Targeted PRINT® nanoparticles for effective cancer therapy

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Alternate title
  • Targeted PRINT nanoparticles for effective cancer therapy
Last Modified
  • March 21, 2019
Creator
  • McGowan, Kelly Marie
    • Affiliation: College of Arts and Sciences, Department of Chemistry
Abstract
  • Conventional therapeutics for the treatment of cancer are often faced with challenges such as systemic biodistribution within the body, drug degradation in vivo, low bioavailability at the site of disease, and off-target toxicity. As such, particulate drug delivery systems have been developed with the aim of minimizing these limitations of current therapies. Through the PRINT® (Particle Replication in Non-wetting Templates) technology, hydrogel nanoparticles, prepared from biocompatible poly(ethylene glycol) and acid-sensitive silyl ether crosslinkers, were functionalized and conjugated with targeting ligands for the folate receptor (FR), HER2 receptor, and transferrin receptor (TfR). By conjugating specific ligands to nanoparticles to impart specificity, highly selective targeting and internalization (>80%) of nanoparticles were demonstrated in various cancer cell lines. The extent of cellular uptake of targeted nanoparticles was dependent on the surface characteristics of the nanoparticles, particle concentration, and kinetics. Because a negative surface charge reduces nonspecific cellular uptake, attaching monoclonal antibodies to the surface of negatively charged PRINT nanoparticles facilitated specific binding of the antibodies to cellular surface receptors that subsequently triggered receptor-mediated endocytosis. Additionally, the multivalent nature of nanoparticles influenced cellular uptake. Specifically, nanoparticles with a higher valence internalized more rapidly and efficiently than those with a lower valence. Nanoparticles that selectively target and accumulate within diseased cells have the potential of minimizing drug degradation under physiological conditions, enhancing bioavailability at the tumor, improving the efficacy of the drug, and reducing toxicity from systemic biodistribution. Drug delivery through targeted nanoparticles was achieved by loading nanoparticles with silyl ether-modified gemcitabine prodrugs. Covalently reacting the prodrug into the nanoparticle matrix minimized drug loss, while the acid-sensitive silyl ether moiety enabled release of gemcitabine at a low pH. Targeted nanoparticles appeared to accumulate intracellularly, through TfR-mediated endocytosis, within acidic vesicles whose environment could trigger degradation of the prodrug and thus, release of gemcitabine. Leveraging the specificity of targeted nanoparticles and acid-sensitive silyl ether-based gemcitabine, targeted nanoparticles (IC50 = 1.8 × 10-2 nM) were far more potent than free gemcitabine (IC50 = 4.1 × 104 nM). Therefore, this system demonstrates the tremendous potential of targeted PRINT nanoparticles as advanced drug delivery agents.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry.
Advisor
  • DeSimone, Joseph M.
Degree granting institution
  • University of North Carolina at Chapel Hill
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