Folate-targeted, cationic liposome-mediated gene transfer into disseminated peritoneal tumors.
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.
Reddy
J A
JA
Endocyte, Inc., West Lafayette, IN, USA.
Abburi
C
C
Hofland
H
H
Howard
S J
SJ
Vlahov
I
I
Wils
P
P
Leamon
C P
CP
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000235:genetics* / Q000378:metabolism; D018390:Gene Targeting / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D008081:Liposomes; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008811:Mice, Inbred DBA; D010534:Peritoneal Neoplasms / Q000378:metabolism / Q000628:therapy*; D011485:Protein Binding; D011956:Receptors, Cell Surface; D014162:Transfection / Q000379:methods
D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D008081:Liposomes; D011956:Receptors, Cell Surface; D005492:Folic Acid; D008156:Luciferases