mp9b01038_si_001.pdf (2.32 MB)
Safe and Efficacious Diphtheria Toxin-Based Treatment for Melanoma: Combination of a Light-On Gene-Expression System and Nanotechnology
journal contribution
posted on 2019-12-11, 17:35 authored by Jiajun Xu, Muye He, Xinyu Hou, Yan Wang, Chenting Shou, Xiaoran Cai, Zeting Yuan, Yu Yin, Minbo Lan, Kaiyan Lou, Yuzheng Zhao, Yi Yang, Xianjun Chen, Feng GaoThe controversy surrounding the use of diphtheria toxin
(DT) as a therapeutic agent against tumor cells arises mainly from
its unexpected harmfulness to healthy tissues. We encoded the cytotoxic
fragment A of DT (DTA) as an objective gene in the Light-On gene-expression
system to construct plasmids pGAVPO (pG) and pU5-DTA (pDTA). Meanwhile,
a cRGD-modified ternary complex comprising plasmids, chitosan, and
liposome (pG&pDTA@cRGD-CL) was prepared as a nanocarrier to ensure
transfection efficiency. Benefiting from spatiotemporal control of
this light-switchable transgene system and the superior tumor targeting
of the carrier, toxins were designed to be expressed selectively in
illuminated lesions. In vitro studies suggested that
pG&pDTA@cRGD-CL exerted arrest of the S phase in B16F10 cells
upon blue light irradiation and, ultimately, induced the apoptosis
and necrosis of tumor cells. Such DTA-based treatment exerted enhanced
antitumor activity in mice bearing B16F10 xenografts and displayed
prolonged survival time with minimal side effects. Hence, we described
novel DTA-based therapy combined with nanotechnology and the Light-On
gene-expression system: such treatment could be a promising strategy
against melanoma.