Self‐Stabilized Hyaluronate Nanogel for Intracellular Codelivery of Doxorubicin and Cisplatin to Osteosarcoma

Osteosarcoma is one of the most serious bone malignancies with rapid speed of deterioration and low survival rate in children and teenagers. Chemotherapy is an important treatment for osteosarcoma, while the conventional small-molecule therapeutics exhibit low efficacies and severe side effects in the clinic. Drug-delivery platforms based on nanotechnology, particularly for self-stabilized delivery platforms with prolonged blood circulation, enhanced intratumoral accumulation, improved antitumor efficacy, and diminished side effects, may break the deadlock on osteosarcoma chemotherapy. Here, a cisplatin (CDDP)-crosslinked hyaluronic acid (HA) nanogel (^CDDPHANG) is prepared for effective delivery of doxorubicin (DOX) to treat osteosarcoma. Importantly, both DOX and CDDP have led clinically used antitumor drugs, and CDDP acts as a crosslinker and ancillary anticarcinogen to prevent the premature release of DOX and to achieve synergistic therapeutic performance. Because of the enhanced stability of the nanogel, this CDDP-crosslinked DOX-loaded nanomedicine (^CDDPHANG/DOX) exhibits an obviously prolonged circulation time compared to free drugs. Moreover, after valid tumor accumulation, DOX and CDDP are synergistically delivered into the tumor cells and synchronously released into the intracellular acidic environment. Based on the synergistic apoptosis-inducing effects of DOX and CDDP, ^CDDPHANG/DOX reveals an evidently enhanced antitumor efficacy compared to free drugs and their combination, indicating its great prospects for the chemotherapy of osteosarcoma.