Dexamethasone-spermine as a local drug and gene delivery vehicle for improved pulmonary gene therapy
Gene delivery to the lung is important for diseases such as Cystic Fibrosis (CF) airway disease, and both viral and non-viral vectors have been used extensively for delivery to the lung, especially lipoplexes and adenovirus (AdV) vectors. Two major barriers to gene delivery exist in the lung: inefficient transgene expression in the airway epithelial cells and immune response to the vectors. Dexamethasone-spermine (DS) has been shown to be an efficient transfection reagent in vitro when formulated with the neutral lipid dioleoylphosphatidylethanolamine (DOPE), and is also an anti-inflammatory glucocorticoid. Delivery of plasmid DNA (pDNA) and AdV vectors in vivo, when formulated with DS/DOPE, was studied in order to increase transgene expression in airway epithelia and reduce the immune response to the vectors through local delivery of glucocorticoid. We demonstrate that pDNA delivery of DS/DOPE to the lung in vivo is significantly more efficient when compared to DC-Chol/DOPE delivery, and significantly reduces IFN-γ in lung homogenate at day 7 post-instillation. Furthermore, formulation of DS with DOPE-PEG2000 significantly increases transgene expression over DS/DOPE liposomes with a concurrent decrease in IL-6 levels, demonstrating that DS/DOPE-PEG liposomes are a superior in vivo transfection reagent. DS/DOPE liposomes formulated with AdV vector resulted in targeting of transgene expression to the airway epithelia, which is shown to be a result of the physical-chemical properties of liposomes. When AdV vector was formulated with DS/DOPE, reduction of several inflammatory mediators, significant decreases in local CD4 and CD8 T-cells, reduction of circulating serum neutralizing antibodies (NABS), and significant levels of transgene expression upon readministration of AdV+DS/DOPE vector were all observed compared to AdV vector. The unique properties of DS/DOPE liposomes results in local delivery of glucocorticoid and reduction in the immune response to both pDNA and AdV vectors in vivo, and also increases AdV-vector mediated transgene expression in the lung airway epithelium. ^
"Dexamethasone-spermine as a local drug and gene delivery vehicle for improved pulmonary gene therapy"
(January 1, 2006).
Dissertations available from ProQuest.