PEGylated graphene oxide as a nanocarrier of the disulfide prodrug of podophyllotoxin for cancer therapy
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RESEARCH PAPER
PEGylated graphene oxide as a nanocarrier of the disulfide prodrug of podophyllotoxin for cancer therapy Yajing Liu & Xiaoguang Lv & Shengli Xia & Bingjie Hao & Xiaoyu Huang & Ping Shi
Received: 20 January 2020 / Accepted: 26 August 2020 # Springer Nature B.V. 2020
Abstract Efficient drug delivery systems are required to increase drug concentrations at tumor sites and to reduce the side effects on normal cells. In this work, we developed a nanoscale drug delivery system based on graphene oxide (GO) and used it to load a disulfide prodrug of podophyllotoxin (DCM-S-PPT), which was linked by a thiol-specific cleavable disulfide bond. In order to improve the biocompatibility in physiological solution, GO was functionalized with 6-armed polyethylene glycol (PEG) and characterized by UV-Vis spectroscopy, Fourier transform infrared spectroscopy, and thermogravimetric analysis. By atomic force microscopy, the size distribution of the nanoparticles was shown to be Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11051-020-05003-5) contains supplementary material, which is available to authorized users. Y. Liu : X. Lv : P. Shi (*) State Key Laboratory of Bioreactor Engineering, Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People’s Republic of China e-mail: [email protected] S. Xia (*) Department of Orthopedics, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, 1500 Zhoupu Zhouyuan Road, Pudong New Area, Shanghai 201318, People’s Republic of China e-mail: [email protected] B. Hao : X. Huang Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of China
25~250 nm. DCM-S-PPT was loaded on GO-PEG via p–p stacking and hydrophobic interactions. The loading rate reached 138%. In vitro cytotoxicity assay showed that GO-PEG/DCM-S-PPT inhibited the proliferation of human cervical adenocarcinoma HeLa cells more than that of human normal kidney 293T cells, which was attributed to the different intracellular concentrations of GSH. After intravenous injection in mice bearing tumors, GO-PEG/DCM-S-PPT showed the better antitumor activity and less side effects than those of DCM-S-PPT and PPT. Compared with DCM-S-PPT or PPT, GO-PEG/ DCM-S-PPT complex showed the best tumor-targeting and specific drug release. Our results provide a novel strategy for the combination of nanocarriers and modified chemotherapy drugs in the future. Keywords Nanocarrier . GO-PEG . DCM-S-PPT . GSH . Tumor-bearing mice . Nanomedicine
Introduction Chemotherapy as a dominant treatment modality against cancer is hindered by its severe side effects on normal cells and tissues because of its nonselectivity and high toxicity (Irvine 2011; Hubbell and Langer, 2013; Mura et al. 2013). Developing controllable drug delivery systems (DDS) that can be triggered by the unique tumor microenvironment is one of the
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