title: Tetracycline-grafted PLGA nanoparticles as bone-targeting drug delivery system.
abstract: OBJECTIVE
  Nanoparticles (NPs) that target bone tissue were developed using poly(lactic-co-glycolic acid) (PLGA) copolymers and tetracycline (TC)-based bone-targeting moieties. These NPs are expected to enable the transport of drugs, such as simvastatin (SIM), for the treatment of osteoporosis.
  
  
  METHODS
  The molecular structures of TC-PLGA were validated by (1)H-NMR, and the SIM-loaded NPs were prepared using the solvent emulsification method. The surface properties, cytotoxicity, cellular uptake, cell mineralization, bone targeting potential, and animal pharmacodynamics of the TC-PLGA NPs were evaluated and compared to those of PLGA NPs.
  
  
  RESULTS
  It was confirmed that the average particle size of the NPs was approximately 220 nm. In phosphate-buffered saline (PBS, pH 7.4), the SIM-loaded NPs exhibited a cumulative release of up to 80% within 72 hours. An in vitro cell evaluation indicated that the NPs had an excellent cellular uptake capacity and showed great biocompatibility with MC3T3-E1 cells, thereby reducing the cytotoxic effects of SIM. The cell mineralization assay showed that the SIM-loaded NPs induced osteogenic differentiation and mineralized nodule formation in MC3T3-E1 cells, thereby achieving the same effect as SIM. Preliminary findings from in vitro and in vivo bone affinity assays indicated that the TC-PLGA NPs may display increased bone-targeting efficiency compared to PLGA NPs lacking a TC moiety. The use of SIM-loaded TC-PLGA NPs in treating osteoporosis was tested through animal pharmacodynamics analyses performed in ovariectomized rats, and the results suggested that the SIM-loaded TC-PLGA NPs can improve the curative effects of SIM on the recovery of bone mineral density compared to either SIM-loaded PLGA NPs or SIM alone.
  
  
  CONCLUSIONS
  Bone-targeting NPs, which were based on the conjugation of TC to PLGA copolymers, have the ability to target bone. These NPs may be developed as a delivery system for hydrophobic drugs, and they are expected to improve the curative effects of drugs, reduce the administered drug doses, and reduce side effects in other organs.
authors.affiliation: Center of Analysis and Measurement, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Shan
authors.initials: S
authors.lastname: Tao
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Guihong
authors.initials: G
authors.lastname: Chai
authors.affiliation: The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Wang
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Fu-Qiang
authors.initials: FQ
authors.lastname: Hu
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects*; D002454:Cell Differentiation; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems; D005260:Female; D019793:Fluorescein / Q000737:chemistry; D019344:Lactic Acid / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008813:Mice, Inbred ICR; D053758:Nanoparticles / Q000737:chemistry*; D010012:Osteogenesis / Q000187:drug effects*; D010024:Osteoporosis / Q000188:drug therapy; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000737:chemistry*; D012997:Solvents; D013499:Surface Properties; D013752:Tetracycline / Q000737:chemistry*
chemical_list: D012997:Solvents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D019821:Simvastatin; D013752:Tetracycline; D019793:Fluorescein
keywords: bone targeting; nanoparticles; osteoporosis; poly(lactic-co-glycolic acid); simvastatin; tetracycline