Development of albumin-binding camptothecin Prodrugs using a peptide Positional scanning library

被引:16
作者
Schmid, Bjoern
Warnecke, Andre
Fichtner, Iduna
Jung, Manfred
Kratz, Felix
机构
[1] Tumor Biol Ctr, Dept Med Oncol, D-79106 Freiburg, Germany
[2] Max Delbruck Ctr, D-13122 Berlin, Germany
[3] Univ Freiburg, Inst Pharmaceut Sci Pharmaceut & Med Chem, D-79104 Freiburg, Germany
关键词
D O I
10.1021/bc0700842
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
Designing truly tumor-specific prodrugs remains a challenge in the field of cancer chemotherapy. As a new strategy, we incubated homogenates of a spectrum of human colon tumor xenografts with a fluorogenic positional scanning tetrapeptide library in order to identify peptide sequences that are preferentially cleaved by colon tumors. Our screening experiments at pH 7.4 revealed that Met, Leu, and Lys were preferred amino acids in the position P, and Tyr, Phe, and Met in P-2, whereas in P-3 and P-4. the cleavage profiles were less characteristic. However, similar results were obtained when testing breast tumor material and homogenates from healthy murine organs. On the basis of these results, we developed albumin-binding camptothecin (CPT) prodrugs of the general formula EMC-Arg-P-4-P-3-P-2-P-1-Ala-CPT (EMC = 6-maleimidocaproic acid) that incorporated two peptide linkers: H-Arg-Ala-Phe-Met-OH and H-Arg-Phe-Tyr-Met-OH (P-4-P-3-P-2-P-1]). The incorporation of two arginine residues rendered the prodrugs water-soluble (>7 mg/mL), while the use of alanine as an amino acid spacer proved to be beneficial for the release of the active agent. Incubation studies with homogenates of HT-29 colon tumor tissue and murine spleen, liver, and kidneys demonstrated cleavage of the peptide linker with CPT-peptide derivatives and CPT being the major cleavage products. Although the peptide sequence is not selectively cleaved in colon tumors, an in vivo study in a HT-29 xenograft model showed that the prodrug EMC-Arg-Arg-Ala-Phe-Met-Ala-CPT demonstrated enhanced antitumor efficacy when compared to CPT [(T/C max: 17% for the prodrug (2 x 12.5 mg/kg CPT equivalents) and 40% for CPT (3 x 12.5 mg/kg)].
引用
收藏
页码:1786 / 1799
页数:14
相关论文
共 41 条
[1]   Synthesis of positional-scanning libraries of fluorogenic peptide substrates to define the extended substrate specificity of plasmin and thrombin [J].
Backes, BJ ;
Harris, JL ;
Leonetti, F ;
Craik, CS ;
Ellman, JA .
NATURE BIOTECHNOLOGY, 2000, 18 (02) :187-193
[2]   Polymer-bound camptothecin: initial biodistribution and antitumour activity studies [J].
Caiolfa, VR ;
Zamai, M ;
Fiorino, A ;
Frigerio, E ;
Pellizzoni, C ;
d'Argy, R ;
Ghiglieri, A ;
Castelli, MG ;
Farao, M ;
Pesenti, E ;
Gigli, M ;
Angelucci, F ;
Suarato, A .
JOURNAL OF CONTROLLED RELEASE, 2000, 65 (1-2) :105-119
[3]  
Chan WC, 2000, PRACTICAL APPROACH S
[4]   Substrate profiling of cysteine proteases using a combinatorial peptide library identifies functionally unique specificities [J].
Choe, Y ;
Leonetti, F ;
Greenbaum, DC ;
Lecaille, F ;
Bogyo, M ;
Brömme, D ;
Ellman, JA ;
Craik, CS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (18) :12824-12832
[5]   Development of a novel albumin-binding prodrug that is cleaved by urokinase-type-plasminogen activator (uPA) [J].
Chung, Da-Eun ;
Kratz, Felix .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (19) :5157-5163
[6]  
Conover CD, 1999, ANTI-CANCER DRUG DES, V14, P499
[7]   Plasminogen activation and cancer [J].
Dano, K ;
Behrendt, N ;
Hoyer-Hansen, G ;
Johnsen, M ;
Lund, LR ;
Ploug, M ;
Romer, J .
THROMBOSIS AND HAEMOSTASIS, 2005, 93 (04) :676-681
[8]   Proteases and metastasis: clinical relevance nowadays? [J].
Decock, J ;
Paridaens, R ;
Cufer, T .
CURRENT OPINION IN ONCOLOGY, 2005, 17 (06) :545-550
[9]   ASSAY OF MATRIX METALLOPROTEASES TYPE-8 AND TYPE-9 BY ELISA IN HUMAN BREAST-CANCER [J].
DUFFY, MJ ;
BLASER, J ;
DUGGAN, C ;
MCDERMOTT, E ;
OHIGGINS, N ;
FENNELLY, JJ ;
TSCHESCHE, H .
BRITISH JOURNAL OF CANCER, 1995, 71 (05) :1025-1028
[10]   Matrix metalloproteinases: roles in cancer and metastasis [J].
Fingleton, B .
FRONTIERS IN BIOSCIENCE-LANDMARK, 2006, 11 :479-491