title: Substrate-mediated delivery of microRNA-145 through a polysorbitol-based osmotically active transporter suppresses smooth muscle cell proliferation: implications for restenosis treatment.
abstract: Smooth muscle cells (SMCs) can grow over a stent surface and block blood flow through the stent, resulting in restenosis. MicroRNAs (miRNAs) are post-transcriptional regulators that contribute to cell proliferation, survival, and metabolism. Several miRNAs, including miR-145, have been identified that regulate vascular SMC proliferation and are down-regulated under conditions of proliferation. We hypothesized that SMC proliferation would be reduced or diminished if miR-145 expression was restored in SMCs. We designed a method to coat the stent surface with miR-145 to suppress the over-growth of SMCs. For effective miRNA delivery, various types of nanocarriers were tested for enhanced transfection efficiency and biocompatibility in the case of surface-mediated delivery. Physico-chemical characterization of the prepared nanoparticles was performed, and the cell viabilities and transfection efficiencies of the carriers were studied and compared to select the most efficient carrier for substrate-mediated delivery. The polysorbitol-based osmotically active transporter (PSOAT) retained its transgene delivery capacity and had higher biocompatibility than the other tested carriers. We detected reporter and therapeutic gene expression at the stent surface following PSOAT-mediated delivery. SMC proliferation after the treatment with PSOAT/miR-145 nanoparticles (PMN) was monitored using the MTS assay, and miR-145 target gene expression after PMN treatment was measured by reverse transcription-polymerase chain reaction. PSOAT-mediated delivery of miR-145 was associated with efficient intracellular expression of the therapeutic gene. A drastic reduction in SMC proliferation was observed after PMN treatment, and miR-145 target proteins were down-regulated upon miR-145 replacement.
authors.forename: Muthunarayanan
authors.initials: M
authors.lastname: Muthiah
authors.forename: Mohammad Ariful
authors.initials: MA
authors.lastname: Islam
authors.forename: Chong Su
authors.initials: CS
authors.lastname: Cho
authors.forename: Jun Eul
authors.initials: JE
authors.lastname: Hwang
authors.forename: Ik-Joo
authors.initials: IJ
authors.lastname: Chung
authors.forename: In Kyu
authors.initials: IK
authors.lastname: Park
mesh_terms: D000818:Animals; D002460:Cell Line; D054855:Drug-Eluting Stents; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006083:Graft Occlusion, Vascular / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology*; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry*; D011094:Polyethyleneimine / Q000031:analogs & derivatives* / Q000737:chemistry; D051381:Rats
chemical_list: C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D053769:Nanocapsules; D011091:Polyesters; C569756:polysorbitol-based osmotically active transporter polymer; D011094:Polyethyleneimine