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Design and synthesis of prostate specific antigen-activated prodrugs
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Aloysius, Herve. Design and synthesis of prostate specific antigen-activated prodrugs. Retrieved from https://doi.org/doi:10.7282/T3BR8QN1

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TitleDesign and synthesis of prostate specific antigen-activated prodrugs
NameAloysius, Herve (author); Hu, Longqin (chair); Lavoie, Edmond (internal member); Rice, Joseph (internal member); Mitra, Kaushik (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2014
Other Date2014-10 (degree)
SubjectMedicinal Chemistry, Antibody-directed enzyme prodrug therapy, Prostate--Cancer--Treatment
Extent1 online resource (xix, 174 p. : ill.)
DescriptionThe 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.
NotePh.D.
NoteIncludes bibliographical references
Noteby Herve Aloysius
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3BR8QN1
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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