Intravascular and endobronchial DNA delivery to murine lung tissue using anovel, nonviral vector

Gene transfer to the lung can be achieved via either the airway or the pulm onary vasculature. We evaluated gene transfer and expression by intravascul ar and endobronchial routes, using DNA complexed with G9 PAMAM dendrimer or naked plasmid DNA. Intravascular tail vein delivery of dendrimer-complexed pCF1CAT plasmid resulted in high levels of transgene expression in the lun g at 12 and 24 hr, followed by a second peak of expression 3 to 5 days afte r administration. After intravenous administration of the complexes, CAT ex pression was never observed in organs other than the lung. There were only minimal levels of CAT protein expressed in the lung after intravenous admin istration of naked plasmid DNA. Repeated intravascular doses of the dendrim er-complexed plasmid, administered four times at 4-day intervals, maintaine d expression at 15-25% of peak concentrations achieved after the initial do se. Endobronchial delivery of naked pCF1CAT plasmid produced significant am ounts of CAT protein in the lung. Comparison of intratracheal and intranasa l routes resulted in similar expression levels of CAT in the lung and trach ea. However, in juxtaposition to vascular delivery, intranasal delivery of dendrimer-complexed plasmid DNA gave lower levels of CAT expression than th at observed with naked plasmid DNA. In situ localization of CAT enzymatic a ctivity suggested that vascular administration seemed to achieve expression in the lung parenchyma, mainly within the alveoli, while endobronchial adm inistration primarily targeted bronchial epithelium. Our results show that intravenously administered G9 dendrimer is an effective vector for pulmonar y gene transfer and that transgene expression can be prolonged by repeated administration of dendrimer-complexed DNA.