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. / Chemical Engineering
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/1830 |
| Date | 06 1900 |
| Creators | Wang, guilin |
| Contributors | Uludag, Hasan (Department of Chemical and Materials Engineering), Unsworth, Larry (Department of Chemical and Materials Engineering), Lobenberg, Raimar (Faculty of Pharmacy and Pharmaceutical Sciences), Choi, Phillip (Department of Chemical and Materials Engineering), Fenniri, Hicham (Department of Chemistry), Wang, Dong (Pharmaceutical Sciences, University of Nebraska Medical Center), Elliott, Janet (Chair only, Department of Chemical and Materials Engineering) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 1726813 bytes, application/pdf |
| Relation | G Wang, H Uludag. Recent developments in nanoparticle-based drug delivery and targeting systems with emphasis on protein-based nanoparticles. Expert Opinion on Drug Delivery. 2008. 5: 499-515., G Wang, K Siggers, S Zhang, H Jiang, Z Xu, RF Zernicke, J Matyas, H Uludag. Preparation of BMP-2 containing bovine serum albumin (BSA) nanoparticles stabilized by polymer coating. Pharmaceutical Research. 2008. 25: 2896-2909, G Wang, C Kucharski, X Lin, H. Uludag. Bisphosphonate-coated BSA nanoparticles lack bone targeting after systemic administration. Journal of Drug Targeting. 2010, 18: 611-626. |
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