Targeted gene delivery to pulmonary endothelium by anti-PECAM antibody.
To achieve efficient systemic gene delivery to the lung with minimal toxicity, a vector was developed by chemically conjugating a cationic polymer, polyethylenimine (PEI), with anti-platelet endothelial cell adhesion molecule (PECAM) antibody (Ab). Transfection of mouse lung endothelial cells with a plasmid expression vector with cDNA to luciferase (pCMVL) complexed with anti-PECAM Ab-PEI conjugate was more efficient than that with PEI-pCMVL complexes. Furthermore, the anti-PECAM Ab-PEI conjugate mediated efficient transfection at lower charge plus-to-minus ratios. Conjugation of PEI with a control IgG (hamster IgG) did not enhance transfection of mouse lung endothelial cells, suggesting that the cellular uptake of anti-PECAM Ab-PEI-DNA complexes and subsequent gene expression were governed by a receptor-mediated process rather than by a nonspecific charge interaction. Conjugation of PEI with anti-PECAM Ab also led to significant improvement in lung gene transfer to intact mice after intravenous administration. The increase in lung transfection was associated with a decrease compared with PEI-pCMVL with respect to circulating proinflammatory cytokine (tumor necrosis factor-alpha) levels. These results indicate that targeted gene delivery to the lung endothelium is an effective strategy to enhance gene delivery to the pulmonary circulation while simultaneously reducing toxicity.
Li
S
S
Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. songli@prophet.pharm.pitt.edu
Tan
Y
Y
Viroonchatapan
E
E
Pitt
B R
BR
Huang
L
L
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D016207:Cytokines / Q000037:antagonists & inhibitors; D004247:DNA / Q000493:pharmacokinetics / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004727:Endothelium / Q000378:metabolism; D018390:Gene Targeting; D018014:Gene Transfer Techniques; D005938:Glucocorticoids / Q000494:pharmacology; D008168:Lung / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology*; D011094:Polyethyleneimine / Q000493:pharmacokinetics / Q000494:pharmacology; D014162:Transfection
D000906:Antibodies; D016207:Cytokines; D005938:Glucocorticoids; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D003907:Dexamethasone; D011094:Polyethyleneimine; D004247:DNA