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Pharmacokinetics and toxicodynamics of intravenously administered rigid microparticles that passively target the pulmonary circulation of rodents
Descriptive
TitleInfo
Title
Pharmacokinetics and toxicodynamics of intravenously administered rigid microparticles that passively target the pulmonary circulation of rodents
Name
(type = personal)
NamePart
(type = family)
Kutscher
NamePart
(type = given)
Hilliard L.
NamePart
(type = date)
1978-
DisplayForm
Hilliard Kutscher
Role
RoleTerm
(authority = RULIB)
author
Name
(type = personal)
NamePart
(type = family)
Sinko
NamePart
(type = given)
Patrick J.
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Patrick J. Sinko
Affiliation
Advisory Committee
Role
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(authority = RULIB)
chair
Name
(type = personal)
NamePart
(type = family)
Cuitino
NamePart
(type = given)
Alberto M.
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Alberto M. Cuitino
Affiliation
Advisory Committee
Role
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(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Hatefi
NamePart
(type = given)
Arash
DisplayForm
Arash Hatefi
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Laskin
NamePart
(type = given)
Debra L.
DisplayForm
Debra L. Laskin
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
outside member
Name
(type = personal)
NamePart
(type = family)
Stone
NamePart
(type = given)
Howard A.
DisplayForm
Howard A. Stone
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
outside member
Name
(type = corporate)
NamePart
Rutgers University
Role
RoleTerm
(authority = RULIB)
degree grantor
Name
(type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm
(authority = RULIB)
school
TypeOfResource
Text
Genre
(authority = marcgt)
theses
OriginInfo
DateCreated
(qualifier = exact)
2012
DateOther
(qualifier = exact);
(type = degree)
2012-10
CopyrightDate
(qualifier = exact)
2012
Place
PlaceTerm
(type = code)
xx
Language
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(authority = ISO639-2b);
(type = code)
eng
Abstract
(type = abstract)
Systemic 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.
Subject
(authority = RUETD)
Topic
Pharmaceutical Science
RelatedItem
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TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier
(type = RULIB)
ETD
Identifier
ETD_4293
PhysicalDescription
Form
(authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
xiii, 170 p. : ill.
Note
(type = degree)
Ph.D.
Note
(type = bibliography)
Includes bibliographical references
Note
(type = vita)
Includes vita
Note
(type = statement of responsibility)
by Hilliard L. Kutscher
Subject
(authority = ETD-LCSH)
Topic
Drug delivery systems
Subject
(authority = ETD-LCSH)
Topic
Pulmonary circulation
Identifier
(type = hdl)
http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000066851
RelatedItem
(type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
Location
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(displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier
(type = doi)
doi:10.7282/T3TX3D4R
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
RightsDeclaration
(ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder
(type = personal)
Name
FamilyName
Kutscher
GivenName
Hilliard
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime
(encoding = w3cdtf);
(qualifier = exact);
(point = start)
2012-10-03 14:44:41
AssociatedEntity
Name
Hilliard Kutscher
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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