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Safe and Efficacious Diphtheria Toxin-Based Treatment for Melanoma: Combination of a Light-On Gene-Expression System
Jiajun Xu1, Muye He1, Xinyu Hou1
1Department of Pharmaceutics, School of Pharmacy , East China University of Science and Technology , Shanghai 200237 , China.
Abstract:
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.
Insights
This study developed a novel light-activated gene therapy using diphtheria toxin fragment A (DTA) delivered via a nanocarrier. The targeted approach selectively destroys melanoma cells upon blue light exposure, offering a promising cancer treatment with minimal side effects.
Area of Science:
- Biotechnology
- Gene Therapy
- Nanomedicine
Background:
- Diphtheria toxin (DT) shows therapeutic potential against tumors but harms healthy tissues.
- Developing targeted delivery systems is crucial for safe and effective DT-based cancer therapies.
Purpose of the Study:
- To create a light-inducible gene expression system for diphtheria toxin fragment A (DTA) delivery.
- To enhance tumor targeting and transfection efficiency using a cRGD-modified nanocarrier.
- To evaluate the efficacy and safety of this novel DTA-based therapy against melanoma.
Main Methods:
- Constructed plasmids pGAVPO (pG) and pU5-DTA (pDTA) encoding DTA within a Light-On gene-expression system.
- Prepared a cRGD-modified ternary complex (pG&pDTA@cRGD-CL) as a nanocarrier for plasmid delivery.
- Investigated *in vitro* effects on B16F10 cells and *in vivo* antitumor activity in mice bearing B16F10 xenografts.
Main Results:
- The nanocarrier system demonstrated effective transfection and light-inducible DTA expression.
- Blue light irradiation induced S-phase arrest, apoptosis, and necrosis in B16F10 tumor cells.
- DTA-based therapy significantly inhibited tumor growth in mice, prolonged survival, and showed minimal toxicity.
Conclusions:
- A novel DTA-based therapy utilizing nanotechnology and a light-switchable gene system was successfully developed.
- This approach enables spatiotemporal control of toxin expression, enhancing therapeutic efficacy against melanoma.
- The combination of targeted delivery and light-inducible gene expression presents a promising strategy for melanoma treatment with reduced side effects.
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