Injectable, Biodegradable, Thermosensitive Nanoparticles-Aggregated Hydrogel with Tumor-Specific Targeting, Penetration, and Release for Efficient Postsurgical Prevention of Tumor Recurrence.

High locoregional recurrence of breast cancer after surgery remains a clinically appealing challenge. Local chemotherapy, especially sustainable delivery of chemotherapeutics at tumor sites by implantable hydrogels, has shown great potential to prevent cancer recurrence. However, the applications of conventional hydrogels are often limited by their intrinsic poor drug penetration into solid tumors and nonspecific drug accumulation in adjacent normal tissues. Herein, we developed a novel modular coassembly strategy to prepare a kind of pH-sensitive, tumor-specific targeting, and penetrating peptide (CRGDK)-modified doxorubicin-based prodrug nanoparticles (PDNPs), whose aqueous dispersion can undergo sol-gel transition after in vivo injection by thermo-induced self-aggregation to in situ form biodegradable hydrogel depot (PDNPs-gel), anchoring high amounts of PDNPs at tumor sites. Because of CRGDK-mediated targeting to overexpressed neuropilin-1 receptors on tumor vessels and tumor cells, PDNPs released from PDNPs-gel can effectively penetrate into tumor tissues, specifically enter tumor cells and finally realize intracellular acid-triggered drug release. In an in vivo incomplete resection of breast cancer model, a single peritumoral administration of PDNP-gel can achieve high inhibition efficacy against tumor recurrence. In addition, the administration of PDNP-gel only involves simple redispersion of PDNPs in water without any pretreatment for gelation, providing great convenience for storage, dosage, and prescription in practical use. Collectively, the reported multifunctional nanoparticles self-aggregated hydrogel system possesses great potential for efficient postsurgical prevention of tumor recurrence.