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

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 CDPS/DOX3 nanogels showing the smallest size (similar to 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 CDPS/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 CDPS/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 CDPS/DOX3 nanogel group possessed a higher level of DOX accumulation in CT-26 tumor xenografted in balb/c mice as well as improved DOX pharmacokinetics in the mice. Intravenous administration of the nanogels afforded significant growth repression of CT-26 tumor with a DOX dosage of 4.0 mg/kg, followed by minor systemic toxicity. Moreover, such an antitumor efficacy was much better for the nanogel group than for the free DOX group. This study highlights high potential of dextran prodrug nanogels for robust cancer chemotherapy.