicated that the CDP5/DOX3 nanogels displayed relatively slow DOX release under physiological conditions but faster DOX release in an acidic endosomal environment by virtue of the hydrolysis of acid-labile hydrazone. In vitro cytotoxicity testings supported that the CDP5/DOX3 nanogels afforded marked antitumor activity in CT-26 and LLC cancer cells as a result of the DOX delivery into the cellular nuclei. In vivo, compared to the free DOX group, the CDP5/DOX3 nanogel group possessed a higher level of DOX accumulation in CT-26 tumor xenografted i...