Polymeric nanoparticles have gained increased popularity for drug delivery as they not only overcome the problem of limited aqueous solubility of many hydrophobic drug molecules, but also have the potential to improve the pharmacologic properties of anticancer drugs by increasing their in vivo half-life.
A series of biodegradable poly(D,L-lactide-co-2-methyl-2-carboxytrimethylene carbonate), P(LA-co-TMCC), was first synthesized by Sn(Oct)2 catalyzed bulk polymerization. In order to obtain the polymer product with a better-defined composition, the polymer synthesis was improved by using organo-catalytic ring-opening copolymerization. The copolymer molar mass and composition were controlled by varying the monomer to initiator ratio and the monomer feed ratio. By grafting amine-terminated polyethylene glycol (PEG-NH2) to the carboxylate groups on the copolymer backbone, amphiphilic copolymers were formed and self-assembled to form nanoparticles with narrow size distribution. The nanoparticle size was observed to be influenced by the polymer composition and the self-assembly conditions. To gain greater insight into the stability of these nanoparticles in blood, they were tested in both fetal bovine serum and individual serum protein solutions. By encapsulating Förster resonance energy transfer (FRET) pairs and following their release by fluorescence, these micelles demonstrated strong thermodynamic and kinetic stability in the presence of serum. By incorporating functional groups (azide or furan) on the PEG chains, either cell adhesive peptides (i.e. alkyne-functionalized GRGDS) or targeting antibodies (i.e. maleimide-modified trastuzumab) were coupled to the surface of the nanoparticles through Huisgen 1,3-dipolar cycloaddition reaction or Diels-Alder chemistry, respectively. The GRGDS modified nanoparticles showed specific binding affinity to rabbit corneal epithelial cells that express αvβ1 integrin receptors.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/32818 |
| Date | 31 August 2012 |
| Creators | Lu, Jiao |
| Contributors | Shoichet, Molly |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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