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Nanopharmaceutical for improved anti-HIV therapy

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TitleInfo
Title
Nanopharmaceutical for improved anti-HIV therapy
Name (type = personal)
NamePart (type = family)
Wan
NamePart (type = given)
Li
DisplayForm
Li Wan
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Sinko
NamePart (type = given)
Patrick
Affiliation
Advisory Committee
DisplayForm
Patrick J. Sinko
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Stein
NamePart (type = given)
Stanley
Affiliation
Advisory Committee
DisplayForm
Stanley Stein
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
You
NamePart (type = given)
Guofeng
Affiliation
Advisory Committee
DisplayForm
Guofeng You
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Leibowitz
NamePart (type = given)
Michael
Affiliation
Advisory Committee
DisplayForm
Michael J. Leibowitz
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)
2007
DateOther (qualifier = exact); (type = degree)
2007
Language
LanguageTerm (authority = ISO 639-3:2007); (type = text)
English
PhysicalDescription
Form (authority = marcform)
electronic
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
xx, 191 pages
Note
Supplementary File: Dissertation-Preliminary Pages
Abstract (type = abstract)
Curing HIV-1 infection has remained elusive due to low and fluctuating drug levels, arising from poor absorption, viral reservoirs and sanctuary sites, toxicity and patient non-adherence. The theme of the current study is to investigate the value of combining AIDS drugs and modifiers of cellular uptake into macromolecular nanocarriers having novel pharmacological properties for improving current anti-HIV therapy. Nanopharmaceuticals were prepared from different combinations of saquinavir (SQV), R.I.CK-Tat9 and the polymeric nanocarrier polyethylene glycol. Anti-HIV activities were measured in MT-2 cells while parallel studies were performed in uninfected cells to determine cellular toxicity. Flow cytometry and confocal microscopy studies suggested that variations in intracellular uptake and intracellular localization, as well as synergistic inhibitory effects of SQV and Tat peptides, contributed to the unexpected and substantial differences in antiviral activity. Our results demonstrate that highly potent multi-drug nanopharmaceuticals with low non-specific toxicity can be produced by combining moieties with anti-HIV agents for different targets onto macromolecules having improved delivery properties.
The present study also addressed the issue of insufficient drug exposure of viral reservoirs in macrophages. Macrophages are a key target and primary cellular reservoir for HIV, and are believed to be responsible for the viral rebound effect observed upon the discontinuation of therapy. In this study, multiple copies of N-formyl-Met-Leu-Phe (fMLF), a known chemo-attractant for macrophages, were conjugated to multifunctional nanocarrier derived from commercially available or novel peptide-based PEGs. The results of uptake studies indicated that appending only two copies of fMLF to the nanocarrier is sufficient for optimal binding and the optimal size of the nanocarrier was about 20 kDa. Further pharmacokinetics and biodistribution studies demonstrated that the attachment of fMLF increased accumulation of PEG nanocarriers in major macrophage-residing tissues such as liver, kidneys and spleen. Taken together, these results demonstrated the feasibility of using macrophage-targeted nanocarriers for enhancing drug uptake in human macrophage-like cells in vitro or macrophages residing in tissues in vivo. These results indicate great promise for enhancing targeted drug delivery to HIV-infected macrophages, which may eventually improve current anti-HIV therapy by improving therapeutic efficacy, minimizing systemic toxicity and simplifying administration regimens.
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references (p. 167-189).
Subject (authority = RUETD)
Topic
Pharmaceutical Science
Subject (authority = ETD-LCSH)
Topic
AIDS vaccines
Subject (authority = ETD-LCSH)
Topic
Viral vaccines
RelatedItem (type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier (type = local)
rucore19991600001
Identifier (type = hdl)
http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.13849
Identifier
ETD_133
Identifier (type = doi)
doi:10.7282/T3M32W7C
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

RightsDeclaration (AUTHORITY = GS); (ID = rulibRdec0006)
The author owns the copyright to this work.
Copyright
Status
Copyright protected
Availability
Status
Open
AssociatedEntity (AUTHORITY = rulib); (ID = 1)
Name
Li Wan
Role
Copyright holder
Affiliation
Rutgers University. Graduate School-New Brunswick
RightsEvent (AUTHORITY = rulib); (ID = 1)
Type
Permission or license
Detail
Non-exclusive ETD license
AssociatedObject (AUTHORITY = rulib); (ID = 1)
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.
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