THE MONONUCLEAR PHAGOCYTE SYSTEM AS A PHENOTYPIC PROBE FOR NANOPARTICLE PHARMACOKINETICS AND PHARMACODYNAMICS IN PRECLINICAL AND CLINICAL SYSTEMS Public Deposited

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  • March 20, 2019
Creator
  • Caron, Whitney P.
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics
Abstract
  • Nanoparticles, or carrier-mediated agents are unique drug delivery platforms that provide numerous advantages, such as greater solubility, duration of exposure, and delivery to the site of action over their small molecule counterparts. However, there is substantial variability in systemic clearance and distribution, tumor delivery, and pharmacologic effects of these agents. This work explores some of the factors that affect the pharmacokinetics and pharmacodynamics of nanoparticle agents in preclinical models and patients. The ultimate goal of this work was to determine whether nanoparticle therapy could be individualized in patients based on some of these factors. The primary biologic focus was to measure the function of circulating cells in the blood known to play a role in the clearance of nanoparticles. It was determined that the function of monocytes and dendritic cells, as measured by phagocytosis and the production of reactive oxygen species (ROS) could serve as a phenotypic probe in patients. A phenotypic probe is a test that can be administered to a patient as a potential indicator of a drug's pharmacokinetics and pharmacodynamics, which can then be used to individualize therapy. This work uses patients with recurrent epithelial ovarian cancer receiving the nanoparticle PEGylated liposomal doxorubicin (PLD; Doxil) as part of their standard of care. This work shows an association between cell function and the clearance of PLD for both phagocytosis (R2= 0.43, P= 0.04) and production of ROS (R2= 0.61, P= 0.008). This is an encouraging finding for patients in light of the high variability seen with nanoparticle agent pharmacokinetics and pharmacodynamics. Ideally this work will be applied to other nanoparticles and disease states in the future.
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  • In Copyright
Advisor
  • Zamboni, William
Degree
  • Doctor of Philosophy
Graduation year
  • 2013
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