title: Optimization of an albumin-binding prodrug of Doxorubicin that is cleaved by prostate-specific antigen.
abstract: We have developed a novel albumin-binding prodrug of doxorubicin that incorporates p-aminobenzyloxycarbonyl (PABC) as a 1,6 self-immolative spacer in addition to the heptapeptide, Arg-Ser-Ser-Tyr-Tyr-Ser-Leu, as a substrate for the prostate-specific antigen (PSA) that is overexpressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. The prodrug exhibited good water solubility and was bound rapidly to the cysteine-34 position of human serum albumin. Incubation studies with PSA demonstrated that the albumin-bound form of the prodrug was cleaved rapidly at the P1-P1' scissile bond, releasing H-Ser-Leu-PABC-DOXO, which was further degraded to release doxorubicin as a final cleavage product within a few hours in prostate tumor tissue homogenates as well as in PSA-positive LNCaP LN cell lysates. Moreover, our prodrug exhibited antiproliferative activity in a low micromolar range against a PSA-expressing prostate cancer cell line (LNCaP).
authors.affiliation: Tumor Biology Center, Division of Macromolecular Prodrugs, Breisacher Strasse 117, 79106 Freiburg, Germany ; Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, P.O. Box No. 71524, Assiut, Egypt.
authors.forename: Bakheet
authors.initials: B
authors.lastname: Elsadek
authors.affiliation: ProQinase GmbH, Breisacher Strasse 117, 79106 Freiburg, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Graeser
authors.affiliation: Tumor Biology Center, Division of Macromolecular Prodrugs, Breisacher Strasse 117, 79106 Freiburg, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Warnecke
authors.affiliation: Tumor Biology Center, Division of Macromolecular Prodrugs, Breisacher Strasse 117, 79106 Freiburg, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Unger
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Assiut University, P.O. Box No. 71526, Assiut, Egypt.
authors.forename: Tahia
authors.initials: T
authors.lastname: Saleem
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Assiut University, P.O. Box No. 71526, Assiut, Egypt.
authors.forename: Nagla
authors.initials: N
authors.lastname: El-Melegy
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, P.O. Box No. 71524, Assiut, Egypt.
authors.forename: Hafez
authors.initials: H
authors.lastname: Madkor
authors.affiliation: Tumor Biology Center, Division of Macromolecular Prodrugs, Breisacher Strasse 117, 79106 Freiburg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Kratz
keywords: Doxorubicin; albumin; drug delivery; prodrug; prostate cancer; prostate-specific antigen