Dark Quenched Matrix Metalloproteinase Fluorogenic Probe for Imaging Osteoarthritis Development <i>in Vivo</i>

Lee, Seulki; Park, Kyeongsoon; Lee, Seung Young; Ryu, Jee Hoon; Park, Jong Woong; Ahn, Hyung Jun; Kwon, Ick Chan; Youn, Inchan; Kim, Kwangmeyung; Choi, Kuiwon

doi:10.1021/bc800264z

Cited by 79 publications

(79 citation statements)

References 16 publications

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“…Any symptoms associated with OA, such as joint effusion, tenderness, crepitation, decreased range of motion, and alignment of the knee joints, are carefully evaluated by physician. Radiographs typically show joint space narrowing, subchondral sclerosis, marginal osteophytes, and, sometimes, subchondral cyst formation 4. In diagnosis of OA, laboratory tests (e.g.…”

Section: Introductionmentioning

confidence: 99%

Measurement of MMP Activity in Synovial Fluid in Cases of Osteoarthritis and Acute Inflammatory Conditions of the Knee Joints Using a Fluorogenic Peptide Probe-Immobilized Diagnostic Kit

et al. 2012

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Purpose: A fluorogenic peptide probe-immobilized diagnostic kit was used to analyze MMP activity in the synovial fluids (SFs) from patients with osteoarthritis (OA) and acute inflammatory conditions of the knee joint.Methods: The MMP diagnostic kit containing a polymer-conjugated MMP probe immobilized on a 96-well plate was utilized for high-throughput screening of MMP activity in SFs from OA patients (n = 33) and patients with acute inflammatory conditions of the knee joint (n = 5).Results: Compared to SF from OA patients, SF from patients with acute inflammatory conditions of the knee joint presented stronger NIR fluorescent signals. In gelatin zymography, most samples from patients with acute inflammatory conditions of the knee joint also displayed 92 kDa (pro-form) MMP-9 and faint 84 kDa (active form) MMP-9, while SF from OA patients did not display detectable MMP-9 activity .Conclusion: The presence of a strong fluorescence signal from the MMP diagnostic kit corresponded well with patients with acute inflammatory conditions of the knee joint. The results suggest that our MMP diagnostic kit can be useful in differentiation between early stages of OA and acute inflammatory conditions of the knee joint.

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Section: Introductionmentioning

confidence: 99%

Measurement of MMP Activity in Synovial Fluid in Cases of Osteoarthritis and Acute Inflammatory Conditions of the Knee Joints Using a Fluorogenic Peptide Probe-Immobilized Diagnostic Kit

et al. 2012

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“…Other strategies for MMP imaging, which do take full advantage of the nature of the target, are directed at the activity of the enzyme and will provide a selective readout of the activated MMP subpopulation and, importantly, lead to signal amplification because a single MMP can continuously activate its substrate (13). Recently, a variety of substrate-flanked fluorescence resonance energy-transfer probes has been developed to sense MMP activity in living organisms (14)(15)(16)(17)(18). Typically, these smart probes consist of one or multiple intramolecularly quenched fluorophores that become fluorescent on activation.…”

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confidence: 99%

Tumor Targeting of MMP-2/9 Activatable Cell-Penetrating Imaging Probes Is Caused by Tumor-Independent Activation

Duijnhoven¹,

Robillard²,

Nicolay³

et al. 2011

J Nucl Med

106

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Activatable cell-penetrating peptides (ACPPs) are a new class of promising molecular imaging probes for the visualization of enzymes in vivo. The cell-penetrating function of a polycationic peptide is efficiently blocked by intramolecular electrostatic interactions with a polyanionic peptide. Proteolysis of a cleavable linker present between the polycationic cell-penetrating peptide and polyanionic peptide affords dissociation of both domains and enables the activated cell-penetrating peptide to enter cells. Here, we aimed to develop an ACPP sensitive to matrix metalloproteinase-2 and -9 (MMP-2/9) for nuclear imaging purposes. Methods: MMP-2/9 ACPPs and nonactivatable cell-penetrating peptides (non-ACPP) were prepared by 9-fluorenylmethyloxycarbonyl solid-phase peptide synthesis and labeled with 177 Lu or 177 Lu/ 125 I for dual-isotope studies. The in vivo biodistribution of these probes was assessed in MMP-2/9-positive tumor-bearing mice (n 5 6) and healthy mice (n 5 4) using g-counting. Furthermore, a radiolabeled cell-penetrating peptide serving as a positive control was evaluated in tumorbearing mice (n 5 6). Results: Biodistribution studies showed a 5-fold-higher retention of ACPP in tumor than in muscle (P , 0.01) and a 6-fold-higher tumor retention relative to non-ACPP (P , 0.01), supporting earlier studies on fluorescently labeled ACPPs proposing activation by tumor-associated MMP-2/9. Surprisingly, however, the uptake of ACPP was significantly higher than that of non-ACPP in almost all tissues (P , 0.01). To unravel the activation process of ACPP in vivo, we developed dual-isotope ACPP analogs (dACPPs) that allowed us to discriminate between uncleaved dACPP and activated dACPP. In vivo biodistribution of dACPP indicated that the tissue-associated counts originated from activated dACPP. Interestingly, dACPP administration to healthy mice, compared with MMP-2/9-positive tumor-bearing mice, resulted in a similar dACPP biodistribution. Furthermore, a radiolabeled cell-penetrating peptide showed tumor-to-tissue ratios equal to those found for ACPP (P . 0.05). Conclusion: This study demonstrates that the tumor targeting of radiolabeled MMP-2/9 ACPPs is most likely caused by the activation in the vascular compartment rather than tumor-specific activation, as suggested earlier.The results in the present paper indicate that different and more tissue-specific enzyme-ACPP combinations are needed to unleash the full potential of the elegant ACPP concept in living animals.

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“…Optical images in various disease models including cancer, atherosclerosis, and myocardial infarction have demonstrated that this probe can image MMP activity in vivo (103–105). Lee et al described the potential use of a dark-quenched MMP-13 activatable peptide probe to image overexpressed MMP-13 in an osteoarthritis (OA) model (106) (Fig. 3).…”

Section: Optical Peptide Probesmentioning

confidence: 99%

“…The spectrofluorometry study clearly demonstrated significant recovery (>30-fold) of the NIR fluorescence signals in the samples containing MMP-13, with inhibition of the signal in the presence of a MMP-13 inhibitor. When the probe was injected into an OA-induced rat model, the symptoms of the early and late stages of OA could be simply monitored, imaged, and analyzed (106). …”

Section: Optical Peptide Probesmentioning

confidence: 99%

Peptide-Based Probes for Targeted Molecular Imaging

2010

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Targeted molecular imaging techniques have become indispensable tools in modern diagnostics because they provide accurate and specific diagnosis of disease information. Conventional nonspecific contrast agents suffer from low targeting efficiency, thus, the use of molecularly targeted imaging probes are needed depending on different imaging modalities. Although recent technologies have yielded various strategies for designing smart probes, utilization of peptide-based probes has been most successful. Phage display technology and combinatorial peptide chemistry have profoundly impacted the pool of available targeting peptides for the efficient and specific delivery of imaging labels. To date, selected peptides that target a variety of disease-related receptors and biomarkers are in place. These targeting peptides can be coupled with the appropriate imaging moieties or nanoplatforms on demand with the help of sophisticated bioconjugation or radiolabeling techniques. This review article examines the current trends in peptide-based imaging probes developed for in vivo applications. We discuss the advantage and challenges in developing peptidebased probes, and summarize current systems with respect to their unique design strategies and applications.

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Dark Quenched Matrix Metalloproteinase Fluorogenic Probe for Imaging Osteoarthritis Development in Vivo

Cited by 79 publications

References 16 publications

Measurement of MMP Activity in Synovial Fluid in Cases of Osteoarthritis and Acute Inflammatory Conditions of the Knee Joints Using a Fluorogenic Peptide Probe-Immobilized Diagnostic Kit

Measurement of MMP Activity in Synovial Fluid in Cases of Osteoarthritis and Acute Inflammatory Conditions of the Knee Joints Using a Fluorogenic Peptide Probe-Immobilized Diagnostic Kit

Tumor Targeting of MMP-2/9 Activatable Cell-Penetrating Imaging Probes Is Caused by Tumor-Independent Activation

Peptide-Based Probes for Targeted Molecular Imaging

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