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Design and synthesis of prostate specific antigen-activated prodrugs
Descriptive
TitleInfo
Title
Design and synthesis of prostate specific antigen-activated prodrugs
Name
(type = personal)
NamePart
(type = family)
Aloysius
NamePart
(type = given)
Herve
NamePart
(type = date)
1973-
DisplayForm
Herve Aloysius
Role
RoleTerm
(authority = RULIB)
author
Name
(type = personal)
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Hu
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Longqin
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Longqin Hu
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
chair
Name
(type = personal)
NamePart
(type = family)
Lavoie
NamePart
(type = given)
Edmond
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Edmond Lavoie
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Rice
NamePart
(type = given)
Joseph
DisplayForm
Joseph Rice
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Mitra
NamePart
(type = given)
Kaushik
DisplayForm
Kaushik Mitra
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
outside member
Name
(type = corporate)
NamePart
Rutgers University
Role
RoleTerm
(authority = RULIB)
degree grantor
Name
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NamePart
Graduate School - New Brunswick
Role
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(authority = RULIB)
school
TypeOfResource
Text
Genre
(authority = marcgt)
theses
OriginInfo
DateCreated
(qualifier = exact)
2014
DateOther
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(type = degree)
2014-10
CopyrightDate
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2014
Place
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(type = code)
xx
Language
LanguageTerm
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(type = code)
eng
Abstract
(type = abstract)
The feasibility of targeted delivery of cytotoxic agents to prostate cancer cells via selective activation of peptide-linked prodrugs by prostate-specific antigen (PSA) has been previously demonstrated. PSA is a chymotryspin-like serine protease that uniquely cleaves after Gln. Using cleavage maps for its natural substrates, semenogelins I and II, the highly specific PSA substrate glutaryl-Hyp-Ala-Ser-Chg-Gln was discovered, and subsequently coupled to various cytotoxic agents as a promoiety to synthesize prodrugs with enhanced selectivity for prostate cancer cells. In order to obtain PSA peptide substrates with improved specificity and plasma stability from the known substrate sequence glutaryl-Hyp-Ala-Ser-Chg-Gln, we systematically replaced the N-terminal segment with D-retro-inverso-peptides and incorporated 7-amino-4-methylcoumarin (7-AMC) after Gln for convenient fluorometric determination and ranking of the PSA substrate activity. Based on PSA cleavage rate and resistance to hydrolysis in plasma, GABA←mGly-Ala-Ser-Chg-Gln and glutaryl-Ser-Ala-Ser-Chg-Gln were identified as optimal promoieties and coupled to doxorubicin or phosphoramide mustard as PSA-cleavable prodrugs, using various linkers. The doxorubicin conjugates demonstrated comparable PSA cleavage rates, equal or improved cytotoxic profiles in PSA-producing tumor cells compared to the prodrug L-377,202 (glutaryl-Ser-Ala-Ser-Chg-Gln-Ser-Leu-Dox). We found that human neprilysin rapidly cleaved L-377,202 through its Ser-Leu linker and may be responsible for prodrug instability in blood and normal tissues. Thus, in addition to enhancing prodrug selectivity against non-PSA-secreting prostate cancer cell lines, stability in normal tissues was improved. Our results indicated that enhanced tumor specificity of peptide prodrugs targeted for activation by PSA in prostate cancer tumors was achievable with peptide sequence and linker modifications.
Subject
(authority = RUETD)
Topic
Medicinal Chemistry
Subject
(authority = ETD-LCSH)
Topic
Antibody-directed enzyme prodrug therapy
Subject
(authority = ETD-LCSH)
Topic
Prostate--Cancer--Treatment
RelatedItem
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TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier
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ETD
Identifier
ETD_5941
PhysicalDescription
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electronic resource
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application/pdf
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text/xml
Extent
1 online resource (xix, 174 p. : ill.)
Note
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Ph.D.
Note
(type = bibliography)
Includes bibliographical references
Note
(type = statement of responsibility)
by Herve Aloysius
RelatedItem
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TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
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rucore19991600001
Location
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(displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier
(type = doi)
doi:10.7282/T3BR8QN1
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
RightsDeclaration
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The author owns the copyright to this work.
RightsHolder
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Name
FamilyName
Aloysius
GivenName
Herve
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime
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(point = start);
(qualifier = exact)
2014-09-29 10:13:37
AssociatedEntity
Name
Herve Aloysius
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
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(point = start);
(qualifier = exact)
2018-10-18
DateTime
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2019-10-31
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after October 31, 2019.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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Technical
RULTechMD
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ETD
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windows xp
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