TY - JOUR
T1 - The in vivo use of chloroquine to promote non-viral gene delivery to the liver via the portal vein and bite duct
AU - Zhang, X H
AU - Sawyer, G J
AU - Dong, X B
AU - Qiu, Y
AU - Collins, L
AU - Fabre, J W
PY - 2003/3
Y1 - 2003/3
N2 - Background Assistance with exit from endocytic vesicles is a key factor for non-viral gene delivery, and is a particular challenge in vivo. We have evaluated the in vivo use of chloroquine administered systemically, orally and/or locally for gene delivery to the liver. Methods The DNA vector (polylysine-molossin) is a 31 amino acid bifunctional synthetic peptide, incorporating an amino terminal chain of 16 lysines for electrostatic binding of DNA. Gene delivery was to the right lateral lobes of the liver by branches of the bile duct or portal vein. Results Single intraperitoneal injections of 8, 25 and 75 mg/kg of chloroquine (the maximum tolerated single intraperitoneal dose) resulted in increasing levels of luciferase reporter gene expression, following gene delivery via the bile duct. 100 mg/kg of chloroquine orally was equivalent to 25 mg intraperitone ally. A 3-day course of intraperitoneal and oral chloroquine gave similar to10-30-fold higher gene expression than an optimal single dose, and resulted in a scattering of positive hepatocytes in the lobule. Gene delivery via the bile duct was much more effective than via the portal vein. Serum chloroquine levels at the time of gene delivery showed a highly significant correlation with gene expression, but the maximum achievable levels in vivo (similar to1-2 muM) were much lower than those required for optimal in vitro gene delivery. Chloroquine (0.2-5 mM) was also given locally in the bile duct with vector/DNA complexes. Maximum gene expression was obtained with 0.5 mM local chloroquine, but the level of gene expression was only equivalent to the 25 mg intraperitoneal dose. Conclusions The in vivo use of chloroquine is effective for promoting gene delivery to the liver, but requires multiple dosing and is limited by systemic toxicity. Copyright (C) 2002 John Wiley Sons, Ltd.
AB - Background Assistance with exit from endocytic vesicles is a key factor for non-viral gene delivery, and is a particular challenge in vivo. We have evaluated the in vivo use of chloroquine administered systemically, orally and/or locally for gene delivery to the liver. Methods The DNA vector (polylysine-molossin) is a 31 amino acid bifunctional synthetic peptide, incorporating an amino terminal chain of 16 lysines for electrostatic binding of DNA. Gene delivery was to the right lateral lobes of the liver by branches of the bile duct or portal vein. Results Single intraperitoneal injections of 8, 25 and 75 mg/kg of chloroquine (the maximum tolerated single intraperitoneal dose) resulted in increasing levels of luciferase reporter gene expression, following gene delivery via the bile duct. 100 mg/kg of chloroquine orally was equivalent to 25 mg intraperitone ally. A 3-day course of intraperitoneal and oral chloroquine gave similar to10-30-fold higher gene expression than an optimal single dose, and resulted in a scattering of positive hepatocytes in the lobule. Gene delivery via the bile duct was much more effective than via the portal vein. Serum chloroquine levels at the time of gene delivery showed a highly significant correlation with gene expression, but the maximum achievable levels in vivo (similar to1-2 muM) were much lower than those required for optimal in vitro gene delivery. Chloroquine (0.2-5 mM) was also given locally in the bile duct with vector/DNA complexes. Maximum gene expression was obtained with 0.5 mM local chloroquine, but the level of gene expression was only equivalent to the 25 mg intraperitoneal dose. Conclusions The in vivo use of chloroquine is effective for promoting gene delivery to the liver, but requires multiple dosing and is limited by systemic toxicity. Copyright (C) 2002 John Wiley Sons, Ltd.
UR - http://www.scopus.com/inward/record.url?scp=0142166338&partnerID=8YFLogxK
U2 - 10.1002/jgm.340
DO - 10.1002/jgm.340
M3 - Article
VL - 5
SP - 209
EP - 218
JO - JOURNAL OF GENE MEDICINE
JF - JOURNAL OF GENE MEDICINE
IS - 3
ER -