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

Date Published: February 15, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Yi Zhang, Feng Wang, Mingqiang Li, Zhiqiang Yu, Ruogu Qi, Jianxun Ding, Zhiyu Zhang, Xuesi Chen.


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.

Partial Text

Osteosarcoma has been reported to be the sixth most common cancer in children and adolescents with just 65% of 5 year survival rate due to frequent local and distant recurrence.1 For a long time, chemotherapy (pre‐ and postoperative) is applied as a standard treatment procedure for osteosarcoma therapy. However, the consequent side effects existed in chemotherapy, such as hypersensitivities, gastrointestinal toxicity, and myelosuppression, which are induced by the low‐target effect and fast body metabolism of small‐molecule drug, result in poor prognosis of osteosarcoma patients.2 Therefore, there is an urgent need to develop a new therapeutic approach, with minimum side effects and maximum antitumor efficacy at a low dosage, for the treatment of osteosarcoma.

CDDPHANG/DOX prepared through a green and innocuous method possessed a stable structure and an outstanding ability on codelivery and subsequently controlled the release of DOX and CDDP. Accompanied with the pH‐responsive release of DOX, CDDP was also dissociative and then exhibited the synergistic antitumor effect. Moreover, after CDDP in situ crosslinking, a striking enhancement could be confirmed on its stability and tolerability. This also led to the optimized biodistribution, enhanced antitumor potency, and reduced multiorgan toxicity side effect of the drug in vivo. Based on these, CDDPHANG/DOX revealed an excellent performance in either delivering drugs into tumor cells in vitro or suppressing the growth of xenografted K7 osteosarcoma in vivo. The significant tumor growth inhibition can be resulted from the prolonged blood circulation, enhanced tumor accumulation, and bioresponsive intracellular release of the drugs, after CDDPHANG/DOX administrated via intravenous injection. Taken together, our CDDP crosslinked DOX‐loaded nanogel is a versatile platform for drug codelivery and holds great potential for synergistic tumor therapy.

The authors declare no conflict of interest.




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