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Engineering tumor-targeted poly(amidoamine) (PAMAM) dendrimers for improved penetration and cellular delivery of short-interfering RNA (siRNA) through solid tumors

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TitleInfo
Title
Engineering tumor-targeted poly(amidoamine) (PAMAM) dendrimers for improved penetration and cellular delivery of short-interfering RNA (siRNA) through solid tumors
Name (type = personal)
NamePart (type = family)
Waite
NamePart (type = given)
Carolyn Leigh
NamePart (type = date)
1983-
DisplayForm
Carolyn Waite
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Roth
NamePart (type = given)
Charles M
DisplayForm
Charles M Roth
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Uhrich
NamePart (type = given)
Kathryn E
DisplayForm
Kathryn E Uhrich
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Moghe
NamePart (type = given)
Prabhas V
DisplayForm
Prabhas V Moghe
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Shreiber
NamePart (type = given)
David I
DisplayForm
David I Shreiber
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Minko
NamePart (type = given)
Tamara
DisplayForm
Tamara Minko
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)
2011
DateOther (qualifier = exact); (type = degree)
2011-10
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Cancer remains the second leading cause of death in the United States, despite significant advances in anticancer research. The standard-of-care for the treatment of cancer includes surgery in conjunction with traditional chemotherapy drugs or radiation therapy. However, the inherent cytotoxicity of conventional chemotherapeutics often causes adverse side effects in patients. Nanoscale materials have found utility for drug delivery to tumors as they accumulate in the tumor vasculature , reducing the necessary drug dose to patients. They have also proven useful to deliver unconventional drugs, including short-interfering RNA (siRNA), which is being explored to silence oncogenes. However, the current lack of safe, efficient siRNA delivery systems limits its widespread clinical use. The objective of this dissertation was to study the ability of poly(amidoamine) (PAMAM) dendrimers to facilitate the delivery of siRNA to malignant glioma on the cellular and tumor tissue levels. The intracellular delivery aspects of PAMAM-mediated siRNA delivery to malignant glioma cells were explored by employing partial surface amine acetylation of PAMAM dendrimers to reduce their net positive charge This work demonstrated the importance of endosomal buffering and the advantages of charge reduction on siRNA delivery. The ability of PAMAM dendrimers to mediate tumor-targeted siRNA delivery to tumor tissue was also studied. Dendrimers were modified to display various numbers of RGD peptides, and the number of peptides present influenced the distribution of siRNA cargo throughout a three-dimensional tumor model of malignant glioma. A biophysical analysis was performed to elucidate the transport mechanisms governing the tumoral penetration of these bioconjugates, and cellular binding affinity was found to influence significantly the transport of the bioconjugate materials through solid tumors. The results from this dissertation provide insights into the mechanisms governing siRNA delivery to cancer on both the cellular and tumor tissue levels. Design guidelines for tumor-targeted nanoscale siRNA delivery vectors were derived, and a methodology was developed to understand the mechanisms governing the penetration and transport of siRNA drugs throughout solid tumors. This work will help other researchers to design more effective drug delivery systems for anticancer applications, and it may impact the effect of siRNA and nanoscale materials on human disease.
Subject (authority = RUETD)
Topic
Chemical and Biochemical Engineering
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_3430
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
xiv, 140 p. : ill.
Note (type = degree)
Ph. D.
Note (type = bibliography)
Includes bibliographical references
Note (type = vita)
Includes vita
Note (type = statement of responsibility)
by Carolyn Leigh Waite
Subject (authority = ETD-LCSH)
Topic
Drug delivery systems
Subject (authority = ETD-LCSH)
Topic
Dendrimers in medicine
Subject (authority = ETD-LCSH)
Topic
Gliomas--Treatment
Subject (authority = ETD-LCSH)
Topic
RNA
Identifier (type = hdl)
http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000063690
RelatedItem (type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier (type = local)
rucore19991600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/T36M35XG
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Waite
GivenName
Carolyn
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2011-05-26 09:02:13
AssociatedEntity
Name
Carolyn Waite
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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