title: Synthesis and characterization of cationic polymeric nanoparticles as simvastatin carriers for enhancing the osteogenesis of bone marrow mesenchymal stem cells.
abstract: Simvastatin (SIM) can increase osteoblast activity and enhance osteogenesis. However, some limitations of SIM have been noted, such as statin-associated rhabdomyolysis and its poor solubility in water. In this study, we fabricated new cationic nanoparticles (NPs) designed for the controlled release of hydrophobic SIM and endocytosis by cells with the aim of reducing the total required amount of SIM administered and enhancing the osteogenesis of bone marrow mesenchymal stem cells (BMSCs). New copolymers of bis(poly(lactic-co-glycolic acid)-phenylalanine-polyethylene glycol)-quaternary ammonium grafted diethyltriamine (bis(PLGA-phe-PEG)-qDETA; BPPD) were created using a diethyltriamine-quaternary ammonium (qDETA) moiety, hetero-bifunctional polyethylene glycol (COOH-PEG-NH2), phenylalanine (phe) and poly(lactic-co-glycolic acid) (PLGA). SIM encapsulated in BPPD NPs (SIM/BPPD) was fabricated using a water-miscible solvent. The size distributions of BPPD NPs and SIM/BPPD NPs, the encapsulation efficacy and the in vitro release profile of SIM in SIM/BPPD NPs over 6days were investigated. Based on the results of Alizarin Red S staining, alkaline phosphatase (ALP) activity assays and quantitative polymerase chain reaction (Q-PCR) results, we propose that SIM/BPPD NPs may induce osteogenesis in BMSCs by enhancing the expression of an osteogenic gene, which subsequently elevates ALP activity and mineralization, resulting in enhanced BMSC osteogenesis. These results suggest that the SIM/BPPD NPs may be used as hydrophobic drug carriers to reduce the total required amount of SIM administered and to provide an effective SIM release mechanism for enhancing BMSC osteogenesis. Surprisingly, BPPD NPs were also shown to have the ability to promote osteogenesis in BMSCs by enhancing the expression of osteogenic genes, especially osteocalcin (OC), and subsequently elevating ALP activity and mineralization.
authors.affiliation: Department of Physiology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Chau-Zen
authors.initials: CZ
authors.lastname: Wang
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Orthopaedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Yin-Chih
authors.initials: YC
authors.lastname: Fu
authors.affiliation: Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Shih-Ciang
authors.initials: SC
authors.lastname: Jian
authors.affiliation: School of Dentistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Yan-Hsiung
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Department of Respiratory Therapy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Po-Len
authors.initials: PL
authors.lastname: Liu
authors.affiliation: Department of Physiology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Ho
authors.affiliation: Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address: ckwang@kmu.edu.tw.
authors.forename: Chih-Kuang
authors.initials: CK
authors.lastname: Wang
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019821:Simvastatin / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004337:Drug Carriers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015675:Osteocalcin; D011092:Polyethylene Glycols; D019821:Simvastatin; D000469:Alkaline Phosphatase
keywords: Bone marrow mesenchymal stem cells; Cationic copolymers; Nanoparticles; Osteogenesis; Simvastatin