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Tumor microenvironment-responsive hyaluronate-calcium carbonate hybrid nanoparticle enables effective chemotherapy for primary and advanced osteosarcomas

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Abstract

Osteosarcoma is the most common malignancy in the bone. Current chemotherapy offers limited efficacy with significant side effects, especially for advanced and relapsed osteosarcomas. Nanoparticle-formulated chemotherapeutic drugs may be used to resolve these issues, but several aspects of these formulations remain unsatisfactory, such as how to improve their stability in the bloodstream, prevent undesirable drug leakage, and enhance targeted drug accumulation in the tumor. In this study, a tumor microenvironment-responsive calcium carbonate (CaCO3)-crosslinked hyaluronate (HA) nanoparticle was prepared via a “green” process to effectively deliver doxorubicin (DOX) for the treatment of various stages of osteosarcoma. The DOX-loaded hyaluronate-calcium carbonate hybrid nanoparticle (HA-DOX/CaCO3) demonstrated superior stability both in vitro and in vivo, and rapidly released DOX at the tumor site when triggered by the acidic tumor microenvironment. Compared with free DOX and a non-crosslinked nanoparticle (HA-DOX), HA-DOX/CaCO3 exhibited the most potent inhibition efficacy toward both primary and advanced models of murine osteosarcoma, resulting in effective tumor inhibition, improved survival time, and reduced adverse effects. Most importantly, in the advanced osteosarcoma model, HA-DOX/CaCO3 potently suppressed tumor growth by 84.6%, which indicates the potential of this platform for osteosarcoma treatment, particularly for advanced and relapsed cases. The proposed polysaccharide nanoparticle would be a promising drug delivery platform to advance osteosarcoma nanomedicine.

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Acknowledgements

The authors gratefully acknowledge Weiqian Jiang at Yale University for his constructive comments and suggestions. This research was financially supported by the National Natural Science Foundation of China (Nos. 51673190, 51603204, 51473165, 51390484, 81402500, and 51520105004), the National Key Specialty Construction Project of Clinical Pharmacy (No. 30305030698), and the Science and Technology Development Program of Jilin Province (Nos. 20160204015SF and 20160204018SF).

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  1. Yi Zhang, Lulu Cai, and Di Li contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China

    Yi Zhang, Di Li, Jianxun Ding & Xuesi Chen

  2. Department of Orthopedics, the Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China

    Yi Zhang & Dingzhuo Liu

  3. Personalized Drug Therapy Key Laboratory of Sichuan Province, Hospital of the University of Electronic Science and Technology of China, Sichuan Provincial People’s Hospital, Chengdu, 610072, China

    Lulu Cai

  4. Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA

    Yeh-Hsing Lao & Mingqiang Li

  5. Guangdong Provincial Key Laboratory of Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China

    Mingqiang Li

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  1. Yi Zhang
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Tumor microenvironment-responsive hyaluronate-calcium carbonate hybrid nanoparticle enables effective chemotherapy for primary and advanced osteosarcomas

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Zhang, Y., Cai, L., Li, D. et al. Tumor microenvironment-responsive hyaluronate-calcium carbonate hybrid nanoparticle enables effective chemotherapy for primary and advanced osteosarcomas. Nano Res. 11, 4806–4822 (2018). https://doi.org/10.1007/s12274-018-2066-0

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