11 research outputs found
Visualization of MMP-2 Activity Using Dual-Probe Nanoparticles to Detect Potential Metastatic Cancer Cells
Matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes capable of degrading extracellular matrix components. Previous studies have shown that the upregulation of MMP-2 is closely related to metastatic cancers. While Western blotting, zymography, and Enzyme-Linked Immunosorbent Assays (ELISA) can be used to measure the amount of MMP-2 activity, it is not possible to visualize the dynamic MMP-2 activities of cancer cells using these techniques. In this study, MMP-2-activated poly(lactic-co-glycolic acid) with polyethylenimine (MMP-2-PLGA-PEI) nanoparticles were developed to visualize time-dependent MMP-2 activities. The MMP-2-PLGA-PEI nanoparticles contain MMP-2-activated probes that were detectable via fluorescence microscopy only in the presence of MMP-2 activity, while the Rhodamine-based probes in the nanoparticles were used to continuously visualize the location of the nanoparticles. This approach allowed us to visualize MMP-2 activities in cancer cells and their microenvironment. Our results showed that the MMP-2-PLGA-PEI nanoparticles were able to distinguish between MMP-2-positive (HaCat) and MMP-2-negative (MCF-7) cells. While the MMP-2-PLGA-PEI nanoparticles gave fluorescent signals recovered by active recombinant MMP-2, there was no signal recovery in the presence of an MMP-2 inhibitor. In conclusion, MMP-2-PLGA-PEI nanoparticles are an effective tool to visualize dynamic MMP-2 activities of potential metastatic cancer cells
A Promising Biocompatible Platform: Lipid-Based and Bio-Inspired Smart Drug Delivery Systems for Cancer Therapy
Designing new drug delivery systems (DDSs) for safer cancer therapy during pre-clinical and clinical applications still constitutes a considerable challenge, despite advances made in related fields. Lipid-based drug delivery systems (LBDDSs) have emerged as biocompatible candidates that overcome many biological obstacles. In particular, a combination of the merits of lipid carriers and functional polymers has maximized drug delivery efficiency. Functionalization of LBDDSs enables the accumulation of anti-cancer drugs at target destinations, which means they are more effective at controlled drug release in tumor microenvironments (TMEs). This review highlights the various types of ligands used to achieve tumor-specific delivery and discusses the strategies used to achieve the effective release of drugs in TMEs and not into healthy tissues. Moreover, innovative recent designs of LBDDSs are also described. These smart systems offer great potential for more advanced cancer therapies that address the challenges posed in this research area
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Biomimetic aggrecan reduces cartilage extracellular matrix from degradation and lowers catabolic activity in ex vivo and in vivo models.
Aggrecan, a major macromolecule in cartilage, protects the extracellular matrix (ECM) from degradation during the progression of osteoarthritis (OA). However, aggrecan itself is also susceptible to proteolytic cleavage. Here, the use of a biomimetic proteoglycan (mAGC) is presented, which functionally mimics aggrecan but lacks the known cleavage sites, protecting the molecule from proteolytic degradation. The objective of this study is to test the efficacy of this molecule in ex vivo (human OA synovial fluid) and in vivo (Sprague-Dawley rats) osteoarthritic models. These results indicate that mAGC's may protect articular cartilage against the loss of key ECM components, and lower catabolic protein and gene expression in both models. This suppression of matrix degradation has the potential to provide a healthy environment for tissue repair
Biomimetic aggrecan reduces cartilage extracellular matrix from degradation and lowers catabolic activity in ex vivo and in vivo models.
Aggrecan, a major macromolecule in cartilage, protects the extracellular matrix (ECM) from degradation during the progression of osteoarthritis (OA). However, aggrecan itself is also susceptible to proteolytic cleavage. Here, the use of a biomimetic proteoglycan (mAGC) is presented, which functionally mimics aggrecan but lacks the known cleavage sites, protecting the molecule from proteolytic degradation. The objective of this study is to test the efficacy of this molecule in ex vivo (human OA synovial fluid) and in vivo (Sprague-Dawley rats) osteoarthritic models. These results indicate that mAGC's may protect articular cartilage against the loss of key ECM components, and lower catabolic protein and gene expression in both models. This suppression of matrix degradation has the potential to provide a healthy environment for tissue repair
Prediction of Antiarthritic Drug Efficacies by Monitoring Active Matrix Metalloproteinase‑3 (MMP-3) Levels in Collagen-Induced Arthritic Mice Using the MMP‑3 Probe
Active matrix metalloproteinase-3
(MMP-3) is a prognostic marker
of rheumatoid arthritis (RA). We recently developed an MMP-3 probe
that can specifically detect the active form of MMP-3. The aim of
this study was to investigate whether detection and monitoring of
active MMP-3 could be useful to predict therapeutic drug responses
in a collagen-induced arthritis (CIA) model. During the period of
treatment with drugs such as methotrexate (MTX) or infliximab (IFX),
MMP-3 mRNA and protein levels were correlated with fluorescence signals
in arthritic joint tissues and in the serum of CIA mice. Also, bone
volume density and erosion in the knee joints and the paws of CIA
mice were measured with microcomputed tomography (micro-CT), X-ray,
and histology to confirm drug responses. In joint tissues and serum
of CIA mice, strong fluorescence signals induced by the action of
active MMP-3 were significantly decreased when drugs were applied.
The decrease in RA scores in drug-treated CIA mice led to fluorescence
reductions, mainly as a result of down-regulation of MMP-3 mRNA or
protein. The micro-CT, X-ray, and histology results clearly showed
marked decreases in bone and cartilage destruction, which were consistent
with the reduction of fluorescence by down-regulation of active MMP-3
in drug-treated CIA mice. We suggest that the MMP-3 diagnostic kit
could be used to detect and monitor the active form of MMP-3 in CIA
mice serum during a treatment course and thereby used to predict the
drug response or resistance to RA therapies at an earlier stage. We
hope that monitoring of active MMP-3 levels in arthritis patients
using the MMP-3 diagnostic kit will be a promising tool for drug discovery,
drug development, and monitoring of drug responses in RA therapy
Detection of Active Matrix Metalloproteinase‑3 in Serum and Fibroblast-Like Synoviocytes of Collagen-Induced Arthritis Mice
The activity of rheumatoid arthritis
(RA) correlates with the expression
of proteases. Among several proteases, matrix metalloproteinase-3
(MMP-3) is one of the biological markers used to diagnose RA. The
active form of MMP-3 is a key enzyme involved in RA-associated destruction
of cartilage and bone. Thus, detection of active MMP-3 in serum or <i>in vivo</i> is very important for early diagnosis of RA. In
this study, a soluble MMP-3 probe was prepared to monitor RA progression
by detecting expression of active MMP-3 in collagen-induced arthritis
(CIA) mice <i>in vivo</i> in both serum and fibroblast-like
synoviocytes (FLSs). The MMP-3 probe exhibited strong sensitivity
to MMP-3 and moderate sensitivity to MMP-7 at nanomolecular concentrations,
but was not sensitive to other MMPs such as MMP-2, MMP-9, and MMP-13.
In an optical imaging study, the MMP-3 probe produced early and strong
NIR fluorescence signals prior to observation of erythema and swelling
in CIA mice. The MMP-3 probe was able to rapidly and selectively detect
and monitor active MMP-3 in diluted serum from CIA mice. Furthermore,
histological data demonstrated that activated FLSs in arthritic knee
joints expressed active MMP-3. Together, our results demonstrated
that the MMP-3 probe may be useful for detecting active MMP-3 for
diagnosis of RA. More importantly, the MMP-3 probe was able to detect
active MMP-3 in diluted serum with high sensitivity. Therefore, the
MMP-3 probe developed in this study may be a very promising probe,
useful as a biomarker for early detection and diagnosis of RA