Journal Article

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

Chen, Kerong, Xu, Yurui, Guo, Leilei, Shan, Xue, Wang, Xiaojian, Ning, Xinghai, Gu, Ting-Ting, Li, Chengjun, Zhang, Lei, Ge, Haixiong, Huang, Xinyu

2020

Overview

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 Vpr 52-96 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 Vpr 52-96 , 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 IC 50 value of about 1 µM, which is four-fold lower than liposomal cisplatin (IC 50 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.

• Publisher: Tsinghua University Press
• Subject: Anticancer properties / Apoptosis / Atomic/Molecular Structure and Spectra / Bioavailability / Biomedical materials / Biomedicine / Biotechnology / Bone cancer / CD44 antigen / Chemistry and Materials Science / Chemotherapy / Cisplatin / Combination therapy / Condensed Matter Physics / Cytotoxicity / Drug resistance / Hyaluronic acid / Liposomes / Materials Science / Multilayers / Nanotechnology / Osteosarcoma / Osteosarcoma cells / Reactive oxygen species / Research Article / Resistance factors / Sarcoma / siRNA / Stimuli / Therapeutic applications / Toxicity / Xenografts / Xenotransplantation