title: Poly aspartic acid peptide-linked PLGA based nanoscale particles: potential for bone-targeting drug delivery applications.
abstract: Delivering drugs specifically to bone tissue is very challenging due to the architecture and structure of bone tissue. Poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) hold great promise for the delivery of therapeutics to bone tissue. The goal of the present research was to formulate a PLGA-based NP drug delivery system for bone tissue exclusively. Since poly-aspartic acids (poly-Asp) peptide sequence has been shown to bind to hydroxyapatite (HA), and has been suggested as a molecular tool for bone-targeting applications, we fabricated PLGA-based NPs linked with poly-Asp peptide sequence. Nanoparticles made of methoxy - poly(ethylene glycol) (PEG)-PLGA and maleimide-PEG-PLGA were prepared using a water-in-oil-in-water double emulsion and solvent evaporation method. Fluorescein isothiocyanate (FITC)-tagged poly-Asp peptide was conjugated to the surface of the nanoparticles via the alkylation reaction between the sulfhydryl groups at the N-terminal of the peptide and the CC double bond of maleimide at one end of the polymer chain to form thioether bonds. The conjugation of FITC-tagged poly-Asp peptide to PLGA NPs was confirmed by NMR analysis and fluorescent microscopy. The developed nanoparticle system is highly aqueous dispersible with an average particle size of ∼80 nm. In vitro binding analyses demonstrated that FITC-poly-Asp NPs were able to bind to HA gel as well as to mineralized matrices produced by human mesenchymal stem cells and mouse bone marrow stromal cells. Using a confocal microscopy technique, an ex vivo binding study of mouse major organ ground sections revealed that the FITC-poly-Asp NPs were able to bind specifically to the bone tissue. In addition, proliferation studies indicated that our FITC-poly-Asp NPs did not induce cytotoxicity to human osteoblast-like MG63 cell lines. Altogether, these promising results indicated that this nanoscale targeting system was able to bind to bone tissue specifically and might have a great potential for bone disease therapy in clinical applications.
authors.affiliation: Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States; The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States; Department of Medicine, Division of Endocrinology, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States; The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States; Department of Orthopedic Surgery, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Yu
authors.affiliation: Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States; The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States; Department of Medicine, Division of Endocrinology, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States.
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Carbone
authors.affiliation: Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States; The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States.
authors.forename: Clarke
authors.initials: C
authors.lastname: Nelson
authors.affiliation: Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States; The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States; Department of Orthopedic Surgery, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States.
authors.forename: Ho Man
authors.initials: HM
authors.lastname: Kan
authors.affiliation: Institute for Regenerative Engineering, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States; The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States; Department of Medicine, Division of Endocrinology, University of Connecticut Health Center, School of Medicine, Farmington, CT 06030, United States; Department of Biomedical Engineering, University of Connecticut, School of Engineering, Storrs, CT 06268, United States. Electronic address: wlo@uchc.edu.
authors.forename: Kevin W-H
authors.initials: KW
authors.lastname: Lo
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004337:Drug Carriers / Q000737:chemistry*; D017886:Durapatite / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D017154:Stromal Cells / Q000378:metabolism; D013499:Surface Properties
chemical_list: D004337:Drug Carriers; D010455:Peptides; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; C017645:polyaspartate; D019344:Lactic Acid; D017886:Durapatite; D016650:Fluorescein-5-isothiocyanate
keywords: Bone diseases; Nanoparticles; Peptides; Targeted drug delivery