A general prodrug nanohydrogel platform for reduction-triggered drug activation and treatment of taxane-resistant malignancies

Chemotherapy has been widely used for treating the vast majority of cancer patients. Unfortunately, only a fraction of patients can respond to chemotherapies, but these patients still experience severe side effects. In this context, a wide range of nanotherapeutic platforms have been developed with the aim of improving treatment outcomes while reducing drug toxicities. Nanohydrogels are highly appealing "smart" biocompatible and biodegradable vehicles for either local or systemic delivery of bioactive com-pounds. Here, we developed prodrug hydrogelators that can undergo one-step distillation-precipitation polymerization to form systemically injectable nanohydrogels. The optimized nanohydrogels were capa-ble of rapidly releasing active agents (e.g., the cytotoxic agent cabazitaxel or the PI3K molecular inhibitor PI103) in response to the reducing tumor microenvironment, while drug release was very slow in the absence of the reductive reagent glutathione. Cabazitaxel-loaded nanogels showed preferential tumor ac-cumulation, and administration of nanogels produced durable tumor regression in a docetaxel-resistant cervical tumor xenograft-bearing mouse model. More significantly, nanogel-based therapy was proven to demonstrate a higher safety profile than solution-based free cabazitaxel. Collectively, this study provides an alternative formulation that meets the essential requirements of high stability in the blood, sponta-neous drug release at diseased sites, favorable safety in vivo , and translational capacity for further inves-tigations. Statement of significance Chemotherapy remains a considerable challenge and only a fraction of patients can respond to chemotherapies. Here we report an intratumoral reducing agent-activatable, tumor-targeting prodrug nanogel platform for therapeutic delivery. To this end, two anticancer agents (e.g., cytotoxic cabazitaxel or PI3K molecular inhibitor PI103) are tested. Prodrug nanogels are stable in the blood but performed reduction-triggered release of chemically unmodified drug molecules in cancerous tissues. Cabazitaxel-loaded nanogels exhibit satisfactory anticancer performance in a preclinical docetaxel-resistant tumor model. This is a practical and expedient approach that combines the prodrug strategy and nanogel scaf-fold to re-engineer a hydrophobic and toxic anticancer drug. The approach also is broadly applicable for the formulation of other agents to improve the therapeutic index. (c) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.