title: Ultrasound-assisted siRNA delivery via arginine-grafted bioreducible polymer and microbubbles targeting VEGF for ovarian cancer treatment.
abstract: The major drawback hampering siRNA therapies from being more widely accepted in clinical practice is its insufficient accumulation at the target site mainly due to poor cellular uptake and rapid degradation in serum. Therefore, we designed a novel polymeric siRNA carrier system, which would withstand serum-containing environments and tested its performance in vitro as well as in vivo. Delivering siRNA with a system combining an arginine-grafted bioreducible polymer (ABP), microbubbles (MBs), and ultrasound technology (US) we were able to synergize the advantages each delivery system owns individually, and created our innovative siRNA-ABP-MB (SAM) complexes. SAM complexes show significantly higher siRNA uptake and VEGF protein knockdown in vitro with serum-containing media when compared to naked siRNA, and 25k-branched-polyethylenimine (bPEI) representing the current standard in nonviral gene therapy. SAM complexes activated by US are also able to improve siRNA uptake in tumor tissue resulting in decelerating tumor growth in vivo.
authors.affiliation: Center for Controlled Chemical Delivery (CCCD), Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, USA.
authors.forename: Stelios
authors.initials: S
authors.lastname: Florinas
authors.affiliation: Center for Controlled Chemical Delivery (CCCD), Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, USA.
authors.forename: Jaesung
authors.initials: J
authors.lastname: Kim
authors.affiliation: Center for Controlled Chemical Delivery (CCCD), Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, USA.
authors.forename: Kihoon
authors.initials: K
authors.lastname: Nam
authors.affiliation: Center for Controlled Chemical Delivery (CCCD), Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, USA; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Utah, Salt Lake City 84132, USA.
authors.forename: Margit M
authors.initials: MM
authors.lastname: Janát-Amsbury
authors.affiliation: Center for Controlled Chemical Delivery (CCCD), Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, USA. Electronic address: sw.kim@pharm.utah.edu.
authors.forename: Sung Wan
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000818:Animals; D001120:Arginine / Q000097:blood / Q000737:chemistry*; D001672:Biocompatible Materials / Q000737:chemistry*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008819:Mice, Nude; D045423:Microbubbles; D008856:Microscopy, Fluorescence; D010051:Ovarian Neoplasms / Q000235:genetics / Q000628:therapy*; D015612:Phonophoresis; D011073:Polyamines / Q000097:blood / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001672:Biocompatible Materials; D004337:Drug Carriers; D011073:Polyamines; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C534803:arginine-grafted bioreducible poly(disulfide amine)polymer; D001120:Arginine
keywords: Cancer; Microbubbles; RNAi; Ultrasound; VEGF; siRNA