Synthesis and biological evaluation of an albumin-binding prodrug of doxorubicin that is cleaved by prostate-specific antigen (PSA) in a PSA-positive orthotopic prostate carcinoma model (LNCaP)

✍ Scribed by Ralph Graeser; Da-Eun Chung; Norbert Esser; Sandra Moor; Christoph Schächtele; Clemens Unger; Felix Kratz

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: French
• Weight: 518 KB
• Volume: 122
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.23050

✦ Synopsis

Abstract

The prostate‐specific antigen (PSA) is a serine protease that is over‐expressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. We have recently investigated a macromolecular prodrug strategy for improved cancer chemotherapy based on 2 features: (i) rapid and selective binding of thiol‐reactive prodrugs to the cysteine‐34 position of endogenous albumin after intravenous administration, and (ii) enzymatic release of the albumin‐bound drug at the tumor site (Mansour et al., Cancer Res 2003, 63, 4062–4066). In this work, we describe an albumin‐binding prodrug, EMC‐Arg‐Ser‐Ser‐Tyr‐Tyr—Ser‐Arg‐DOXO [EMC: ϵ‐Maleimidocaproic acid; DOXO = doxorubicin; X = amino acid] that is cleaved by PSA. Because of the incorporation of 2 arginine residues, the prodrug exhibited excellent water‐solubility and was rapidly and selectively bound to endogenous albumin. Incubation studies with PSA and tumor homogenates from PSA‐positive tumors (LNCaP) demonstrated that the albumin‐bound form of the prodrug was efficiently cleaved by PSA at the P~1~–P′ ~1~ scissile bond releasing the doxorubicin dipeptide H‐Ser‐Arg‐DOXO, which was further degraded to doxorubicin as the final cleavage product. In cell culture experiments, the prodrug was ∼100‐fold less active against LNCaP cells than the free drug. In contrast, in a mouse model of human prostate cancer using luciferase transduced LNCaP cells orthotopically implanted in SCID mice, the prodrug showed enhanced antitumor efficacy when compared to doxorubicin. Doxorubicin treatment at a dose of 2 × 4 mg/kg caused significant weight loss and mortality (−25%), and did not result in a significant antitumor response at the end of the experiment. The prodrug at 3 × 12 mg/kg doxorubicin equivalents, however, was well tolerated and induced a significant reduction in tumor size of 62% (±25%, **p = 0.003) as well as a decrease of the metastatic burden in the lungs as detected in luciferase assays (−50%, SD ± 115%, *p = 0.038). © 2007 Wiley‐Liss, Inc.