Spatiotemporally controllable diphtheria toxin expression using a light-switchable transgene system combining multifunctional nanoparticle delivery system for targeted melanoma therapy

Muye He; Yan Wang; Xianjun Chen; Yuzheng Zhao; Kaiyan Lou; Yujie Wang; Lei Huang; Xinyu Hou; Jiajun Xu; Xiaoran Cai; Yi Cheng; Minbo Lan; Yi Yang; Feng Gao

doi:10.1016/j.jconrel.2019.12.015

Spatiotemporally controllable diphtheria toxin expression using a light-switchable transgene system combining multifunctional nanoparticle delivery system for targeted melanoma therapy

J Control Release. 2020 Mar 10:319:1-14. doi: 10.1016/j.jconrel.2019.12.015. Epub 2019 Dec 12.

Authors

Muye He¹, Yan Wang², Xianjun Chen³, Yuzheng Zhao³, Kaiyan Lou², Yujie Wang², Lei Huang², Xinyu Hou², Jiajun Xu², Xiaoran Cai², Yi Cheng², Minbo Lan⁴, Yi Yang⁵, Feng Gao⁶

Affiliations

¹ Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, China; Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
² Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
³ Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China; Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China; Optogenetics & Molecular Imaging Interdisciplinary Research Center, CAS Center for Excellence in Brain Science, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
⁴ Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, China.
⁵ Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China; Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China; Optogenetics & Molecular Imaging Interdisciplinary Research Center, CAS Center for Excellence in Brain Science, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China. Electronic address: yiyang@ecust.edu.cn.
⁶ Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, China; Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China. Electronic address: fgao@ecust.edu.cn.

PMID: 31838205
DOI: 10.1016/j.jconrel.2019.12.015

Abstract

Gene therapy with external gene insertion (e. g. a suicide gene) and expression specifically in mutated tumor cells has shown to be a promising strategy in treatment of tumors. However, current tumor gene therapy often suffered from low efficiency in gene expression and off-target effects which may cause damage to normal tissues. To address these issues, in this study, a light-switchable transgene nanoparticle delivery system loaded with a diphtheria toxin A (DTA) segment encoded gene, a suicide gene for tumor cells, was developed. The nanoparticles contained vitamin E succinate-grafted polyethyleneimine core and arginylglycylaspartic acid (RGD)-modified pegylated hyaluronic acid shell for targeted delivery of the loaded gene to tumor cells via receptor-mediated (CD44 and αvβ3) endocytosis. Notably, the expression of target proteins in tumor cells could be conveniently regulated by adjusting the blue light intensity in the Light-On system. In in-vitro studies in cultured B16-F10 cells, the pG-DTA-loaded nano-micelles showed greatly improved inhibitory rate compared with the pG-DTA group. Moreover, in the tumor-bearing C57BL/6 mice model, the pG-DTA-loaded nanoparticle exhibited greatly improved efficacy and reduced systemic toxicity with significantly increased survival rate after 21 days. Significantly suppressed tumor angiogenesis was also identified in the nanoparticle-treated group likely due to the targeting ability of the RGD-modified nanoparticle. All the above results indicated that the combination of a light-switchable transgene system with a nanoparticle-based targeted delivery system have great potentials in gene therapy of malignant tumors with improved precision and efficacy.

Keywords: Diphtheria toxin; Light-switchable gene expression; Melanoma; Nanoparticle delivery system.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Diphtheria Toxin
Drug Delivery Systems
Melanoma* / drug therapy
Mice
Mice, Inbred C57BL
Multifunctional Nanoparticles*
Nanoparticles*
Transgenes

Substances

Diphtheria Toxin