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Design, synthesis, and characterization of amphiphilic molecules for biomedical applications

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TitleInfo
Title
Design, synthesis, and characterization of amphiphilic molecules for biomedical applications
Name (type = personal)
NamePart (type = family)
Zhang
NamePart (type = given)
Yingyue
NamePart (type = date)
1990-
DisplayForm
Yingyue Zhang
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Uhrich
NamePart (type = given)
Kathryn
DisplayForm
Kathryn Uhrich
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
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)
2016
DateOther (qualifier = exact); (type = degree)
2016-10
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2016
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Amphiphilic molecules, comprised of both hydrophilic and hydrophobic domains, have been extensively developed and investigated for various biomedical applications. In this dissertation, polymeric and small molecular weight amphiphiles were rationally designed and utilized as atherosclerotic therapeutics, antimicrobials, and liposome stabilizing agent. Atherosclerosis, a leading cause of mortality in developed countries, is characterized by the buildup of oxidized low-density lipoprotein (oxLDL) within the vascular intima, unregulated oxLDL uptake by macrophages, and ensuing formation of arterial plaque. Amphiphilic macromolecules (AMs) comprised of a branched hydrophobic domain and a hydrophilic poly(ethylene glycol) (PEG) tail have shown promising anti-atherogenic effects through direct inhibition of oxLDL uptake by macrophages. In this study, five AMs with controlled variations were evaluated for their micellar and structural stability in the presence of serum and lipase, respectively, to develop underlying structure-atheroprotective activity relations. In parallel, molecular dynamics simulations were performed to explore the AM conformational preferences within an aqueous environment. Notably, AMs with ether linkages between the hydrophobic arms and sugar backbones demonstrated enhanced degradation stability and storage stability, and also elicited enhanced anti-atherogenic bioactivity. Additionally, AMs with increased hydrophobicity elicited increased atheroprotective bioactivity in the presence of serum. These studies provide key insights for designing more serum-stable polymeric micelles as prospective cardiovascular nanotherapies. The rapid emergence of antibiotic-resistant bacteria and lack of efficacious treatments have prompted extensive research in development of novel antimicrobial agents. Inspired by the unique membrane-targeting mechanism of naturally occurring antimicrobial peptides (AMPs), two series of cationic amphiphiles (CAms) were strategically designed with hydrophilic head groups and non-polar domains segregated to opposite sides of the amphiphiles’ backbone, known as a facially amphiphilic conformation. This orientation has been determined to be critical to elicit membrane-lytic properties. The CAms self-assembled into supramolecular nanostructures above their respective critical micelle concentrations (CMCs) upon direct dissolution. By systematically tuning the hydrophobicity, CAms with optimized compositions exhibited potent activity against both Gram-positive and Gram-negative bacteria as well as displaying negligible hemolytic activity. Scanning electron microscope and transmission electron microscope images revealed the morphology and ultrastructure changes of bacterial membranes induced by CAm treatment and further attested to their membrane-disrupting mechanism. Additionally, an all-atom molecular dynamics simulation was employed to understand the CAm-membrane interaction on a molecular level. This study shows that these CAms can serve as viable scaffolds for rationally designing the next generation of AMP mimics as effective antimicrobials to combat drug-resistant pathogens. Sterically stabilized liposomes have been widely used as long-circulating delivery vehicles. They are typically prepared with poly(ethylene glycol)- (PEG-) modified lipids, where the lipid portion is inserted in the lipid bilayers as an anchor and the hydrophilic PEG coats the surface to prevent liposome aggregation and rapid clearance in vivo. However, these steric protection effects are compromised upon systemic administration due to low retention of PEGylated lipids within liposome membranes upon dilution. Bolaamphiphiles (bolas), comprised of two hydrophilic head groups connected by a hydrophobic domain, can predominantly adopt a membrane-spanning configuration that confers robust bilayer retention. Hence, a series of PEG-bolas were developed to increase retention in the lipid bilayer, presumably leading to enhanced integrity of the PEG protective layer, and thus improved colloidal and biological stability (i.e., phagocytosis by macrophages) of resulting liposome formulations. We hypothesized that PEG-bolas with a sufficiently long hydrophobic domain and rigid central group could preferentially extend across lipid bilayers. Liposomes stabilized by PEG-bolas comprised of a biphenyl core and twelve-carbon alkyl chain exhibited similar storage and biological stability compared to conventional PEGylated lipid stabilized liposomes, but with significantly improved retention upon dilution. In this thesis, bioinspired amphiphiles were rationally designed by mimicking key characteristics of relevant biological molecules. Through systematic structure-activity relationship studies, the physicochemical properties and bioactivity of amphiphiles can be optimized for specific applications.
Subject (authority = RUETD)
Topic
Chemistry and Chemical Biology
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_7434
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (xxi, 143 p. : ill.)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Subject (authority = ETD-LCSH)
Topic
Macromolecules
Subject (authority = ETD-LCSH)
Topic
Drug delivery systems
Note (type = statement of responsibility)
by Yingyue Zhang
RelatedItem (type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier (type = local)
rucore19991600001
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/T3542QXK
Genre (authority = ExL-Esploro)
ETD doctoral
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RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Zhang
GivenName
Yingyue
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2016-07-05 13:01:02
AssociatedEntity
Name
Yingyue Zhang
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.
RightsEvent
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2016-10-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2017-10-31
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after October 31st, 2017.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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