Therapeutic Polymeric Gene Delivery

摘要

@@A local gene delivery system, nontoxic water soluble lipopolymer (WSLP), poly(ethylenimine)-co-[N-(2-aminoethyl) ethylenimine]-co-N-(N-cholesteryloxycarbongl- (2-aminoethyl)- ethylenimine) was synthesized. Branched polyethylenimine (PEI MW 1800) and cholesteryl chloroformate were used. This nontoxic WSLP was used to deliver a hypoxia-inducible plasmid construct expressing VEGF, Prtp801-VEGF, to treat myocardial ischemia and infarction. Rat mycoardiocytes, H9C2 and rat aortic smooth muscle A7R5 cells were transfected with PRT801-VEGF under hypoxia conditions. WSLP delivery of PRT P801-VEGF complex was not toxic. Rabbits underwent ligation of the proximal circumflex coronary artery and were immediately injected with an ischemia-inducible VEGF gene (RTP801-VEGF) or a constitutively expressed VEGF gene (SV-VEGF); or no injection therapy using this WSLP. Four weeks following treatment, ligation alone resulted in an infarction of 487% of the left ventricle. The constitutively expressed gene construct, SV-VEGF, reduced infarct size to 327%, while the ischemia-inducible gene construct, RTP801-VEGF, reduced infarct size to 134%. RTP801-VEGF was associated with a decrease in apoptosis and an increase in capillary growth compared to the SV-VEGF construct.