Safe and Efficacious Diphtheria Toxin-Based Treatment for Melanoma: Combination of a Light-On Gene-Expression System and Nanotechnology.
Jiajun XuMuye HeXinyu HouYan WangChenting ShouXiaoran CaiZeting YuanYu YinMinbo LanKaiyan LouYuzheng ZhaoYi YangXianjun ChenFeng GaoPublished in: Molecular pharmaceutics (2019)
The 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.
Keyphrases
- gene expression
- escherichia coli
- dna methylation
- cell cycle arrest
- stem cells
- radiation therapy
- cell death
- cell proliferation
- induced apoptosis
- bone marrow
- metabolic syndrome
- cell cycle
- skeletal muscle
- signaling pathway
- mesenchymal stem cells
- gold nanoparticles
- radiation induced
- klebsiella pneumoniae
- cell therapy
- drug induced
- insulin resistance
- reduced graphene oxide