Folate-targeted, cationic liposome-mediated gene transfer into disseminated peritoneal tumors

• Published in: Gene therapy Vol. 9; no. 22; pp. 1542 - 1550
• Main Authors: REDDY, J. A, ABBURI, C, HOFLAND, H, HOWARD, S. J, VLAHOV, I, WILS, P, LEAMON, C. P
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.11.2002
• Subjects: Animals; Biological and medical sciences; Biotechnology; Carrier Proteins - metabolism; Cell Line; Cholesterol; Deoxyribonucleic acid; DNA; Female; Folate Receptors, GPI-Anchored; Folic acid; Folic Acid - genetics; Folic Acid - metabolism; Fundamental and applied biological sciences. Psychology; Gastric cancer; Gene Targeting - methods; Gene therapy; Gene transfer; Genetic Therapy - methods; Health. Pharmaceutical industry; Industrial applications and implications. Economical aspects; Lipids; Liposomes; Luciferases - genetics; Mice; Mice, Inbred DBA; Peritoneal Neoplasms - metabolism; Peritoneal Neoplasms - therapy; Phosphatidylethanolamine; Polyethylene glycol; Protein Binding; Receptors, Cell Surface; Transfection; Transfection - methods; Tumors; Vitamin B; Cationic complex; tumor targeting; Enzyme; Luciferase; Rodentia; folate receptor; gene therapy; Gene expression; Folate; Genetic transfer; Vertebrata; Mammalia; Cell line; Mouse; lipoplex; Tumor; Receptor protein; cationic liposome; Oxidoreductases; Disseminated; Peritoneum
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3301833

A folate-targeted, cationic lipid based transfection complex was developed and found to specifically transfect folate receptor-expressing cells and tumors. These liposomal vectors were comprised of protamine-condensed plasmid DNA, a mixture of cationic and neutral lipids, and a folic acid-cysteine-polyethyleneglycol-phosphatidylethanolamine (FA-Cys-PEG-PE) conjugate. Pre-optimization studies revealed that inclusion of low amounts (0.01 to 0.03%) of FA-Cys-PEG-PE yielded the highest binding activity of dioleoylphosphatidylcholine/cholesterol liposomes to folate receptor-bearing cells. In contrast, higher amounts (>0.5%) of FA-Cys-PEG-PE progressively decreased cellular binding of the liposomes. In vitro studies with cationic lipid/dioleoylphosphatidylethanolamine formulations indicated that as little as 0.01 to 0.3% of FA-Cys-PEG-PE was needed to produce optimal targeted expression of plasmid DNA. Similarly, using a disseminated intraperitoneal L1210A tumor model, maximum in vivo transfection activity occurred with intraperitoneally administered formulations that contained low amounts (0.01 mol%) of the FA-Cys-PEG-PE targeting lipid. Overall, folate-labeled formulations produced an eight- to 10-fold increase in tumor-associated luciferase expression, as compared with the corresponding non-targeted cationic lipid/DNA formulations. These results collectively indicate that transfection of widespread intraperitoneal cancers can be significantly enhanced using folate-targeted techniques.