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Development of Albumin‐binding Doxorubicin Prodrugs that are Cleaved by Prostate‐specific Antigen
Author(s) -
Kratz Felix,
Mansour Ahmed,
Soltau Jens,
Warnecke Andre,
Fichtner Iduna,
Unger Clemens,
Drevs Joachim
Publication year - 2005
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200500130
Subject(s) - doxorubicin , chemistry , prodrug , dipeptide , arginine , in vivo , amino acid , biochemistry , pharmacology , stereochemistry , medicine , biology , chemotherapy , microbiology and biotechnology
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 P 1 ‐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.