Poly(cationic lipid)-mediated in vivo gene delivery to mouse liver.
We have previously demonstrated that liposomes generated from poly(cationic lipid) (PCL) and cholesterol (Chol) have low cytotoxicity, are serum resistant, and display a transfection efficiency in vitro similar to commercially available cationic liposomes. Our in vivo experiments demonstrated that PCL-Chol liposomes bound much less avidly to serum proteins than did liposomes composed of 1,2-bis(dioleoyloxy)-3-(trimethylamonio)propane (DOTAP)-Chol or DOTAP-L-alpha dioleoyl phosphatidylethanolamine (DOPE). Injection of the lipoplexes (PCL-Chol+DNA) through the portal vein after partial hepatectomy (PH) led to much higher reporter gene expression (luciferase) in the liver than did naked DNA injection. Marked green fluorescent protein expression was visualized in almost all hepatocytes in the liver of mice receiving lipoplex injection, even in the absence of PH. Subcutaneous injection of thyroid hormone triiodothyromine (T(3)) significantly promoted hepatocyte regeneration and markedly enhanced PCL-Chol-mediated gene transfer in mouse liver when the lipoplex was administrated through either portal or tail vein. With T(3) pretreatment, PCL-Chol exerted a better gene transfer efficacy in mouse liver than DOTAP-Chol or DOTAP-DOPE. Two injections of lipoplexes through an indwelling catheter in the portal vein extended the transgene expression at a high level when T(3) injection was repeated. In conclusion, our findings demonstrate that the polymerized cationic liposomes are very stable in the blood and are effective agents for in vivo gene delivery, and that thyroid hormone administration offers a non-invasive approach to enhance liposome-mediated liver gene delivery.
Liu
L
L
Department of Internal Medicine, Transplant Research Institute, University of California-Davis Medical Center, 4635 2nd Avenue, Sacramento, CA 95817, USA.
Zern
M A
MA
Lizarzaburu
M E
ME
Nantz
M H
MH
Wu
J
J
D000818:Animals; D002784:Cholesterol; D018390:Gene Targeting / Q000379:methods*; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000008:administration & dosage*; D049452:Green Fluorescent Proteins; D006498:Hepatectomy; D007275:Injections, Intravenous; D008055:Lipids / Q000235:genetics; D008081:Liposomes; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D051379:Mice; D011073:Polyamines; D000071228:Polyelectrolytes; D011169:Portal Vein; D013963:Thyroid Hormones / Q000494:pharmacology; D014162:Transfection / Q000379:methods*
D002784:Cholesterol; D049452:Green Fluorescent Proteins; D008055:Lipids; D008081:Liposomes; D008156:Luciferases; D008164:Luminescent Proteins; D011073:Polyamines; D000071228:Polyelectrolytes; D013963:Thyroid Hormones