Development of albumin-binding doxorubicin prodrugs that are cleaved by prostate-specific antigen.
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 = epsilon-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.
Kratz
Felix
F
Tumor Biology Center, Freiburg, Germany. felix@tumorbio.uni-freiburg.de
Mansour
Ahmed
A
Soltau
Jens
J
Warnecke
Andre
A
Fichtner
Iduna
I
Unger
Clemens
C
Drevs
Joachim
J
D000418:Albumins / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D008297:Male; D008301:Maleimides / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000737:chemistry / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology; D011485:Protein Binding; D012995:Solubility; D023041:Xenograft Model Antitumor Assays
D000418:Albumins; D000903:Antibiotics, Antineoplastic; D008301:Maleimides; D011355:Prodrugs; D004317:Doxorubicin; D017430:Prostate-Specific Antigen