title: Target-specific delivery of siRNA by stabilized calcium phosphate nanoparticles using dopa-hyaluronic acid conjugate.
abstract: Low cytotoxicity and high cellular gene delivery capability are among the most important prerequisites for the selection of a non-viral carrier. Although calcium phosphate (CAP) nanoparticles have been long used for animal cell transfection, its rapid and uncontrollable crystal growth and lack of tissue specificity are among the most challenging problems that limit its use in the clinic. In this study, we report the development of CAP nanoparticles stabilized by a conjugate of the mussel-inspired adhesive molecule, 3,4-dihydroxy-l-phenylalanine (dopa), and a nontoxic hydrophilic natural polymer, hyaluronic acid (HA), for targeted siRNA delivery to tumors. CAP/siRNA/dopa-HA can form compact nanoparticles that effectively protect siRNA from enzymatic degradation despite the structural drawbacks of siRNA, such as low charge density and short and rigid structure. In addition, stabilized CAP nanoparticles were able to maintain their colloidal stability in a physiological salt condition for over a week. The superior ability of CAP/siRNA/dopa-HA to maintain the integrity of encapsulated siRNA and the stability in solution of the nanoparticles allow this formulation to achieve improved intratumoral accumulation of siRNA and a high level of target gene silencing in solid tumors after systemic administration. Considering its biocompatibility, transfection efficacy, and tumor targeting capability, this stabilized calcium phosphate nanoparticle-based gene delivery platform should be considered a promising candidate carrier for systemic siRNA delivery and targeted cancer therapy.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Min Sang
authors.initials: MS
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: The Graduate School of Nanoscience & Technology (WCU), Department of Chemistry, KAIST, Daejeon 305-701, Republic of Korea.
authors.forename: Eunkyoung
authors.initials: E
authors.lastname: Byun
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Nak Won
authors.initials: NW
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Kyuri
authors.initials: K
authors.lastname: Lee
authors.affiliation: The Graduate School of Nanoscience & Technology (WCU), Department of Chemistry, KAIST, Daejeon 305-701, Republic of Korea.
authors.forename: Haeshin
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Chemical and Biological Engineering, Korea University, Seoul 136-713, Republic of Korea.
authors.forename: Sang Jun
authors.initials: SJ
authors.lastname: Sim
authors.affiliation: School of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Doo Sung
authors.initials: DS
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: jhjeong@skku.edu.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
mesh_terms: D000818:Animals; D002130:Calcium Phosphates / Q000737:chemistry*; D045744:Cell Line, Tumor; D004295:Dihydroxyphenylalanine / Q000737:chemistry*; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D014162:Transfection
chemical_list: D002130:Calcium Phosphates; D034741:RNA, Small Interfering; D004295:Dihydroxyphenylalanine; D006820:Hyaluronic Acid; C020243:calcium phosphate
keywords: 3,4-Dihydroxy-l-phenylalanine; Calcium phosphate nanoparticle; Gene delivery; Hyaluronic acid; Targeted delivery