Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The design, synthesis, and initial biological evaluation of a doxorubicin prodrug that contains a dual tumor specific moiety, which allows enhanced tumor recognition potential, is reported. Both a tumor-specific recognition site and a tumor selective enzymatic activation sequence are incorporated in the prodrug. The first tumor-specific sequence is the bicyclic CDCRGDCFC (RGD-4C) peptide that selectively binds alpha v beta 3 and alpha v beta 5 integrins. These integrins are highly overexpressed on invading tumor endothelial cells. The second tumor-specific sequence is a D-Ala-Phe-Lys tripeptide that is selectively recognized by the tumor-associated protease plasmin, which is involved in tumor invasion and metastasis. An aminocaproyl residue was incorporated as a spacer between the two peptide sequences, whereas a self-eliminating 4-aminobenzyl alcohol spacer was inserted between the plasmin substrate and doxorubicin. Although the prodrug showed a decreased binding affinity as compared with the unconjugated reference peptide, it was still a potent ligand for alpha v beta 3 and alpha v beta 5 integrin receptors. The synthesized construct also possessed plasmin substrate properties as demonstrated by doxorubicin release from 1 upon incubation with plasmin. The release of doxorubicin from 1 was not complete, possibly related to low prodrug solubility. In vitro prodrug 1 showed plasmin-dependent cytotoxicity for endothelial cells and HT1080 fibrosarcoma cells. On the basis of these in vitro results, derivatives of 1 with improved water solubility are considered good candidates for additional development and in vivo evaluation of this dual targeting concept.
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PMID:Design, synthesis, and biological evaluation of a dual tumor-specific motive containing integrin-targeted plasmin-cleavable doxorubicin prodrug. 1248 11

Cathepsin B and plasmin are intra- or extracellular proteases that are overexpressed by several solid tumors. In order to exploit both proteases as molecular targets for tumor-specific cleavage of prodrugs, an albumin-binding formulation of methotrexate was developed that incorporated the peptide sequence D-Ala-Phe-Lys as the protease substrate. Albumin is a suitable carrier for cytostatic agents due to passive accumulation in solid tumors. Synthesis was performed by coupling the peptide linker EMC-D-Ala-Phe-Lys(Boc)-Lys-OH (EMC = epsilon-maleimidocaproic acid) to the gamma-COOH group of alpha-tert-butyl protected methotrexate. After cleavage of the protective groups and purification on reverse phase HPLC, a highly water-soluble methotrexate-peptide derivative was obtained that binds rapidly and selectively to human serum albumin. The albumin-bound form of the prodrug was shown to be efficiently cleaved by cathepsin B and plasmin as well as in an ovarian carcinoma homogenate (OVCAR-3) liberating a methotrexate-lysine derivative. In an OVCAR-3 xenograft model, the prodrug at a dose of 4x15 mg/kg methotrexate equivalents demonstrated distinctly superior antitumor efficacy compared to free methotrexate at a dose of 4x100 mg/kg [T/C(%) for MTX = 69; T/C(%) for MTX prodrug = 29]. The data provide a further proof of concept for the development of albumin-binding, enzymatically cleavable prodrugs of anticancer drugs.
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PMID:Synthesis, cleavage profile, and antitumor efficacy of an albumin-binding prodrug of methotrexate that is cleaved by plasmin and cathepsin B. 1762 30

Herein we describe the synthesis and rheological characterization of a series of enzymatically sensitive PEG and peptide-based hydrogels by the Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction. The hydrogels were synthesized by a combination of alkyne-functionalized star-shaped PEG molecules (two 4-armed PEGs with M(w) 10 and 20 kDa, respectively, and one 8-armed PEG of 20 kDa) and the protease-sensitive bis-azido peptide, N(alpha)-(azido)-D-alanyl-phenylalanyl-lysyl-(2-azidoethyl)-amide (6) in the presence of CuSO(4) and sodium ascorbate in aqueous solution. The swelling ratio and the storage modulus (G') of the hydrogels could be tailored by several parameters, for example, the initial solid content of the hydrogel, the molecular weight of the PEG derivative, and by the architecture of the PEG molecule (4- versus 8-armed PEG derivative). The peptide sequence, D-Ala-Phe-Lys, was sensitive toward the proteases plasmin and trypsin to render the hydrogels biodegradable.
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PMID:Synthesis and characterization of enzymatically biodegradable PEG and peptide-based hydrogels prepared by click chemistry. 2049 5