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Nano Research 2020, 13(3): 630-637 https://doi.org/10.1007/s12274-020-2660-9
Research Article | Issue | Published: 18 March 2020

Stimuli-responsive combination therapy of cisplatin and Nrf2 siRNA for improving antitumor treatment of osteosarcoma

Show Author's Information Ting-Ting Gu1,§,  Chengjun Li2,§( ),  Yurui Xu1,§,  Lei Zhang1,  Xue Shan1,  Xinyu Huang1,  Leilei Guo1,  Kerong Chen1,  Xiaojian Wang3,  Haixiong Ge1( ),  Xinghai Ning1,4( )
National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences, Nanjing University, Nanjing 210093, China
Jinling Hospital, Department of Orthopedics, School of medicine, Nanjing University, Nanjing 210002, China
Institute of advanced synthesis, Nanjing Tech University, Nanjing 210093, China
Chemstry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing 210093, China

§ Ting-Ting Gu, Chengjun Li, and Yurui Xu contributed equally to this work.

Keywords:
reactive oxygen species (ROS), combination therapy, osteosarcoma, stimuli-responsive liposome, NF-E2-related factor 2 (Nrf2) siRNA (siNrf2)
Topics:
Biochemistry Chemotherapy DiseasesMammalsTumors
Cite this article:
Gu T-T, Li C, Xu Y, et al. Stimuli-responsive combination therapy of cisplatin and Nrf2 siRNA for improving antitumor treatment of osteosarcoma. Nano Research, 2020, 13(3): 630-637. https://doi.org/10.1007/s12274-020-2660-9
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Abstract Full text Electronic supplementary material About this article

Cisplatin is a widely applied therapeutics for the treatment of osteosarcoma. However, its clinical applications have been hindered due to low efficacy and bioavailability, and particularly frequent emergence of reactive oxygen species (ROS)-decrease induced drug resistance. The transcription factor NF-E2-related factor 2 (Nrf2) is increased in cancer patients and induces poor outcome in osteosarcoma treatment, making it a novel target to improve the efficacy of chemotherapy. Herein, a hyaluronidase-responsive multi-layer liposome (HLCN) for co-delivery of cisplatin and Nrf2 siRNA (siNrf2) is developed. It is composed of Vpr52-96 modified liposome covered with hyaluronic acid (HA). HLCN selectively accumulates in osteosarcoma by targeting tumor-specific CD44, and can be degraded by endosomal hyaluronidase to generate cationic liposome, which promotes the endosomal escape of Vpr52-96, cisplatin and siNrf2. HLCN can effectively decrease Nrf2 level, promote ROS generation, activate itochondrial apoptotic pathway, and consequently enhance anticancer efficacy of cisplatin. Particularly, HLCN shows high cytotoxicity to osteosarcoma cells with an IC50 value of about 1 μM, which is four-fold lower than liposomal cisplatin (IC50 4 μM), indicating that Nrf2 silence can significantly improve cisplatin sensitivity in cancer cells. Importantly, HLCN can remarkably inhibit tumor growth in the xenograft osteosarcoma mice with minimal systemic adverse effects. Therefore, this novel stimuli-responsive combination therapy of cisplatin and siNrf2 provides a promising strategy for the treatment of osteosarcoma.


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About this article

Stimuli-responsive combination therapy of cisplatin and Nrf2 siRNA for improving antitumor treatment of osteosarcoma

Show Author's information Ting-Ting Gu1,§, Chengjun Li2,§( ), Yurui Xu1,§, Lei Zhang1, Xue Shan1, Xinyu Huang1, Leilei Guo1, Kerong Chen1, Xiaojian Wang3, Haixiong Ge1( ), Xinghai Ning1,4( )
National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences, Nanjing University, Nanjing 210093, China
Jinling Hospital, Department of Orthopedics, School of medicine, Nanjing University, Nanjing 210002, China
Institute of advanced synthesis, Nanjing Tech University, Nanjing 210093, China
Chemstry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing 210093, China

§ Ting-Ting Gu, Chengjun Li, and Yurui Xu contributed equally to this work.

Abstract

Cisplatin is a widely applied therapeutics for the treatment of osteosarcoma. However, its clinical applications have been hindered due to low efficacy and bioavailability, and particularly frequent emergence of reactive oxygen species (ROS)-decrease induced drug resistance. The transcription factor NF-E2-related factor 2 (Nrf2) is increased in cancer patients and induces poor outcome in osteosarcoma treatment, making it a novel target to improve the efficacy of chemotherapy. Herein, a hyaluronidase-responsive multi-layer liposome (HLCN) for co-delivery of cisplatin and Nrf2 siRNA (siNrf2) is developed. It is composed of Vpr52-96 modified liposome covered with hyaluronic acid (HA). HLCN selectively accumulates in osteosarcoma by targeting tumor-specific CD44, and can be degraded by endosomal hyaluronidase to generate cationic liposome, which promotes the endosomal escape of Vpr52-96, cisplatin and siNrf2. HLCN can effectively decrease Nrf2 level, promote ROS generation, activate itochondrial apoptotic pathway, and consequently enhance anticancer efficacy of cisplatin. Particularly, HLCN shows high cytotoxicity to osteosarcoma cells with an IC50 value of about 1 μM, which is four-fold lower than liposomal cisplatin (IC50 4 μM), indicating that Nrf2 silence can significantly improve cisplatin sensitivity in cancer cells. Importantly, HLCN can remarkably inhibit tumor growth in the xenograft osteosarcoma mice with minimal systemic adverse effects. Therefore, this novel stimuli-responsive combination therapy of cisplatin and siNrf2 provides a promising strategy for the treatment of osteosarcoma.

Keywords: reactive oxygen species (ROS), combination therapy, osteosarcoma, stimuli-responsive liposome, NF-E2-related factor 2 (Nrf2) siRNA (siNrf2)

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Publication history
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Acknowledgements

Publication history

Received: 27 November 2019
Revised: 13 January 2020
Accepted: 14 January 2020
Published: 18 March 2020
Issue date: March 2020

Copyright

© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020

Acknowledgements

This work was supported by the National Key Research and Development Program of China (No. 2019YFA0802800), the Key Research and Development Program of Jiangsu Provincial Department of Science and Technology of China (No. BE2019002), the Medical Key Young Talents Programs of Jiangsu Province (No. QNRC2016915), "The Six Top Talents" of Jiangsu Province (No. WSW-112), the Fundamental Research Funds for the Central Universities (No. 021314380120), the National Key Research and Development Program of China (No. 2018YFB1105400), the National Natural Science Foundation of China (No. 21708019), and Natural Science Foundation of Jiangsu (No. BK20170987).

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