title: Sustained local delivery of siRNA from an injectable scaffold.
abstract: Controlled gene silencing technologies have significant, unrealized potential for use in tissue regeneration applications. The design described herein provides a means to package and protect siRNA within pH-responsive, endosomolytic micellar nanoparticles (si-NPs) that can be incorporated into nontoxic, biodegradable, and injectable polyurethane (PUR) tissue scaffolds. The si-NPs were homogeneously incorporated throughout the porous PUR scaffolds, and they were shown to be released via a diffusion-based mechanism for over three weeks. The siRNA-loaded micelles were larger but retained nanoparticulate morphology of approximately 100 nm diameter following incorporation into and release from the scaffolds. PUR scaffold releasate collected in vitro in PBS at 37 °C for 1-4 days was able to achieve dose-dependent siRNA-mediated silencing with approximately 50% silencing achieved of the model gene GAPDH in NIH3T3 mouse fibroblasts. This promising platform technology provides both a research tool capable of probing the effects of local gene silencing and a potentially high-impact therapeutic approach for sustained, local silencing of deleterious genes within tissue defects.
authors: Biomedical Engineering, Vanderbilt University, 5824 Stevenson Center, PMB 351631, 2301 Vanderbilt Place, Nashville, TN 37235-1631, USA.
authors: Christopher E
authors: CE
authors: Nelson
authors: Mukesh K
authors: MK
authors: Gupta
authors: Elizabeth J
authors: EJ
authors: Adolph
authors: Joshua M
authors: JM
authors: Shannon
authors: Scott A
authors: SA
authors: Guelcher
authors: Craig L
authors: CL
authors: Duvall
mesh_terms: D000818:Animals; D003692:Delayed-Action Preparations / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007267:Injections; D051379:Mice; D041681:NIH 3T3 Cells; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D011140:Polyurethanes / Q000737:chemistry*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D003692:Delayed-Action Preparations; D011140:Polyurethanes; D034741:RNA, Small Interfering