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Design, synthesis, and characterization of amphiphilic colloidal formulations for biomedical and personal care applications

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TitleInfo
Title
Design, synthesis, and characterization of amphiphilic colloidal formulations for biomedical and personal care applications
Name (type = personal)
NamePart (type = family)
Moretti
NamePart (type = given)
Alysha Eileen
NamePart (type = date)
1899-
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Alysha Eileen Moretti
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RoleTerm (authority = RULIB)
author
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Baum
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Jean
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Jean Baum
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Advisory Committee
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chair
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Uhrich
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Kathryn
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Kathryn Uhrich
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Advisory Committee
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internal member
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Romsted
NamePart (type = given)
Laurence
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Laurence Romsted
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Advisory Committee
Role
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internal member
Name (type = personal)
NamePart (type = family)
Joseph
NamePart (type = given)
Laurie
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Laurie Joseph
Affiliation
Advisory Committee
Role
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outside member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Graduate Studies
Role
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school
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Text
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theses
OriginInfo
DateCreated (qualifier = exact)
2017
DateOther (qualifier = exact); (type = degree)
2017-10
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2017
Place
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xx
Language
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eng
Abstract (type = abstract)
Amphiphilic molecules comprised of a hydrophilic and hydrophobic domain are able to self-assemble into a variety of higher order aggregates. These aggregate structures, and their diverse morphologies, have been utilized for the delivery of bioactive agents. Additionally, amphiphiles can be tailored to exhibit inherent bioactivity. This dissertation describes the design and synthesis of amphiphilic molecules that self-assemble into aggregate structures with defined physicochemical properties. Their formulation and biological activity for diverse biomedical and personal care applications are fully characterized. Amphiphilic macromolecules (AMs) conjugated to ligands known to activate the G-coupled protein receptor TGR5 were investigated as nanoparticle (NP) formulations for the reduction of inflammation in atherosclerotic macrophages. Macrophages propagate the atherosclerotic cascade by uncontrolled internalization of oxidized low-density lipoprotein (oxLDL) and subsequent secretion of inflammatory cytokines. AMs, based on an acylated sugar backbone conjugated to poly(ethylene glycol) (PEG), were synthesized containing a lithocholic acid (LCA) moiety, a known TGR5 agonist. Ligand-conjugated AMs were formulated into NPs to mitigate the lipid burden and inflammatory phenotype by competitively inhibiting oxLDL uptake through scavenger receptor (SR) interactions and activating the athero-protective receptor TGR5. Ligand-conjugated AM NPs significantly reduce oxLDL uptake compared to untreated controls and lower expression of inflammatory genes under direct control of TGR5. These studies demonstrate the potential of ligand-conjugated AM NPs to reduce the atherosclerotic phenotype in activated macrophages. Modifications were also made to AMs to enable their incorporation into distearoylphosphatidylcholine- (DSPC-) based liposomes for delivery applications. Liposome use has aided in the bioavailability, solubility, and improved pharmacokinetic profiles of a wide variety of active ingredients for biomedical and personal care products. This work expands upon the AM design to generate two series of molecules that simultaneously stabilize liposome colloidal properties and can be utilized to fine-tune release profiles of encapsulated cargo. Two series of AMs were synthesized with variations in their hydrophobic domains. All AMs improve upon stability properties at storage and physiological temperatures compared to DSPC-based liposomes alone. The chemical features of AMs, particularly the degree of unsaturation in the hydrophobic domain, influence release of hydrophilic molecules from liposomes’ interior. Molecular dynamics (MD) simulations reveal that AMs’ chemical structures influence local lipid properties, leading to the experimentally observed results. Together, this data offers insight that can be applied to design AMs with desirable physicochemical properties for bioactive delivery. Small molecule cationic amphiphiles (CAms) were designed to combat the rapid rise in drug resistant bacteria. CAms were designed to target and compromise the structural integrity of bacteria membranes, leading to cell rupture and death. Discrete structural features of CAms were varied and structure-activity relationship studies were performed to guide the rational design of potent antimicrobials with desirable selectivity and cytocompatibility profiles. In particular, the effect of cationic conformational flexibility, hydrophobic domain flexibility, and hydrophobic domain architecture were evaluated. Their influence on antimicrobial efficacy in Gram-positive and Gram-negative bacteria was determined, and their safety profiles established by assessing their impact on mammalian cells. All CAms have potent activity against bacteria and hydrophobic domain rigidity and branched architecture contribute to specificity. The insights gained from this project will aid in the optimization of CAm structures. Together, these three primary projects build upon the design of biocompatible amphiphiles that enable the delivery of bioactive molecules. Thorough structure-activity relationship studies were performed in each chapter to identify and generate amphiphiles with desirable outcomes for the specific application.
Subject (authority = RUETD)
Topic
Chemistry and Chemical Biology
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Title
Rutgers University Electronic Theses and Dissertations
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ETD_8451
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electronic resource
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application/pdf
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text/xml
Extent
1 online resource (xxv, 143 p. : ill.)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Alysha Eileen Moretti
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School of Graduate Studies Electronic Theses and Dissertations
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rucore10001600001
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NjNbRU
Identifier (type = doi)
doi:10.7282/T3377CVV
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

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The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Moretti
GivenName
Alysha
MiddleName
Eileen
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2017-09-29 00:31:52
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Alysha Moretti
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Affiliation
Rutgers University. School of Graduate Studies
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Author Agreement License
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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
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2017-10-31
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2018-10-31
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Access to this PDF has been restricted at the author's request. It will be publicly available after October 31st, 2018.
Copyright
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Copyright protected
Availability
Status
Open
Reason
Permission or license
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