title: Selective local delivery of RANK siRNA to bone phagocytes using bone augmentation biomaterials.
abstract: Fracture healing and fracture fixation in the context of osteoporosis is extremely difficult. To inhibit osteoclast-induced bone resorption and associated implant loosening in this pathology, we describe a local delivery strategy to delivery RNA interfering technology to bone sites to target and down-regulate osteoclast formation and function. Resorbable polymer, poly(lactic-co-glycolic acid) (PLGA) microparticles were exploited as a passive phagocyte-targeting carrier to deliver RANK siRNA to both osteoclast precursors and osteoclasts - the professional phagocytes in bone. These natural phagocytes internalize micron-sized particles while most other non-targeted cells in bone cannot. PLGA-siRNA microparticles were dispersed within biomedical grade calcium-based injectable bone cement clinically used in osteoporosis as a bone augmentation biomaterial for fragility fracture prevention and fixation. siRNA released from this formulation in vitro retains bioactivity against the cell target, RANK, in cultured osteoclast precursor cells, inhibiting their progression toward the osteoclastic phenotype. These data support the proof-of-concept to utilize a clinically relevant approach to locally deliver siRNA to phagocytes in bone and improve fragility fracture healing in the context of osteoporosis. This local delivery system delivers siRNA therapeutics directly to osteoporosis sites from clinically familiar injected bone augmentation materials but could be extended to other injectable biomaterials for local siRNA delivery.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112-5820, USA. Yuwei.wang@utah.edu
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Wang
authors.forename: Kenny K
authors.initials: KK
authors.lastname: Tran
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.forename: David W
authors.initials: DW
authors.lastname: Grainger
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D001843:Bone Cements / Q000737:chemistry*; D002130:Calcium Phosphates / Q000737:chemistry; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010586:Phagocytes / Q000378:metabolism*; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001672:Biocompatible Materials; D001843:Bone Cements; D002130:Calcium Phosphates; D034741:RNA, Small Interfering; D053246:Receptor Activator of Nuclear Factor-kappa B; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C020243:calcium phosphate