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.
J Control Release
; 165(3): 216-25, 2013 Feb 10.
Article
em En
| MEDLINE
| ID: mdl-23142578
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA
/
Doença de Crohn
/
Moléculas de Adesão Celular
/
Técnicas de Transferência de Genes
/
Molécula 1 de Adesão de Célula Vascular
/
Microbolhas
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article