Matrix Metalloproteinases (MMPs) in Targeted Drug Delivery: Synthesis of a Potent and Highly Selective Inhibitor against Matrix Metalloproteinase- 7.
Cancer treatment
Inhibitor
MMP inhibitors (MMPIs)
MMP-7
Matrix metalloproteinases (MMPs)
Targeted drug delivery
Journal
Current topics in medicinal chemistry
ISSN: 1873-4294
Titre abrégé: Curr Top Med Chem
Pays: United Arab Emirates
ID NLM: 101119673
Informations de publication
Date de publication:
2020
2020
Historique:
received:
11
10
2019
revised:
20
01
2020
accepted:
20
02
2020
pubmed:
25
7
2020
medline:
2
7
2021
entrez:
25
7
2020
Statut:
ppublish
Résumé
Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that play a key role in both physiological and pathological tissue degradation. MMPs have reportedly shown great potentials in the degradation of the Extracellular Matrix (ECM), have shown great potentials in targeting bioactive and imaging agents in cancer treatment. MMPs could provoke Epithelial to Mesenchymal Transition (EMT) of cancer cells and manipulate their signaling, adhesion, migration and invasion to promote cancer cell aggressiveness. Therefore, targeting and particularly inhibiting MMPs within the tumor microenvironment is an effective strategy for cancer treatment. Based on this idea, different MMP inhibitors (MMPIs) have been developed to manipulate the tumor microenvironment towards conditions appropriate for the actions of antitumor agents. Studies are ongoing to improve the selectivity and specificity of MMPIs. Structural optimization has facilitated the discovery of selective inhibitors of the MMPs. However, so far no selective inhibitor for MMP-7 has been proposed. This study aims to comprehensively review the potentials and advances in applications of MMPs particularly MMP-7 in targeted cancer treatment approaches with the main focus on targeted drug delivery. Different targeting strategies for manipulating and inhibiting MMPs for the treatment of cancer are discussed. MMPs are upregulated at all stages of expression in cancers. Different MMP subtypes have shown significant targeting applicability at the genetic, protein, and activity levels in both physiological and pathophysiological conditions in a variety of cancers. The expression of MMPs significantly increases at advanced cancer stages, which can be used for controlled release in cancers in advance stages. Moreover, this study presents the synthesis and characteristics of a new and highly selective inhibitor against MMP-7 and discusses its applications in targeted drug delivery systems for therapeutics and diagnostics modalities. Our findings showed that the structure of the inhibitor P3' side chains play the crucial role in developing an optimized MMP-7 inhibitor with high selectivity and significant degradation activities against ECM. Optimized NDC can serve as a highly potent and selective inhibitor against MMP-7 following screening and optimization of the P3' side chains, with a Ki of 38.6 nM and an inhibitory selectivity of 575 of MMP-7 over MMP-1.
Sections du résumé
BACKGROUND
Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that play a key role in both physiological and pathological tissue degradation. MMPs have reportedly shown great potentials in the degradation of the Extracellular Matrix (ECM), have shown great potentials in targeting bioactive and imaging agents in cancer treatment. MMPs could provoke Epithelial to Mesenchymal Transition (EMT) of cancer cells and manipulate their signaling, adhesion, migration and invasion to promote cancer cell aggressiveness. Therefore, targeting and particularly inhibiting MMPs within the tumor microenvironment is an effective strategy for cancer treatment. Based on this idea, different MMP inhibitors (MMPIs) have been developed to manipulate the tumor microenvironment towards conditions appropriate for the actions of antitumor agents. Studies are ongoing to improve the selectivity and specificity of MMPIs. Structural optimization has facilitated the discovery of selective inhibitors of the MMPs. However, so far no selective inhibitor for MMP-7 has been proposed.
AIMS
This study aims to comprehensively review the potentials and advances in applications of MMPs particularly MMP-7 in targeted cancer treatment approaches with the main focus on targeted drug delivery. Different targeting strategies for manipulating and inhibiting MMPs for the treatment of cancer are discussed. MMPs are upregulated at all stages of expression in cancers. Different MMP subtypes have shown significant targeting applicability at the genetic, protein, and activity levels in both physiological and pathophysiological conditions in a variety of cancers. The expression of MMPs significantly increases at advanced cancer stages, which can be used for controlled release in cancers in advance stages.
METHODS
Moreover, this study presents the synthesis and characteristics of a new and highly selective inhibitor against MMP-7 and discusses its applications in targeted drug delivery systems for therapeutics and diagnostics modalities.
RESULTS
Our findings showed that the structure of the inhibitor P3' side chains play the crucial role in developing an optimized MMP-7 inhibitor with high selectivity and significant degradation activities against ECM.
CONCLUSION
Optimized NDC can serve as a highly potent and selective inhibitor against MMP-7 following screening and optimization of the P3' side chains, with a Ki of 38.6 nM and an inhibitory selectivity of 575 of MMP-7 over MMP-1.
Identifiants
pubmed: 32703131
pii: CTMC-EPUB-108394
doi: 10.2174/1568026620666200722104928
doi:
Substances chimiques
Antineoplastic Agents
0
Drug Carriers
0
Matrix Metalloproteinase Inhibitors
0
Matrix Metalloproteinase 7
EC 3.4.24.23
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
2459-2471Subventions
Organisme : National Natural Science Foundation of China (NSFC)
ID : 21062023, 21768004
Informations de copyright
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