Long circulating XTEN864-HGV-Apoptin fusion protein for selective cancer therapy

Le résumé fourni par la source

The virus protein CAV-Apoptin and its homologue HGV-Apoptin selectively kill cancer cells but are not suitable for systemic treatment. The aim was to develop Apoptin-based fusion proteins for intravenous application in cancer therapy, which also contain the hydrophilic polypeptide XTEN, a cleavage site for MMP-2/9, and a TAT peptide for cell penetration. Expression of XTEN864-HGV-Apoptin in E. coli and purification using XTEN as a tag yielded 100 mg protein/L tissue culture. The expression of XTEN864-CAV-Apoptin did not generate a sufficient yield. Cytotoxic effects were assessed using MTT and Annexin A5 assays, whereas cellular uptake was visualized using Cy3.5-XTEN864-HGV-Apoptin. Blood half-life and biodistribution were evaluated with 99m Tc-XTEN864-HGV-Apoptin using SPECT-CT and gamma counting. The fusion protein significantly reduced cancer cell growth and induced apoptosis with minimal effects on non-cancerous cells. It accumulates in the nucleus and associates with F-actin. In mice, the protein showed a blood half-life of 0.68 (fast phase) and 17 h (slow phase), with a tumor/muscle ratio of 9.36 ± 6.22 (SD). In a 4 T1 mouse tumor model, it effectively inhibited tumor growth. The cancer-specific cytotoxicity and prolonged circulation of XTEN864-HGV-Apoptin suggest its potential for systemically applicable, biodegradable, and E. coli -producible antitumor drugs.

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