An Injectable and Tumor-Specific Responsive Hydrogel with Tissue-Adhesive and Nanomedicine-Releasing Abilities for Precise Locoregional Chemotherapy

Abstract

Locoregional chemotherapy, especially using implantable hydrogel depots to sustainably deliver chemotherapeutics at tumor site, has shown great potential for improving anti-tumorefficacy and reducing systemic toxicity. However, the hydrogel applications are limited by some intrinsic constraints, especially the contradiction between increasing drug penetration and accumulation in tumor and decreasing random drug diffusion into surrounding normal tissues. Herein, we report a unique “Jekyll and Hyde” nanoparticle-hydrogel (NP-gel) hybrid platform, which can keep dormant in adjacent normal tissues but be activated by mildly acidic and hyaluronidase-rich microenvironment in malignant tumor tissues to unidirectionally release tumor-targeting and penetrative doxorubicin (DOX)-loaded NPs. Apart from tumor-specific recognition, penetration, internalization and release, NP-gel features:shear-thinning behavior for injection, tissue-adhesiveness for continuous on-site activation, and full biodegradability for safe use. Precise delivery was clearly demonstrated in both tumor-grafted and tumor-resected mice. A single peritumoral injection of DOX-loaded NP-gelexhibited a significantly higher drug accumulation in tumor for 3 weeks than in nontargetorgans and thus long-term tumor remission. More importantly, significant inhibition in tumor recurrence without detectable toxicity to healthy organs was demonstrated when applied after tumor resection. The designed system displayed long-acting and precise anticancer efficacy,paving the way toward effective tumor locoregional treatment.