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Nano Research 2018, 11(9): 4806-4822 https://doi.org/10.1007/s12274-018-2066-0
Research Article | Issue | Published: 25 April 2018

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

Show Author's Information Yi Zhang1,2,§,  Lulu Cai3,§,  Di Li1,§,  Yeh-Hsing Lao4,  Dingzhuo Liu2,  Mingqiang Li4,5( ),  Jianxun Ding1( ),  Xuesi Chen1
Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of SciencesChangchun130022China
Department of Orthopedics the Fourth Affiliated Hospital of China Medical UniversityShenyang110032China
Personalized Drug Therapy Key Laboratory of Sichuan Province Hospital of the University of Electronic Science and Technology of China Sichuan Provincial People’s HospitalChengdu610072China
Department of Biomedical Engineering Columbia University New YorkNY10027USA
Guangdong Provincial Key Laboratory of Liver Disease The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou510630China

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

Keywords:
chemotherapy, hybrid nanomedicine, tumor-acidity responsiveness, controlled drug delivery, multi-stage osteosarcoma
Cite this article:
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 Research, 2018, 11(9): 4806-4822. https://doi.org/10.1007/s12274-018-2066-0
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Abstract Full text Electronic supplementary material About this article

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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Electronic supplementary material
About this article

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

Show Author's information Yi Zhang1,2,§, Lulu Cai3,§, Di Li1,§, Yeh-Hsing Lao4, Dingzhuo Liu2, Mingqiang Li4,5( ), Jianxun Ding1( ), Xuesi Chen1
Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of SciencesChangchun130022China
Department of Orthopedics the Fourth Affiliated Hospital of China Medical UniversityShenyang110032China
Personalized Drug Therapy Key Laboratory of Sichuan Province Hospital of the University of Electronic Science and Technology of China Sichuan Provincial People’s HospitalChengdu610072China
Department of Biomedical Engineering Columbia University New YorkNY10027USA
Guangdong Provincial Key Laboratory of Liver Disease The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou510630China

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

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.

Keywords: chemotherapy, hybrid nanomedicine, tumor-acidity responsiveness, controlled drug delivery, multi-stage osteosarcoma

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Publication history
Copyright
Acknowledgements

Publication history

Received: 30 January 2018
Revised: 24 March 2018
Accepted: 25 March 2018
Published: 25 April 2018
Issue date: September 2018

Copyright

© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Acknowledgements

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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