In vivo evaluation of a novel albumin-binding prodrug of doxorubicin in an orthotopic mouse model of prostate cancer (LNCaP).
PSA, which is overexpressed in prostate carcinoma, represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. In this study, we report on the in vivo antitumor efficacy of an efficacious albumin-binding prodrug of doxorubicin (PSA9) that incorporates p-aminobenzyloxycarbonyl (PABC) as a self-immolative spacer in addition to the heptapeptide, Arg-Ser-Ser-Tyr-Tyr-Ser-Leu, which serves as a substrate for PSA. The prodrug is cleaved very efficiently by PSA releasing H-Ser-Leu-PABC-doxorubicin and subsequently doxorubicin in PSA-positive cell lysates and prostate tumor homogenates as the final cleavage product. PSA9 at 3 × 6 mg kg(-1) doxorubicin equivalents (intravenous) was compared with conventional doxorubicin at equitoxic doses (at 3 × 3 mg kg(-1); intravenous) in an orthotopic mouse model of prostate cancer using LNCaP lentiviral luciferase-neomycin cells transduced with luciferase. Whereas doxorubicin did not show any efficacy against the primary tumor or metastases, the prodrug reduced the primary tumor by 30-50% and circulating PSA levels, and in addition, showed a pronounced reduction in lung and bone metastases by ∼77% and ∼96%, respectively, and a positive trend regarding the activity against liver and lymph-node metastases compared with control and doxorubicin-treated animals. The incorporation of PABC as a self-immolative spacer together with a PSA substrate demonstrates superior antitumor effects over doxorubicin attributed to an efficient cleavage by PSA releasing doxorubicin as the final active agent in prostate tumor homogenates. Using this approach for developing effective prodrugs against prostate cancer, is worthy of further preclinical optimization.
Division of Macromolecular Prodrugs, Tumor Biology Center, Freiburg, Germany.
B
B
Elsadek
R
R
Graeser
N
N
Esser
C
C
Schäfer-Obodozie
C
C
Tsurumi
K
K
Abu Ajaj
A
A
Warnecke
C
C
Unger
T
T
Saleem
F
F
Kratz
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000378:metabolism / Q000627:therapeutic use*; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D011355:Prodrugs; D012709:Serum Albumin; D004317:Doxorubicin; D017430:Prostate-Specific Antigen