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Research Article

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

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.

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Graphical Abstract

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

stimuli-responsive liposomeNF-E2-related factor 2 (Nrf2) siRNA (siNrf2)reactive oxygen species (ROS)osteosarcomacombination therapy

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Nano Research
Volume 13 Issue 3,
March 2020
Pages 630-637
DOI: 10.1007/s12274-020-2660-9
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
Topics:
Biochemistry Chemotherapy DiseasesMammalsTumors

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Received: 27 November 2019
Revised: 13 January 2020
Accepted: 14 January 2020
Published: 18 March 2020
© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020
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