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Pharmacokinetics and toxicodynamics of intravenously administered rigid microparticles that passively target the pulmonary circulation of rodents
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Kutscher, Hilliard L.. Pharmacokinetics and toxicodynamics of intravenously administered rigid microparticles that passively target the pulmonary circulation of rodents. Retrieved from https://doi.org/doi:10.7282/T3TX3D4R

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TitlePharmacokinetics and toxicodynamics of intravenously administered rigid microparticles that passively target the pulmonary circulation of rodents
NameKutscher, Hilliard L. (author); Sinko, Patrick J. (chair); Cuitino, Alberto M. (internal member); Hatefi, Arash (internal member); Laskin, Debra L. (outside member); Stone, Howard A. (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2012
Other Date2012-10 (degree)
SubjectPharmaceutical Science, Drug delivery systems, Pulmonary circulation
Extentxiii, 170 p. : ill.
DescriptionSystemic treatment of localized diseases, currently the most widely used method of drug delivery, often results in dose limiting toxicity. Reducing the amount of drug administered to minimize toxicity often reduces treatment effectiveness. Many drug delivery systems actively target their site based on an over-expression of cell surface receptors that may differ during disease or treatment progression. The purpose of this thesis was to determine the optimal size/number of intravenously administered rigid polystyrene microparticles (MPs) that are passively filtered by the pulmonary circulation system prior to causing dose-limiting toxicity and to develop an appropriately sized rigid yet biodegradable MP for future use. Passive entrapment of MPs in the lung depended upon size. In a rat model, rigid, non-degradable 10 μm polystyrene MPs were trapped in the lung capillary and remained for the duration of the 1-week study. Smaller MPs (6 μm) were initially trapped in the lung but migrated to the liver and spleen over 48 h whereas 3 μm MPs eluded the lung’s filtering capability and became entrapped in the liver by 1 h. To devise a non-invasive technique to detect early toxicity, a mathematical algorithm based on a clinically-relevant, non-invasive method developed in humans was adapted to study pulmonary gas exchange in young CD-1 mice. A threshold MP dosage that resulted in a rapid decrease in function was found for different MP sizes. The ventilation-perfusion ratio (VA/Q) was dramatically reduced from pre-treatment to Day 1 post-treatment when ≥550,000 10 μm MPs/g, ≥40,000 25 μm MPs/g or ≥4,000 45 μm MPs/g were administered. Shunt increased slightly with MP burden but was not a consistent early marker for impaired gas exchange from microemboli. Of interest was that by Day 7, the resulting hypoxemia was resolved. Finally, the manufacture of biodegradable, albumin-based MPs was optimized to create an appropriately-sized narrow distribution using an emulsion technique. Increased heating (150 °C vs. 120 °C) caused an increase in lysinoalanine formation and decreased the lung clearance rate, while not changing MP size. In summary, understanding of the pharmacokinetics, toxicodynamics, and design of passively targeted intravenously administered MPs was significantly advanced.
NotePh.D.
NoteIncludes bibliographical references
NoteIncludes vita
Noteby Hilliard L. Kutscher
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3TX3D4R
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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