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In vivo antero-posterior images of apoE-/-mice injected with AA5 or 5 at three different time points.
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Dysregulation of matrix metalloproteinase (MMP) activity can lead to a wide range of disease states such as atherosclerosis, inflammation or cancer. The ability to image MMP activity non-invasively in vivo, by radiolabelled synthetic inhibitors, would allow the characterisation of atherosclerotic plaques, inflammatory lesions or tumors. Here we pre...
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Extracellular proteases including matrix metalloproteinases (MMPs) are speculated to play a significant role in chronic lung diseases such as asthma. Although increased protease expression has been correlated with lung pathogenesis, the relationship between localized enzyme activity and disease progression remains poorly understood. We report the a...
Patients with head and neck squamous cell carcinoma (HNSCC) containing TP53 mutation and 3p deletion ("double-hit") have poorer prognosis compared to patients with either event alone ("single-hit"). The etiology for worse clinical outcomes in patients with "double-hit" cancers is unclear. We compared radiosensitivity of cell lines containing both T...
Citations
... Throughout the years, PET equipment has been updated and revised making this technique considerably sensible to a wide range of positron emitters and very precise toward the diagnosis of many cancer diseases [7][8][9]. 18 F is by far the most widely employed positron emitter for PET studies owing to its excellent nuclear properties: half time of 110 min that allows preparing radiopharmaceuticals without an in situ PET and a low positron emission energy (635 keV) which allows obtaining images with a better spatial resolution [6,7]. The glucose-analog 2-deoxy-2-([18]F) fluoro-D-glucose (FDG) is considered the pioneer PET compound due to its ability to detect several oncoproliferative diseases [8][9][10]. ...
... These studies convert MMP members into very important, critical molecular targets in the development of novel therapeutic and diagnosing agents for oncoproliferative diseases. Previous studies conducted with radiolabeled MMPs inhibitors using PET and Single Photon Emission Computed Tomography (SPECT) as imaging techniques have demonstrated the importance of monitoring the activity of MMPs through imaging techniques [17,18]. However, new PET radiopharmaceuticals components, based on compounds with previously demonstrated experimental MMP affinity, could be helpful to better understand the role of MMPs in tumor metastasis, cell invasion and diagnosis of cancer diseases. ...
Metalloproteinase-9 (MMP-9) is a key protein in cancer advancement and metastasis owing to its ability to degrade some extracellular matrix components. Mangiferin, a natural polyphenolic compound, has demonstrated through experimental and theoretical studies to be a great anticancer agent for the selective inhibition of MMP-9. This work aimed to evaluate the utility of several fluorinated compounds obtained from MF as possible Positron Emission Tomography (PET) radiopharmaceuticals oriented to MMP-9. Density Functional Theory calculations of MF were made to obtain the most active sites toward electrophilic and nucleophilic reactions and propose a synthetic route to produce its fluorinated derivatives. The reactivity study allowed us to propose a late-stage synthetic route based on click chemistry to obtain three fluorinated MF-based derivatives. Molecular docking calculations suggested that the derivative F-propyl-MF could be suitable as PET radiopharmaceutical owing to the establishment of a five-coordinated complex with the catalytic Zn atom belonging to the active site of MMP-9, crucial factor in the inhibition of MMP-9.
... Positive [101][102][103] AAA, abdominal aortic aneurysm; ECs, endothelial cells; VSMCs, vascular smooth muscle cells; pDCs, plasmacytoid dendritic cells; DCs, dendritic cells; IFN, interferon; NETs, neutrophils extracellular traps; Tregs, regulatory T cells; MCP-1, monocyte chemotactic protein 1; NK, natural killer cell; COX2, cyclooxygenase 2; PGE2, prostaglandin E2; MMP, matrix metalloproteinase. ...
... Molecular imaging can track MMP expression and activity and thus be used an index of disease progression [119,120]. Widely used MMP inhibitors (MMPIs) such as TPPTS, 111 In-DTPA-RP782, 123 I-HO-CGS 27023A [101], 18F-BR-351 [102], 18F-BR420 [103,121], 111 In-RP782 11a, 99 mTc-RP805 11b [120], and other tracers can specifically bind to MMPs. Some tracers can even identify special subtypes or activated forms of MMPs, improving the disease diagnoses. ...
... Ref.[35][36][37][38][39][40][41][42][43][44]47,49,50,54,56,57,67,68,70,71,[77][78][79][80][87][88][89][93][94][95][96][97][98][99][100][101][102][103]). ...
Abdominal aortic aneurysm (AAA) is the most common and critical aortic disease. Bleeding is the most serious complication from a ruptured AAA, which often results in death. Therefore, early diagnosis and treatment are the only effective means to reduce AAA associated mortality. Positron emission tomography/computed tomography (PET/CT) combines functional and anatomical imaging. The expanded application of PET/CT in the medical field could have benefits for the diagnosis and treatment of patients with AAA. This review explores the efficiency of PET/CT in the diagnosis of AAA based on our understanding of the underlying molecular mechanisms of AAA development.
... The list of diagnostic imaging methods used by researchers and clinicians has recently been expanded with magnetic resonance imaging (MRI)-based techniques (functional MRI, MRI spectroscopy, high-resolution MRI, etc.) providing information on the spatiotemporal pattern of tissue vascularity and perfusion, cellularity, extracellular pH within the tumor niche and other metabolic features [212][213][214]. The activity of enzymes playing a role in TME organization, for example, matrix metalloproteinases and cysteine cathepsins can be visualized with radioisotope-labeled tracers by positron emission tomography (PET) and single-photon emission tomography (SPECT) [215][216][217]. The multiple options include multiple imaging techniques to study tumor-associated inflammation and immune cell populations, hypoxia, glycolysis, matrix proteins, etc. (see for review [218][219][220]. ...
Simple Summary
Connexins are proteins which comprise gap junctions in cells. These junctions can directly connect neighboring cells and the cell interior with the extracellular microenvironment and thus they act as tissue integrators. Alterations in connexin regulation can lead to unfavorable shifts in the tissue adhesive context thus eradicating the constraints of the normal tissue microenvironment, triggering (or enhancing) cell motility. This review tries to examine the role of connexins in orchestrating the tumor microenvironment and hence their role in malignancy.
Abstract
Today’s research on the processes of carcinogenesis and the vital activity of tumor tissues implies more attention be paid to constituents of the tumor microenvironment and their interactions. These interactions between cells in the tumor microenvironment can be mediated via different types of protein junctions. Connexins are one of the major contributors to intercellular communication. They form the gap junctions responsible for the transfer of ions, metabolites, peptides, miRNA, etc., between neighboring tumor cells as well as between tumor and stromal cells. Connexin hemichannels mediate purinergic signaling and bidirectional molecular transport with the extracellular environment. Additionally, connexins have been reported to localize in tumor-derived exosomes and facilitate the release of their cargo. A large body of evidence implies that the role of connexins in cancer is multifaceted. The pro- or anti-tumorigenic properties of connexins are determined by their abundance, localization, and functionality as well as their channel assembly and non-channel functions. In this review, we have summarized the data on the contribution of connexins to the formation of the tumor microenvironment and to cancer initiation and progression.
... By relying on MMP inhibitors scaffold (see also the section on MMP inhibitors), numerous imaging agents have been designed for different types of imaging modalities, including positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging, and optical imaging (Matusiak et al., 2013;Rangasamy et al., 2019). Two types of imaging probes can be distinguished: those possessing an imaging reporter of small size (e.g., a radioisotope such as 18 F, 11 C, or 123 I) that is directly inserted within the structure of the MMP inhibitors, and those incorporating a reporter of comparable size to that of the MMP inhibitor scaffold (e.g., NIR dye, encaged 68 Ga or 99m Tc). ...
The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. SIGNIFICANCE STATEMENT: Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.
... Since matrix metalloproteinases (MMPs)-or matrixins-represent a family of proteinases with multiple and crucial roles in the inflammatory processes, imaging the MMPs could provide insights not on the density of macrophages, like most probes, but on their activity to promote inflammation and plaque ruptures. In this context, the [ 111 In]-DTPA-RP782-radiolabeled MMP inhibitor has been considered for molecular imaging of atherosclerosis and aneurysm and, particularly, monitoring of distinctive MMP activities [402][403][404][405]. More preclinical and clinical studies are mandatory to further assess its feasibility; nevertheless, the development of these selective MMP inhibitors is already in progress [406][407][408] in order to minimize the side effects of treatments. ...
Positron emission tomography (PET) uses radioactive tracers and enables the functional imaging of several metabolic processes, blood flow measurements, regional chemical composition, and/or chemical absorption. Depending on the targeted processes within the living organism, different tracers are used for various medical conditions, such as cancer, particular brain pathologies, cardiac events, and bone lesions, where the most commonly used tracers are radiolabeled with 18F (e.g., [18F]-FDG and NA [18F]). Oxygen-15 isotope is mostly involved in blood flow measurements, whereas a wide array of 11C-based compounds have also been developed for neuronal disorders according to the affected neuroreceptors, prostate cancer, and lung carcinomas. In contrast, the single-photon emission computed tomography (SPECT) technique uses gamma-emitting radioisotopes and can be used to diagnose strokes, seizures, bone illnesses, and infections by gauging the blood flow and radio distribution within tissues and organs. The radioisotopes typically used in SPECT imaging are iodine-123, technetium-99m, xenon-133, thallium-201, and indium-111. This systematic review article aims to clarify and disseminate the available scientific literature focused on PET/SPECT radiotracers and to provide an overview of the conducted research within the past decade, with an additional focus on the novel radiopharmaceuticals developed for medical imaging.
... The non-invasive detection and assessment of locally upregulated and activated matrix metalloproteinases (MMPs) in vivo using MMP inhibitor-based radiotracers for positron emission tomography (PET) or single photon emission computed tomography (SPECT) is still a challenge [4]. However, if successful, the visualization of MMP activity by means of aforementioned scintigraphic technologies would become a breakthrough by improving diagnosis and assessment of disease progression [5]. ...
... Several groups are working on the design, improvement, and evaluation of MMP inhibitor-based radiotracers aiming at the non-invasive imaging of MMP-associated diseases by means of SPECT or PET [4,[6][7][8][9][10][11][12]. For this purpose, different classes of radiolabeled MMP inhibitors (MMPIs) have been developed and explored as radiotracers. ...
Introduction
Dysregulated activity of matrix metalloproteinases (MMPs) drives a variety of pathophysiological conditions. Non-invasive imaging of MMP activity in vivo promises diagnostic and prognostic value. However, current targeting strategies by small molecules are typically limited with respect to the bioavailability of the labeled MMP binders in vivo . To this end, we here introduce and compare three chemical modifications of a recently developed barbiturate-based radiotracer with respect to bioavailability and potential to image MMP activity in vivo .
Methods
Barbiturate-based MMP inhibitors with an identical targeting unit but varying hydrophilicity were synthesized, labeled with technetium-99m, and evaluated in vitro and in vivo . Biodistribution and radiotracer elimination were determined in C57/BL6 mice by serial SPECT imaging. MMP activity was imaged in a MMP-positive subcutaneous xenograft model of human K1 papillary thyroid tumors. In vivo data were validated by scintillation counting, autoradiography, and MMP immunohistochemistry.
Results
We prepared three new 99m Tc‐labeled MMP inhibitors, bearing either a glycine ([ 99m Tc] MEA39 ), lysine ([ 99m Tc] MEA61 ), or the ligand HYNIC with the ionic co-ligand TPPTS ([ 99m Tc] MEA223 ) yielding gradually increasing hydrophilicity. [ 99m Tc] MEA39 and [ 99m Tc] MEA61 were rapidly eliminated via hepatobiliary pathways. In contrast, [ 99m Tc] MEA223 showed delayed in vivo clearance and primary renal elimination. In a thyroid tumor xenograft model, only [ 99m Tc] MEA223 exhibited a high tumor-to-blood ratio that could easily be delineated in SPECT images.
Conclusion
Introduction of HYNIC/TPPTS into the barbiturate lead structure ([ 99m Tc] MEA223 ) results in delayed renal elimination and allows non-invasive MMP imaging with high signal-to-noise ratios in a papillary thyroid tumor xenograft model.
... The half-lives of isotopes used in PET or SPECT tracers are usually short, posing a unique barrier to commonplace application of these modalities for protease imaging. Nevertheless, the technology was successfully demonstrated for imaging metalloproteases [263][264][265], cysteine cathepsins [266][267][268] and caspases [269,270] in preclinical settings. In CT imaging modalities, X-rays are used to create cross-sectional images with high resolution and this technique is widely used for noninvasive clinical imaging [271]. ...
... Activity-based probes + Sensitive detection of proteases in situ in cells and animal models + Excellent selectivity for target proteases − No signal amplification Metalloproteases [213][214][215], serine proteases [216] including neutrophil proteases [217] and inflammation-related serine proteases [218], cysteine cathepsins [219,220], caspases [221,222] and legumain [223,224], aspartic proteases [225], and proteasome [226,227] Protease-cleavable fluorescent substrate probes + Signal amplification + Selectivity can be improved by designs that incorporate unnatural amino acids − Background fluorescence and signal diffusion Profiling of caspases [222], cathepsins [238,239], neutrophil proteases [217] and kallikreins [240] QDs + Sensitivity of integrated FRET + Versatile platform − Toxicity of nanoparticles Imaging and detection MMPs [247,248], caspase-1, collagenase, chymotrypsin and thrombin [249], uPAR [250], caspase-3 [251] and kallikrein [252] PET and SPECT probes + High sensitivity and resolution − Short half-life of reagents because of radioactive isotopes − Costly detection modalities Protease-responsive contrast agents for metalloproteases [263][264][265], cysteine cathepsins [266][267][268] and caspases [269,270] MRI probes + High sensitivity and resolution for soft tissues − Expensive detection modality MMP-2 in tumors [274], caspase activity after drug-induced apoptosis [275], caspase-3 [276], digestive elastases [277], cysteine cathepsins [279] and furin [280] CT probes + Resolution for in-depth tissue imaging − Lack of suitable protease-sensitive probes ...
In recent decades, dysregulation of proteases and atypical proteolysis have become increasingly recognized as important hallmarks of cancer, driving community-wide efforts to explore the proteolytic landscape of oncologic disease. With more than 100 proteases currently associated with different aspects of cancer development and progression, there is a clear impetus to harness their potential in the context of oncology. Advances in the protease field have yielded technologies enabling sensitive protease detection in various settings, paving the way towards diagnostic profiling of disease-related protease activity patterns. Methods including activity-based probes and substrates, antibodies, and various nanosystems that generate reporter signals, i.e., for PET or MRI, after interaction with the target protease have shown potential for clinical translation. Nevertheless, these technologies are costly, not easily multiplexed, and require advanced imaging technologies. While the current clinical applications of protease-responsive technologies in oncologic settings are still limited, emerging technologies and protease sensors are poised to enable comprehensive exploration of the tumor proteolytic landscape as a diagnostic and therapeutic frontier. This review aims to give an overview of the most relevant classes of proteases as indicators for tumor diagnosis, current approaches to detect and monitor their activity in vivo, and associated therapeutic applications.
... For instance, near-infrared fluorophores joined by peptide protease substrates become de-quenched upon cleavage [146]. Protease cleavage can also lead to aggregation and signal enhancement of magnetic nanoparticles for MRI [147], and 18 F PET tracers have been developed based on tight binding protease inhibitors [148]. scRNAseq and imaging data underline the heterogeneity of protease activities at sites of disease across patients, particularly in solid cancers, due to variability in both the level of immune-cell infiltration, and in the regulated expression and activity of proteases in the cells that are present [37]. ...
Macrophages have been associated with drug response and resistance in diverse settings, thus raising the possibility of using macrophage imaging as a companion diagnostic to inform personalized patient treatment strategies. Nanoparticle-based contrast agents are especially promising because they efficiently deliver fluorescent, magnetic, and/or radionuclide labels by leveraging the intrinsic capacity of macrophages to accumulate nanomaterials in their role as professional phagocytes. Unfortunately, current clinical imaging modalities are limited in their ability to quantify broad molecular programs that may explain (a) which particular cell subsets a given imaging agent is actually labeling, and (b) what mechanistic role those cells play in promoting drug response or resistance. Highly multiplexed single-cell approaches including single-cell RNA sequencing (scRNAseq) have emerged as resources to help answer these questions. In this review, we query recently published scRNAseq datasets to support companion macrophage imaging, with particular focus on using dextran-based nanoparticles to predict the action of anti-cancer nanotherapies and monoclonal antibodies.
... Однако большинство из предложенных химических составов молекул-векторов до сих пор находятся на этапе апробации на животных. Одним из таких является радиофармпрепарат Маримастат-ArB[1FF]F₃ -ингибитор матриксной металлопротеиназы-2 на основе изотопа фтора [73], который хорошо показал себя на модели атеросклероза, но в большей степени получил свое применение в онкологии [74]. ...
This literature review dedicated to molecular imaging of inflammation in a thoracic aortic aneurysm. The article describes current approaches in the molecular diagnosis of aortic pathology, as well as radiopharmaceuticals used in clinical practice and at the stage of experimental research; their advantages and disadvantages are discussed. The authors consider current problems of modern molecular imaging of inflammation, unresolved issues in this area, as well as prospects for the development of molecular technologies in terms of diagnostics of the inflammatory process in the extended aortic wall. Literature search was performed using electronic bibliographic databases such as PubMed, E-library, Medline, GoogleShcolar. © 2020 Russian Electronic Journal of Radiology. All rights reserved.
... The addition of a solubility switch cleaved by a MMP such as MMP-2 reduces contrast agent solubility increasing its accumulation in the cells and therefore enhancing its sensitivity. Another interesting alternative is the use of radioisotopes with the ABPs and its visualization through photon emission tomography (PET) or single photon emission computed tomography (SPECT) (Matusiak et al., 2013). Likewise, activatable cell penetrating peptides (ACPPs) were developed to improve cell specific uptake and increase sensitivity. ...
Matrix metalloproteinases (MMPs) participate from the initial phases of cancer onset to the settlement of a metastatic niche in a second organ. Their role in cancer progression is related to their involvement in the extracellular matrix (ECM) degradation and in the regulation and processing of adhesion and cytoskeletal proteins, growth factors, chemokines and cytokines. MMPs participation in cancer progression makes them an attractive target for cancer therapy. MMPs have also been used for theranostic purposes in the detection of primary tumor and metastatic tissue in which a particular MMP is overexpressed, to follow up on therapy responses, and in the activation of cancer cytotoxic pro-drugs as part of nano-delivery-systems that increase drug concentration in a specific tumor target. Herein, we review MMPs molecular characteristics, their synthesis regulation and enzymatic activity, their participation in the metastatic process, and how their functions have been used to improve cancer treatment.
