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Development of albumin-binding doxorubicin prodrugs that are cleaved by prostate-specific antigen

Item Type:Article
Title:Development of albumin-binding doxorubicin prodrugs that are cleaved by prostate-specific antigen
Creators Name:Kratz, F. and Mansour, A. and Soltau, J. and Warnecke, A. and Fichtner, I. and Unger, C. and Drevs, J.
Abstract:Prostate-specific antigen (PSA) is a serine protease that is overexpressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. In this work, 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) or EMC-Arg-Arg-Ser-Ser-Tyr-Tyr–Ser-Gly-DOXO (EMC = ε-maleimidocaproic acid; X = amino acid). The maleimide Doxorubicin derivatives bound rapidly to the cysteine-34 position of endogenous and exogenous albumin and were efficiently cleaved by PSA at the P1-P′1 scissile bond, releasing a respective Doxorubicin dipeptide (Ser-Gly-DOXO or Phe-Gln-DOXO). The derivative containing arginine residues (EMC-Arg-Arg-Ser-Ser-Tyr-Tyr–Ser-Gly-DOXO) exhibited excellent water solubility for intravenous administration. Subsequent biological evaluation was focused on a PSA-negative xenograft model (PC 3) and a 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.
Keywords:Doxorubicin, Human serum albumin, Macromolecular prodrug, Prostate-specific antigen (PSA)
Source:Archiv der Pharmazie
Page Range:462-472
Date:7 October 2005
Official Publication:https://doi.org/10.1002/ardp.200500130
PubMed:View item in PubMed

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