title: Anti-VEGF PolysiRNA Polyplex for the Treatment of Choroidal Neovascularization.
abstract: Choroidal neovascularization (CNV) is a major cause of severe vision loss in patients with age-related macular degeneration (AMD). Present ocular siRNA delivery technology is limited due to poor delivery through the retina to the choroid, where CNV originates. Our goal was to develop an optimized nanosized polyRNAi-based therapeutic delivery system to the subretinal space. We developed it by siRNA multimerization (polysiRNA) followed by coating with branched polyethylenimine and hyaluronic acid, and then evaluated its efficacy in vitro and in vivo. The polysiRNA polyplex showed a narrow size distribution (260.7 ± 43.27 nm) and negative charge (-4.98 ± 0.47 mV) owing to the hyaluronic acid outer layer. In vitro uptake of the polysiRNA polyplex by human ARPE cells was discovered, and the direct inhibition of VEGF mRNA translation was confirmed in B16F10 cells. The intravitreally administered polysiRNA polyplex overcame both the vitreous and retina barriers in vivo and reached the subretinal space efficiently. Intravitreal injection of the polysiRNA polyplex was not toxic to the retina in histopathology. Furthermore, intravitreal injections of the polysiRNA polyplex at both 1 and 7 days after laser photocoagulation inhibited laser-induced choroidal neovascularization, compared to that of the control (p < 0.05). These results suggest that anti-VEGF polysiRNA polyplexes show great potential in delivering multimeric RNAi-based therapeutics to treat retinal or choroidal disorders.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Sogang University , 35 Baekbeom-ro, Mapo-gu, Seoul 121-742, Republic of Korea.
authors.forename: Jihwang
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Ophthalmology, Seoul National University Bundang Hospital , 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of Korea.|Department of Ophthalmology, Seoul National University College of Medicine , 71, Ihwajang-gil, Jongno-gu, Seoul, Korea.
authors.forename: Na-Kyung
authors.initials: NK
authors.lastname: Ryoo
authors.affiliation: Department of Chemical and Biomolecular Engineering, Sogang University , 35 Baekbeom-ro, Mapo-gu, Seoul 121-742, Republic of Korea.
authors.forename: Hyounkoo
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Ophthalmology, Seoul National University Bundang Hospital , 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of Korea.
authors.forename: Hye Kyoung
authors.initials: HK
authors.lastname: Hong
authors.affiliation: Department of Ophthalmology, Seoul National University Bundang Hospital , 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of Korea.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Ophthalmology, Seoul National University Bundang Hospital , 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of Korea.|Department of Ophthalmology, Seoul National University College of Medicine , 71, Ihwajang-gil, Jongno-gu, Seoul, Korea.
authors.forename: Sang Jun
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Ophthalmology, Seoul National University Bundang Hospital , 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of Korea.|Department of Ophthalmology, Seoul National University College of Medicine , 71, Ihwajang-gil, Jongno-gu, Seoul, Korea.
authors.forename: Yong-Kyu
authors.initials: YK
authors.lastname: Kim
authors.affiliation: Department of Chemical and Biomolecular Engineering, Sogang University , 35 Baekbeom-ro, Mapo-gu, Seoul 121-742, Republic of Korea.
authors.forename: Changbeom
authors.initials: C
authors.lastname: Sim
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST) , Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Ophthalmology, Seoul National University Bundang Hospital , 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of Korea.|Department of Ophthalmology, Seoul National University College of Medicine , 71, Ihwajang-gil, Jongno-gu, Seoul, Korea.
authors.forename: Se Joon
authors.initials: SJ
authors.lastname: Woo
authors.affiliation: Department of Ophthalmology, Seoul National University Bundang Hospital , 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of Korea.|Department of Ophthalmology, Seoul National University College of Medicine , 71, Ihwajang-gil, Jongno-gu, Seoul, Korea.
authors.forename: Kyu Hyung
authors.initials: KH
authors.lastname: Park
authors.affiliation: Department of Chemical and Biomolecular Engineering, Sogang University , 35 Baekbeom-ro, Mapo-gu, Seoul 121-742, Republic of Korea.
authors.forename: Hyuncheol
authors.initials: H
authors.lastname: Kim
mesh_terms: D000818:Animals; D020256:Choroidal Neovascularization / Q000188:drug therapy*; D004195:Disease Models, Animal; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry; D058449:Intravitreal Injections / Q000379:methods; D008268:Macular Degeneration / Q000188:drug therapy; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D011094:Polyethyleneimine / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D000067492:RNAi Therapeutics / Q000379:methods; D012160:Retina / Q000187:drug effects; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D011094:Polyethyleneimine; D006820:Hyaluronic Acid
keywords: choroidal neovascularization; intravitreal injection; polyplex; polysiRNA