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Interplay of polymer and oligonucleotide properties in the nature of antisense effects

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TitleInfo (displayLabel = Citation Title); (type = uniform)
Title
Interplay of polymer and oligonucleotide properties in the nature of antisense effects
Name (ID = NAME001); (type = personal)
NamePart (type = family)
Sundaram
NamePart (type = given)
Sumati
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Sumati Sundaram
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author
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NamePart (type = family)
Roth
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Charles
Affiliation
Advisory Committee
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Charles Roth
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chair
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NamePart (type = family)
Pedersen
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Henrik
Affiliation
Advisory Committee
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Henrik Pedersen
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RoleTerm (authority = RULIB)
internal member
Name (ID = NAME004); (type = personal)
NamePart (type = family)
Moghe
NamePart (type = given)
Prabhas
Affiliation
Advisory Committee
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Prabhas Moghe
Role
RoleTerm (authority = RULIB)
internal member
Name (ID = NAME005); (type = personal)
NamePart (type = family)
Kim
NamePart (type = given)
Sobin
Affiliation
Advisory Committee
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Sobin Kim
Role
RoleTerm (authority = RULIB)
internal member
Name (ID = NAME006); (type = personal)
NamePart (type = family)
Minko
NamePart (type = given)
Tamara
Affiliation
Advisory Committee
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Tamara Minko
Role
RoleTerm (authority = RULIB)
outside member
Name (ID = NAME007); (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (ID = NAME008); (type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm (authority = RULIB)
school
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Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2008
DateOther (qualifier = exact); (type = degree)
2008-01
Language
LanguageTerm
English
PhysicalDescription
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electronic
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application/pdf
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text/xml
Extent
ix, 142 pages
Abstract
Antisense oligonucleotides can be utilized to silence the expression of a target gene via sequence-specific complementary base pairing. Antisense technology is applied as a basic research tool and is being developed therapeutically for a wide range of indications including cancer, inflammatory diseases and viral diseases. Its widespread application is impeded by the poor cellular delivery of oligonucleotides (ONs). Rational design of carriers for enhanced ON delivery demands a better understanding of the role of the vector on the extent and time course of antisense effects. This work highlights the interplay of polymer and ON properties in the nature of polymer mediated antisense responses. First, we demonstrate that ON structure exerts a significant influence on the strength of ON binding to, and dissociation from, the cationic polymer, poly-L-lysine. The finding implicates secondary structure as a relevant design parameter for antisense ONs and stresses the need for a comprehensive evaluation of ON-polymer structure-activity effects. Next, using well-characterized cationic polymer polyethyleneimine (PEI), we focus on understanding the effects of polymer molecular weight (MW) and ON backbone chemistry on antisense activity. We measure physico-chemical properties of complexes between PEI and phosphodiester and phosphorothioate backbone ONs, and evaluate their ability to deliver ONs to cells, leading to an antisense response. Our key finding is that the antisense activity is not determined solely by PEI MW or by ON chemistry, but rather by the interplay of both factors. Of particular importance is the strength of interactions between the carrier and the ON, which determines the rate at which the ONs are delivered intracellularly. Finally, we utilize the chemistry of the ONs as a means to influence the strength of interactions between PEI and ONs, and hence control the final antisense response. We show that it is possible to improve dramatically the efficiency of lower PEI MWs as ON carriers by manipulating the degree of phosphorothioate substitution in the ON chemistry. By correlating the PEI MW & ON chemistry with the observed antisense effects, we draw insightful structure-property relationships that will aid the rational design of ON carriers.
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references (p. 129-137).
Subject (ID = SUBJ1); (authority = RUETD)
Topic
Chemical and Biochemical Engineering
Subject (ID = SUBJ2); (authority = ETD-LCSH)
Topic
Oligonucleotides
Subject (ID = SUBJ3); (authority = ETD-LCSH)
Topic
Antisense nucleic acids
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.17225
Identifier
ETD_706
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/T36W9BDV
Genre (authority = ExL-Esploro)
ETD doctoral
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The author owns the copyright to this work.
Copyright
Status
Copyright protected
Availability
Status
Open
AssociatedEntity (AUTHORITY = rulib); (ID = 1)
Name
Sumati Sundaram
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
RightsEvent (AUTHORITY = rulib); (ID = 1)
Type
Permission or license
Detail
Non-exclusive ETD license
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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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