Bisphosphonate-modified nanoparticles as drug delivery systems for bone diseases

  • Author / Creator
    Wang, guilin
  • The objective of this thesis is to design nanoparticle (NP)-based drug delivery systems suitable for treatment of bone diseases. Two types of nanocarriers, (1) polymer coated bovine serum albumin (BSA) NPs and (2) lipid based NPs (micelles and liposomes) were investigated. The BSA NPs were prepared by a coacervation method and stabilized with a polymer coating approach. For bone-specific delivery of bone morphogenetic protein-2 (BMP-2), a copolymer polyethyleneimine-graft-poly(ethylene glycol) conjugated with 2-(3-mercaptopropylsulfanyl)-ethyl-1,1-bisphosphonic acid (PEI-PEG-thiolBP) was synthesized and used for coating the BSA NPs. The particle size and ζ-potential of the NPs could be effectively modulated by the processing parameters. All the NPs showed no or low cytotoxicity (except for a high concentration of PEI), and the NP encapsulated BMP-2 displayed full retention of its bioactivity. By encapsulating 125I-labeled BMP-2, the polymer-coated NPs were assessed for hydroxyapatite (HA) affinity; all NP-encapsulated BMP-2 showed significant affinity to HA as compared with free BMP-2 in vitro, and the PEI-PEG-thiolBP coated NPs improved the in vivo retention of BMP-2 compared with uncoated NPs. However, the biodistribution of NPs after intravenous injection in a rat model indicated no beneficial effects of thiolBP-coated NPs for bone targeting. Alternatively, micelles and liposomes were prepared with a conjugate of distearoylphosphoethanolamine-polyethyleneglycol with thiolBP (DSPE-PEG-thiolBP) to create mineral-binding nanocarriers. The thiolBP-decorated liposomes also displayed a stronger binding affinity to HA and a collagen/HA (Col/HA) scaffold and gave increased retention in the scaffold in a subcutaneous implant model in rats. Taking advantage of the high HA affinity of the BP-liposomes, a sustainable release system was developed by sequestering the liposomal drugs in the Col/HA scaffolds. Three different model drugs, carboxyfluorescein, doxorubicin and lysozyme, were used to evaluate the drug release profiles from the liposome-loaded scaffolds, and all showed a slowing effect of the BP on the release of the liposome-encapsulated drugs from the Col/HA scaffolds. This liposome-scaffold combination will provide a platform for the application of various therapeutic agents for bone regeneration. In conclusion, the BP-modified NPs showed strong mineral-binding affinity. Although the systemic bone targeting was limited by physiological barriers, these NPs are promising in local delivery and controlled release of bioactive molecules for treatment of bone diseases.

  • Subjects / Keywords
  • Graduation date
    Spring 2011
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Lobenberg, Raimar (Faculty of Pharmacy and Pharmaceutical Sciences)
    • Elliott, Janet (Chair only, Department of Chemical and Materials Engineering)
    • Fenniri, Hicham (Department of Chemistry)
    • Wang, Dong (Pharmaceutical Sciences, University of Nebraska Medical Center)
    • Choi, Phillip (Department of Chemical and Materials Engineering)
    • Unsworth, Larry (Department of Chemical and Materials Engineering)