title: A delivery system targeting bone formation surfaces to facilitate RNAi-based anabolic therapy.
abstract: Metabolic skeletal disorders associated with impaired bone formation are a major clinical challenge. One approach to treat these defects is to silence bone-formation-inhibitory genes by small interference RNAs (siRNAs) in osteogenic-lineage cells that occupy the niche surrounding the bone-formation surfaces. We developed a targeting system involving dioleoyl trimethylammonium propane (DOTAP)-based cationic liposomes attached to six repetitive sequences of aspartate, serine, serine ((AspSerSer)(6)) for delivering siRNAs specifically to bone-formation surfaces. Using this system, we encapsulated an osteogenic siRNA that targets casein kinase-2 interacting protein-1 (encoded by Plekho1, also known as Plekho1). In vivo systemic delivery of Plekho1 siRNA in rats using our system resulted in the selective enrichment of the siRNAs in osteogenic cells and the subsequent depletion of Plekho1. A bioimaging analysis further showed that this approach markedly promoted bone formation, enhanced the bone micro-architecture and increased the bone mass in both healthy and osteoporotic rats. These results indicate (AspSerSer)(6)-liposome as a promising targeted delivery system for RNA interference-based bone anabolic therapy.
authors.affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Baosheng
authors.initials: B
authors.lastname: Guo
authors.forename: Heng
authors.initials: H
authors.lastname: Wu
authors.forename: Tao
authors.initials: T
authors.lastname: Tang
authors.forename: Bao-Ting
authors.initials: BT
authors.lastname: Zhang
authors.forename: Lizhen
authors.initials: L
authors.lastname: Zheng
authors.forename: Yixin
authors.initials: Y
authors.lastname: He
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Yang
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Pan
authors.forename: Heelum
authors.initials: H
authors.lastname: Chow
authors.forename: Kinwah
authors.initials: K
authors.lastname: To
authors.forename: Yaping
authors.initials: Y
authors.lastname: Li
authors.forename: Dahu
authors.initials: D
authors.lastname: Li
authors.forename: Xinluan
authors.initials: X
authors.lastname: Wang
authors.forename: Yixiang
authors.initials: Y
authors.lastname: Wang
authors.forename: Kwongman
authors.initials: K
authors.lastname: Lee
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Hou
authors.forename: Nan
authors.initials: N
authors.lastname: Dong
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Kwoksui
authors.initials: K
authors.lastname: Leung
authors.forename: Leungkim
authors.initials: L
authors.lastname: Hung
authors.forename: Fuchu
authors.initials: F
authors.lastname: He
authors.forename: Lingqiang
authors.initials: L
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Qin
mesh_terms: D045930:Anabolic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D047390:Casein Kinase II / Q000037:antagonists & inhibitors; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D008081:Liposomes / Q000008:administration & dosage / Q000627:therapeutic use; D018613:Microscopy, Confocal; D010006:Osteoblasts / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D010024:Osteoporosis / Q000188:drug therapy; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D045930:Anabolic Agents; D008081:Liposomes; D034741:RNA, Small Interfering; D047390:Casein Kinase II