Systemic co-administration of depsipeptide selectively targets transfection enhancement to specific tissues and cell...

Area of Science:

• Oncology
• Molecular Biology
• Gene Therapy

Background:

• Depsipeptide is a histone deacetylase (HDAC) inhibitor with known antitumor activity.
• It enhances gene expression from lipoplex-delivered genes in cultured tumor cells and via direct injection.
• Systemic gene delivery faces challenges in targeting specific cells and tissues.

Purpose of the Study:

• To investigate the effect of co-administering depsipeptide with polyethylenimine (PEI):DNA complexes on gene expression in vivo.
• To determine if depsipeptide enhances gene expression selectively in tumor cells and specific tissues.
• To explore the potential of HDAC inhibitors for targeted gene delivery.

Main Methods:

• Co-intravenous (i.v.) injection of depsipeptide with PEI:DNA complexes in normal and tumor-bearing mice.
• Analysis of gene expression at both tissue and cellular levels.
• Delivery of the wild-type human p53 gene to metastatic breast cancer cells.

Main Results:

• Co-injection of depsipeptide significantly increased PEI-delivered gene expression in both normal and tumor-bearing mice.
• Depsipeptide-mediated enhancement of gene expression was selectively targeted to the lung, liver, and spleen.
• Gene expression was significantly increased in metastatic breast cancer cells but not in adjacent normal cells.

Conclusions:

• Depsipeptide selectively enhances the expression of systemically delivered genes at both tissue and cellular levels.
• This enhancement occurs without the need for ligand- or promoter-based targeting strategies.
• HDAC-based targeting of gene expression may reveal host genes crucial for controlling systemically delivered gene expression.