Cationic liposome-mediated gene delivery to the liver and to hepatocellular carcinomas in mice.
The potential of cationic liposomes as nonviral vectors for in vivo gene delivery to the liver and to intrahepatic hepatocellular carcinoma (HCC) was investigated. Mice were injected via the tail vein or portal vein with a cationic lipid complexed to plasmid DNA (pDNA) encoding the chloramphenicol acetyltransferase (CAT) reporter gene at various cationic lipid:pDNA molar ratios to analyze the efficiency of gene delivery after intravenous administration. Tail vein injection resulted in high CAT expression levels in lung and spleen and low levels in the liver. Portal vein injection, by comparison, significantly enhanced hepatic reporter gene expression but also resulted in pronounced hepatic toxicity. Gene delivery to intrahepatic tumors produced by intrahepatic injection of human HCC cells was analyzed in nude mice. Tail vein injection as well as portal vein injection resulted in low levels of gene expression in intrahepatic tumors. By comparison, high levels of gene expression were achieved by direct, intratumoral injection of liposome-pDNA complexes, with only minimal expression in the surrounding normal liver. Therefore, direct liposome-pDNA complex injection appears far superior to systemic or portal intravenous administration for gene therapy of localized intrahepatic tumors, and may be a useful adjunct in the treatment of human HCCs.
Mohr
L
L
Molecular Hepatology Laboratory, Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. mohrl@sun11.ukl.uni-freiburg.de
Yoon
S K
SK
Eastman
S J
SJ
Chu
Q
Q
Scheule
R K
RK
Scaglioni
P P
PP
Geissler
M
M
Heintges
T
T
Blum
H E
HE
Wands
J R
JR
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002412:Cations / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D016503:Drug Delivery Systems / Q000009:adverse effects / Q000379:methods; D015870:Gene Expression; D017930:Genes, Reporter / Q000235:genetics; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism; D007267:Injections; D007275:Injections, Intravenous; D008081:Liposomes / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D011169:Portal Vein / Q000502:physiology; D019076:Transgenes / Q000235:genetics
D002412:Cations; D008081:Liposomes; D015500:Chloramphenicol O-Acetyltransferase