Multi-component polymeric system for tumour cell-specific gene delivery using a universal bungarotoxin linker

Area of Science:

• Biotechnology
• Gene Therapy
• Nanomedicine

Background:

• Adenoviral vectors are widely used for gene delivery but often lack specificity.
• Modifying adenoviral tropism is crucial for targeted therapies, especially in cancer treatment.
• Developing universal tools for precise vector modification is an ongoing challenge in virotherapy.

Purpose of the Study:

• To create a universal tool for attaching recombinant antibody fragments to polymer-modified adenoviruses.
• To regulate the tropism of adenoviral gene delivery vectors for targeted therapy.
• To enable specific infection of prostate cancer cells using antibody-mediated targeting.

Main Methods:

• Surface modification of adenoviral vectors (Ad) with a copolymer (PHPMA) bearing an alpha-bungarotoxin-binding peptide (BTXbp).
• Non-covalent linkage of alpha-bungarotoxin (BTX) fusion proteins to the modified adenoviral vectors.
• Conjugation of a prostate-specific membrane antigen (PSMA)-targeting single-chain variable fragment bearing BTX (scFv-BTX) to the Ad-PHPMA-BTXbp system.

Main Results:

• Copolymer-coated adenoviruses showed significantly reduced binding to anti-adenovirus antibodies.
• Infection efficiency of copolymer-coated adenoviruses was approximately 100-fold lower than unmodified adenoviruses in prostate cancer cell lines.
• Conjugation of scFv-BTX restored infection by 5-10 fold in PSMA-positive LNCaP cells, with no enhancement in PSMA-negative PC-3 cells.

Conclusions:

• The Ad-PHPMA-BTXbp/scFv-BTX system serves as a universal tool for receptor-specific virotherapy.
• This approach allows for precise control over adenoviral vector tropism.
• The system demonstrates potential for targeted gene delivery in prostate cancer treatment.