FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2905804703> ?p ?o ?g. }

• W2905804703 endingPage "333" @default.
• W2905804703 startingPage "333" @default.
• W2905804703 abstract "1424 We have recently investigated a macromolecular prodrug strategy for improved cancer chemotherapy based on two features: (a) rapid and selective binding of thiol-reactive prodrugs to the cysteine-34 position of endogenous albumin after intravenous administration, and (b) acid-sensitive or enzymatic release of the albumin-bound drug at the tumor site (1,2). In the present work we set out to develop albumin-binding prodrugs of doxorubicin that are cleaved by prostate-specific antigen (PSA). PSA is a serine protease that is over-expressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. Based on our synthetic experience, we developed albumin-binding prodrugs with the structures MT-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO; MT-Asn-Ser-Ser-Tyr-–Phe-Gln-DOXO [MT = maleimidotriethyleneglycol acid; DOXO = doxorubicin), EMC-(Arg)-Arg-Ser-Ser-Tyr-Tyr-Ser-X-DOXO [EMC: e-Maleimidocaproic acid; X = amino acid]. All of the maleimide derivatives bound rapidly to the cysteine-34 position of endogenous and exogenous albumin and were efficiently cleaved by PSA at the P1-P′1scissile bond releasing a respective doxorubicin dipeptide. The derivatives containing arginine residues (EMC-(Arg)-Arg-Ser-Ser-Tyr-Tyr-Ser-X-DOXO) exhibited excellent water-solubility for intravenous administration. Subsequent biological evaluation was focused on a PSA-negative xenograft model (PC 3) and PSA-positive xenograft model (CWR22) in order to assess the selectivity of our therapeutic approach. EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO showed no in vivo activity in the PSA-negative PC-3 model, but good activity in the CWR22 PSA-positive model that was comparable to doxorubicin. Incubation studies with CWR22 tumor homogenates revealed, however, that the full potential of EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO had not been exploited considering that a less active doxorubicin dipeptide DOXO-Gly-Ser and not doxorubicin was released in PSA-positive prostate carcinoma tissues. We thus optimized the structure of this prodrug by substituting Arg for Gly in the C-terminal position. In incubation studies with CWR22 tumor homogenates, the resulting albumin conjugate of EMC-Arg-Ser-Ser-Tyr-Tyr-Ser-Arg-DOXO initially released Ser-Arg-DOXO which was further degraded to doxorubicin as the final cleavage product. In vivo studies with this optimized PSA specific prodrug are underway. Kratz et al., Journal of Medicinal Chemistry. 45, 5523-33, 2002 Mansour et al., Cancer Res. 63, 4062-4066, 2003" @default.
• W2905804703 created "2019-01-01" @default.
• W2905804703 creator A5000949407 @default.
• W2905804703 creator A5007440695 @default.
• W2905804703 creator A5015041062 @default.
• W2905804703 creator A5025693952 @default.
• W2905804703 creator A5033629025 @default.
• W2905804703 creator A5070242893 @default.
• W2905804703 creator A5082857859 @default.
• W2905804703 creator A5085549201 @default.
• W2905804703 creator A5089659539 @default.
• W2905804703 date "2005-05-01" @default.
• W2905804703 modified "2023-10-17" @default.
• W2905804703 title "Using N-(2-hydroxypropyl)methacrylamide copolymer drug bioconjugate as a novel approach to deliver a Bcl-2-targeting compound HA14-1 in vivo" @default.
• W2905804703 hasPublicationYear "2005" @default.
• W2905804703 type Work @default.
• W2905804703 sameAs 2905804703 @default.
• W2905804703 citedByCount "0" @default.
• W2905804703 crossrefType "journal-article" @default.
• W2905804703 hasAuthorship W2905804703A5000949407 @default.
• W2905804703 hasAuthorship W2905804703A5007440695 @default.
• W2905804703 hasAuthorship W2905804703A5015041062 @default.
• W2905804703 hasAuthorship W2905804703A5025693952 @default.
• W2905804703 hasAuthorship W2905804703A5033629025 @default.
• W2905804703 hasAuthorship W2905804703A5070242893 @default.
• W2905804703 hasAuthorship W2905804703A5082857859 @default.
• W2905804703 hasAuthorship W2905804703A5085549201 @default.
• W2905804703 hasAuthorship W2905804703A5089659539 @default.
• W2905804703 hasConcept C108215921 @default.
• W2905804703 hasConcept C126322002 @default.
• W2905804703 hasConcept C150903083 @default.
• W2905804703 hasConcept C181199279 @default.
• W2905804703 hasConcept C185592680 @default.
• W2905804703 hasConcept C207001950 @default.
• W2905804703 hasConcept C2776125364 @default.
• W2905804703 hasConcept C2776694085 @default.
• W2905804703 hasConcept C2777468819 @default.
• W2905804703 hasConcept C2779138802 @default.
• W2905804703 hasConcept C2779201268 @default.
• W2905804703 hasConcept C2781303535 @default.
• W2905804703 hasConcept C515207424 @default.
• W2905804703 hasConcept C55493867 @default.
• W2905804703 hasConcept C71924100 @default.
• W2905804703 hasConcept C86803240 @default.
• W2905804703 hasConcept C98274493 @default.
• W2905804703 hasConceptScore W2905804703C108215921 @default.
• W2905804703 hasConceptScore W2905804703C126322002 @default.
• W2905804703 hasConceptScore W2905804703C150903083 @default.
• W2905804703 hasConceptScore W2905804703C181199279 @default.
• W2905804703 hasConceptScore W2905804703C185592680 @default.
• W2905804703 hasConceptScore W2905804703C207001950 @default.
• W2905804703 hasConceptScore W2905804703C2776125364 @default.
• W2905804703 hasConceptScore W2905804703C2776694085 @default.
• W2905804703 hasConceptScore W2905804703C2777468819 @default.
• W2905804703 hasConceptScore W2905804703C2779138802 @default.
• W2905804703 hasConceptScore W2905804703C2779201268 @default.
• W2905804703 hasConceptScore W2905804703C2781303535 @default.
• W2905804703 hasConceptScore W2905804703C515207424 @default.
• W2905804703 hasConceptScore W2905804703C55493867 @default.
• W2905804703 hasConceptScore W2905804703C71924100 @default.
• W2905804703 hasConceptScore W2905804703C86803240 @default.
• W2905804703 hasConceptScore W2905804703C98274493 @default.
• W2905804703 hasLocation W29058047031 @default.
• W2905804703 hasOpenAccess W2905804703 @default.
• W2905804703 hasPrimaryLocation W29058047031 @default.
• W2905804703 hasRelatedWork W1979545097 @default.
• W2905804703 hasRelatedWork W2001065425 @default.
• W2905804703 hasRelatedWork W2064725610 @default.
• W2905804703 hasRelatedWork W2086775138 @default.
• W2905804703 hasRelatedWork W2092704250 @default.
• W2905804703 hasRelatedWork W2094074154 @default.
• W2905804703 hasRelatedWork W2094831430 @default.
• W2905804703 hasRelatedWork W2315900328 @default.
• W2905804703 hasRelatedWork W2587722915 @default.
• W2905804703 hasRelatedWork W2811836689 @default.
• W2905804703 hasRelatedWork W2823033001 @default.
• W2905804703 hasRelatedWork W2823326536 @default.
• W2905804703 hasRelatedWork W2835895747 @default.
• W2905804703 hasRelatedWork W2836020753 @default.
• W2905804703 hasRelatedWork W2837622522 @default.
• W2905804703 hasRelatedWork W2846565635 @default.
• W2905804703 hasRelatedWork W2874893897 @default.
• W2905804703 hasRelatedWork W2931210285 @default.
• W2905804703 hasRelatedWork W2977832522 @default.
• W2905804703 hasRelatedWork W3110047565 @default.
• W2905804703 hasVolume "65" @default.
• W2905804703 isParatext "false" @default.
• W2905804703 isRetracted "false" @default.
• W2905804703 magId "2905804703" @default.
• W2905804703 workType "article" @default.