Biocompatible micellar nanovectors achieve efficient gene transfer to vascular lesions without cytotoxicity and thrombus formation.
Gene therapy, a promising treatment for vascular disease, requires appropriate gene vectors with high gene transfer efficiency, good biocompatibility and low cytotoxicity. To satisfy these requirements from the approach of nonviral vectors, a novel block copolymer, poly(ethylene glycol) (PEG)-block-polycation, carrying ethylenediamine units in the side chain (PEG-b-P[Asp(DET)]) was prepared. PEG-b-P[Asp(DET)] formed a polyplex micelle through polyion complex formation with plasmid DNA (pDNA). The PEG-b-P[Asp(DET)] polyplex micelle showed efficient gene expression with low cytotoxicity against vascular smooth muscle cells in vitro. It also showed reduced interactions with blood components, offering its feasibility of gene delivery via the vessel lumen. To evaluate in vivo gene transfer efficiency for vascular lesions, PEG-b-P[Asp(DET)] micelle was instilled into rabbit carotid artery with neointima by an intravascular method, and expression of the reporter gene in vascular lesions was assessed. Polyplexes from homopolymer P[Asp(DET)] and branched polyethyleneimine (BPEI) were used as controls. Ultimately, only the polyplex micelle showed appreciable gene transfer into vascular lesions without any vessel occlusion by thrombus, which was in strong contrast to BPEI and P[Asp(DET)] polyplexes which frequently showed occlusion with thrombus. These findings suggest that the PEG-b-P[Asp(DET)] polyplex micelle may have promising potential as a nonviral vector for the treatment of vascular diseases.
Akagi
D
D
Division of Vascular Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Oba
M
M
Koyama
H
H
Nishiyama
N
N
Fukushima
S
S
Miyata
T
T
Nagawa
H
H
Kataoka
K
K
D000818:Animals; D020212:Carotid Artery Injuries / Q000473:pathology / Q000628:therapy; D002478:Cells, Cultured; D004586:Electrophoresis; D004903:Erythrocyte Aggregation; D005029:Ethylenediamines; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D017078:Laser-Doppler Flowmetry; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008823:Micelles; D023421:Models, Animal; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D036103:Nanotechnology; D010974:Platelet Aggregation; D011092:Polyethylene Glycols; D011108:Polymers; D011817:Rabbits; D014162:Transfection / Q000379:methods; D014652:Vascular Diseases / Q000628:therapy*
D005029:Ethylenediamines; D008823:Micelles; D011108:Polymers; D011092:Polyethylene Glycols; C031234:ethylenediamine; D008156:Luciferases