Endothelial cell dysfunction occurs in a variety of acute and chronic pulmonary diseases including pulmonary hypertension,viral and bacterial pneumonia,bronchopulmonary dysplasia,and congenital lung diseases such as a...Endothelial cell dysfunction occurs in a variety of acute and chronic pulmonary diseases including pulmonary hypertension,viral and bacterial pneumonia,bronchopulmonary dysplasia,and congenital lung diseases such as alveolar capillary dysplasia with misalignment of pulmonary veins(ACDMPV).To correct endothelial dysfunction,there is a critical need for the development of nanoparticle systems that can deliver drugs and nucleic acids to endothelial cells with high efficiency and precision.While several nanoparticle delivery systems targeting endothelial cells have been recently developed,none of them are specific to lung endothelial cells without targeting other organs in the body.In the present study,we successfully solved this problem by developing non-toxic poly(β-amino)ester(PBAE)nanoparticles with specific structure design and fluorinated modification for high efficiency and specific delivery of nucleic acids to the pulmonary endothelial cells.After intravenous administration,the PBAE nanoparticles were capable of delivering non-integrating DNA plasmids to lung microvascular endothelial cells but not to other lung cell types.IVIS whole body imaging and flow cytometry demonstrated that DNA plasmid were functional in the lung endothelial cells but not in endothelial cells of other organs.Fluorination of PBAE was required for lung endothelial cell-specific targeting.Hematologic analysis and liver and kidney metabolic panels demonstrated the lack of toxicity in experimental mice.Thus,fluorinated PBAE nanoparticles can be an ideal vehicle for gene therapy targeting lung microvascular endothelium in pulmonary vascular disorders.展开更多
文摘Endothelial cell dysfunction occurs in a variety of acute and chronic pulmonary diseases including pulmonary hypertension,viral and bacterial pneumonia,bronchopulmonary dysplasia,and congenital lung diseases such as alveolar capillary dysplasia with misalignment of pulmonary veins(ACDMPV).To correct endothelial dysfunction,there is a critical need for the development of nanoparticle systems that can deliver drugs and nucleic acids to endothelial cells with high efficiency and precision.While several nanoparticle delivery systems targeting endothelial cells have been recently developed,none of them are specific to lung endothelial cells without targeting other organs in the body.In the present study,we successfully solved this problem by developing non-toxic poly(β-amino)ester(PBAE)nanoparticles with specific structure design and fluorinated modification for high efficiency and specific delivery of nucleic acids to the pulmonary endothelial cells.After intravenous administration,the PBAE nanoparticles were capable of delivering non-integrating DNA plasmids to lung microvascular endothelial cells but not to other lung cell types.IVIS whole body imaging and flow cytometry demonstrated that DNA plasmid were functional in the lung endothelial cells but not in endothelial cells of other organs.Fluorination of PBAE was required for lung endothelial cell-specific targeting.Hematologic analysis and liver and kidney metabolic panels demonstrated the lack of toxicity in experimental mice.Thus,fluorinated PBAE nanoparticles can be an ideal vehicle for gene therapy targeting lung microvascular endothelium in pulmonary vascular disorders.
