title: siRNA Delivery Impedes the Temporal Expression of Cytokine-Activated VCAM1 on Endothelial Cells.
abstract: Leukocyte recruitment plays a key role in chronic inflammatory diseases such as cardiovascular disease, rheumatoid arthritis, and cancer. Leukocyte rolling and arrest are mediated in part by the temporally-regulated surface expression of vascular cell adhesion molecule-1 (VCAM1) on endothelial cells (ECs). In this paper, we engineered a pH-responsive vehicle comprised of 30 mol% dimethylaminoethyl methacrylate (30D) and 70 mol% hydroxyethyl methacrylate (70H) to encapsulate, protect, and deliver VCAM1 small interfering RNA (siRNA). The ability of siRNA to reduce VCAM1 gene expression is in direct opposition to its activation by cytokines. At 12 h post-activation, VCAM1 gene knockdown was 90.1 ± 7.5% when delivered via 30D/70H nanoparticles, which was on par with a leading commercial transfection agent. This translated into a 68.8 ± 6.7% reduction in the surface density of VCAM1 on cytokine-activated ECs. The pH-responsive delivery of VCAM1 siRNA efficiently reduced temporal surface protein expression, which may be used to avert leukocyte recruitment.
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA.|The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, CA, 94143, USA.
authors.forename: Theodore T
authors.initials: TT
authors.lastname: Ho
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA.|Department of Engineering Chemistry, Chungbuk National University, Cheongju, 361-763, Republic of Korea.
authors.forename: Jin-Oh
authors.initials: JO
authors.lastname: You
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA. dauguste@ccny.cuny.edu.|Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA. dauguste@ccny.cuny.edu.|Grove School of Engineering, The City College of New York, 160 Convent Avenue, New York, NY, 10031, USA. dauguste@ccny.cuny.edu.
authors.forename: Debra T
authors.initials: DT
authors.lastname: Auguste
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D015870:Gene Expression; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053582:Interleukin-1alpha / Q000494:pharmacology; D008689:Methacrylates / Q000737:chemistry; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*
chemical_list: D053582:Interleukin-1alpha; D008689:Methacrylates; D034741:RNA, Small Interfering; D019010:Vascular Cell Adhesion Molecule-1; C005044:hydroxyethyl methacrylate
keywords: DMAEMA; Drug delivery; pH-responsive