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In Vivo Evaluation of a Novel Albumin-Binding Prodrug of Doxorubicin in an Orthotopic Mouse Model of Prostate Cancer (Lncap)

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In Vivo Evaluation of a Novel Albumin-Binding Prodrug of Doxorubicin in an Orthotopic Mouse Model of Prostate Cancer (Lncap) Prostate Cancer and Prostatic Diseases (2011) 14, 14–21 & 2011 Macmillan Publishers Limited All rights reserved 1365-7852/11 www.nature.com/pcan ORIGINAL ARTICLE In vivo evaluation of a novel albumin-binding prodrug of doxorubicin in an orthotopic mouse model of prostate cancer (LNCaP) B Elsadek1, R Graeser2, N Esser2, C Scha¨fer-Obodozie2, C Tsurumi3, K Abu Ajaj1, A Warnecke1, C Unger1, T Saleem4 and F Kratz1 1Division of Macromolecular Prodrugs, Tumor Biology Center, Freiburg, Germany; 2ProQinase GmbH, In vivo Testing, Freiburg, Germany; 3Clinic for Radiotherapy, University Hospital Freiburg, Freiburg, Germany and 4Faculty of Medicine, Department of Biochemistry, Assiut University, Assiut, Egypt 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 Â 6mgkgÀ1 doxorubicin equivalents (intravenous) was compared with conventional doxorubicin at equitoxic doses (at 3 Â 3mgkgÀ1; 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 B77% and B96%, 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. Prostate Cancer and Prostatic Diseases (2011) 14, 14–21; doi:10.1038/pcan.2010.43; published online 2 November 2010 Keywords: human serum albumin; PSA; orthotopic animal model Introduction achieved with taxotere.3 Recent data obtained from two large phase III clinical trials, TAX327 and SWOG 9916, Prostate cancer is one of the leading causes of cancer- indicated that taxotere supplemented with prednisone related death in men and remains incurable in the can achieve a survival benefit in some patients with metastatic setting, especially after the formation of hormone-resistant metastatic prostate cancer, whereas osteoblastic bone metastases that remain the most lethal treatment with mitoxantrone supplemented with corti- aspect of prostate cancer.1,2 Despite the initial response to costeroids alleviated symptoms but did not improve androgen deprivation, the disease gradually progresses overall patient survival.4–6 Thus, the benefit of therapy to a hormone-refractory state as a result of cumulative with antineoplastic agents is limited because of systemic genetic alterations in tumor cells or the microenviron- toxicity and lack of tumor selectivity, and there is an ment. At present, there is no effective therapy for men urgent medical need to design drug delivery systems, with hormone-resistant metastatic prostate cancer, and which transport the anticancer agent to the primary and among the approved anticancer agents, taxotere, mitox- metastatic tumors. antrone and estramustine phosphate, the best results are In the past, we along with others have developed low- or high-molecular-weight prodrugs that are cleaved by PSA, a serine protease that is overexpressed in metastatic Correspondence: Dr F Kratz, Division of Macromolecular Prodrugs, prostate carcinoma.7–9 These prodrugs were developed Tumor Biology Center, Breisacher Strae 117, D-79106 Freiburg, Germany. E-mail: [email protected] with the aim of reducing toxicity and improving both the Received 19 August 2010; revised 20 September 2010; accepted 20 efficacy and the selectivity of chemotherapeutic agents September 2010; published online 2 November 2010 for treating hormone-refractory prostate cancer. Prodrug of doxorubicin B Elsadek et al Over the last decade, we have intensively investigated peptide substrate with p-aminobenzyloxycarbonyl (PABC) 15 human serum albumin (HSA) as a drug carrier which is as a self-immolative spacer. having an increasing role in the clinical setting for PSA9 exhibited good water solubility (B4mgmlÀ1 in delivering anticancer drugs to the tumor.10 Uptake of isotonic 5% glucose solution), was bound rapidly to the albumin in tumors is mediated by the EPR effect, that is, cysteine-34 position of circulating HSA, and its albumin- the enhanced permeability and retention of macromole- bound form (HSA9) was cleaved efficiently by PSA cules in relation to passive tumor targeting.11 Our tumor- releasing H-Ser-Leu-PABC-DOXO.14 This doxorubicin targeting strategy that exploits albumin as a drug carrier dipeptide was further degraded in LNCaP prostate is based on two features: (1) in situ binding of a thiol- tumor tissue homogenates and in PSA-positive LNCaP binding prodrug to the cysteine-34 position of circulating luciferase-neomycin cell lysates to release doxorubicin as albumin after intravenous administration with sub- a final cleavage product within few hours by adventi- sequent accumulation of the drug albumin conjugate tious proteases.14 After cleavage and deacylation, the in the tumor due to passive targeting and (2) release of PABC spacer decomposes in 1,6-benzylelimination and the albumin-bound drug at the tumor site due to the spontaneously releases the free drug.15 incorporation of a cleavable bond between the drug Moreover, the dipeptide H-Ser-Leu-PABC-DOXO was and the carrier. Anthracyclines, such as doxorubicin, significantly more active against a PSA-expressing have frequently been used by us for the development of prostate cancer cell line (LNCaP lentiviral luciferase- such albumin-binding prodrugs.12 The first and most neomycin (LLN)) than either H-Ser-Arg-DOXO, the advanced prototype of these prodrugs is the (6-maleimi- cleavage product of PSA5, or H-Ser-Leu-DOXO that docaproyl)hydrazone derivative of doxorubicin (abbre- both do not contain the PABC spacer.14 viated DOXO-EMCH, now INNO-206), an acid-sensitive As a consequence and as a main goal of this study, we prodrug of doxorubicin that is under phase II clinical set out to investigate the antitumor efficacy of PSA9 in development13 (also see http://www.cytrx.com). comparison with conventional doxorubicin in a mouse Inspired by the translational research with DOXO- model of human prostate cancer using luciferase- EMCH, we developed a PSA-cleavable albumin-binding transduced LNCaP cells orthotopically implanted in the prodrug of doxorubicin, that is, EMC-Arg-Ser-Ser-Tyr- prostate of severe combined immunodeficiency (SCID) Tyr-Ser-Arg-DOXO (abbreviated PSA5, Figure 1a).9 PSA5 mice. As the LNCaP LLN cell line used in this study was was shown to rapidly bind to the circulating albumin genetically altered to express luciferase, tumor growth and was superior over doxorubicin in an orthotopic PSA- could be followed in vivo, and bone, lung, liver and positive model (LNCaP) with respect to antitumor inguinal lymph nodes as the most susceptible organs for efficacy on the primary tumor but showed some but the formation of metastases in progressive prostate not statistically significant activity only against lung cancer could be analysed using an in vitro luciferase metastases.9 The major drawback of this prodrug was assay. that although it was cleaved efficiently by PSA, it liberated the less active doxorubicin dipeptide H-Ser- Arg-DOXO as the major cleavage product, which only showed marginal cleavage to H-Arg-DOXO or doxo- Materials and methods rubicin in tumor homogenates of PSA-positive LNCAP tumors. All animal experiments were performed in accordance Thus, to exploit the full potential of our prodrug with the German Animal License Regulations approach, we developed an optimized albumin-binding (Tierschutzgesetz) identical to the United Kingdom prodrug of doxorubicin (abbreviated PSA9, Figure 1b), Coordinating Committee on Cancer Research guidelines which releases doxorubicin effectively as the final for the welfare of animals in experimental neoplasia.9,16 cleavage product. PSA9 combines a PSA-cleavable Male SCID (C.B-17/IcrHanHsd-Prkdc-scid) mice were O OH O OH O O OH N H Arg-Ser-Ser-Tyr-Tyr–Ser-Arg N O OH O O O CH3 O HO Maleimide PSA cleavable peptide Doxorubicin CH3 O OH O O OH O H N N OH Arg-Ser-Ser-Tyr-Tyr–Ser-Leu H O O N O OH O O CH3 O O HO Maleimide PSA cleavable peptide PABC CH3 Doxorubicin Figure 1 Structures of the PSA-cleavable prodrugs (a) PSA5 and (b) PSA9. PABC, p-aminobenzyloxycarbonyl. Prostate Cancer and Prostatic Diseases Prodrug of doxorubicin B Elsadek et al 16 obtained from Harlan Winkelmann GmbH (Borchen, cells, suspended in 20 ml phosphate-buffered saline, were Germany). To test novel antitumor agents in a setting injected into the anterior part of the prostate
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