Ultrasound-based molecular imaging and specific gene delivery to mesenteric vasculature by endothelial adhesion molecule targeted microbubbles in a mouse model of Crohn's disease.
Ultrasound-based molecular imaging and specific gene delivery to mesenteric vasculature by endothelial adhesion molecule targeted microbubbles in a mouse model of Crohn's disease.
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DOI：
10.1016/j.jconrel.2012.10.021
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发表时间：
2013-02-10
期刊：
影响因子：
--
通讯作者：
Lawrence MB
中科院分区：
文献类型：
--
作者：
Tlaxca JL;Rychak JJ;Ernst PB;Konkalmatt PR;Shevchenko TI;Pizarro TT;Rivera-Nieves J;Klibanov AL;Lawrence MB
Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract (GI) for which treatments with immunosuppressive drugs have significant side-effects. Consequently, there is a clinical need for site-specific and non-toxic delivery of therapeutic genes or drugs for CD and related disorders such as inflammatory bowel disease. The aim of this study was to validate a gene delivery platform based on ultrasound-activated lipid-shelled microbubbles (MBs) targeted to inflamed mesenteric endothelium in the CD-like TNFΔARE mouse model. MBs bearing luciferase plasmid were functionalized with antibodies to MAdCAM-1 (MB-M) or VCAM-1 (MB-V), biomarkers of gut endothelial cell inflammation and evaluated in an in vitro flow chamber assay with appropriate ligands to confirm targeting specificity. Following MB retro-orbital injection in TNFΔARE mice, the mean contrast intensity in the ileocecal region from accumulated MB-M and MB-V was 8.5-fold and 3.6-fold greater, respectively, compared to MB-C. Delivery of luciferase plasmid to the GI tract in TNFΔARE mice was achieved by insonating the endothelial cell-bound agents using a commercial sonoporator. Luciferase expression in the midgut was detected 48 h later by bioluminescence imaging and further confirmed by immunohistochemical staining. The liver, spleen, heart, and kidney had no detectable bioluminescence following insonation. Transfection of the microcirculation guided by a targeted, acoustically-activated platform such as an ultrasound contrast agent microbubble has the potential to be a minimally-invasive treatment strategy to ameliorate CD and other inflammatory conditions.
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