Synthesis and Characterization of Dextran−Peptide−Methotrexate Conjugates for Tumor Targeting via Mediation by Matrix Metalloproteinase II and Matrix Metalloproteinase IX
| Autor: | Frederick E. Tan, Robert Langer, Ying Chau |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Serum
Cell Survival Matrix metalloproteinase inhibitor Biomedical Engineering Pharmaceutical Science Antineoplastic Agents Bioengineering Peptide Matrix Metalloproteinase Inhibitors Matrix metalloproteinase chemistry.chemical_compound Drug Delivery Systems Cell Line Tumor Humans Enzyme kinetics Pharmacology chemistry.chemical_classification Molecular Structure Organic Chemistry Dextrans Combinatorial chemistry Cross-Linking Reagents Methotrexate Enzyme Dextran Matrix Metalloproteinase 9 chemistry Biochemistry Matrix Metalloproteinase 2 Peptides Linker Biotechnology Conjugate |
| Zdroj: | Bioconjugate Chemistry. 15:931-941 |
| ISSN: | 1520-4812 1043-1802 |
| DOI: | 10.1021/bc0499174 |
| Popis: | We designed and synthesized new dextran-peptide-methotrexate conjugates for tumor-targeted delivery of chemotherapeutics via the mediation of matrix metalloproteinase II (MMP-2) and matrix metalloproteinase IX (MMP-9), both being widely known tumor-associated enzymes. A robust and flexible synthesis procedure and process monitoring chromatography assays were developed. The linker chemistry and the backbone charge were optimized to allow high sensitivity of the conjugates toward the targeted enzymes. The optimal conjugate carries Pro-Val-Gly-Leu-Ile-Gly as the peptide linker, and the charge on the dextran backbone is fully neutralized. In the presence of the targeted enzymes, the peptide was cleaved and peptidyl methotrexate was released, with a kcat/Km value of 1.21 x 10(5) M(-1) s(-1) for MMP-2 and 3.60 x 10(3) M(-1) s(-1) for MMP-9, respectively. Satisfactory stability of the new conjugates was demonstrated in serum containing conditions, suggesting the conjugates can remain intact in systemic circulation. These findings supported the tumor targeting capability of the new conjugates and warranted further investigation with in vivo study. |
| Databáze: | OpenAIRE |
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