Abnormal enzymatic activities are directly related to the development of cancers. Identifying the location and expression levels of these enzymes in live cancer cells have considerable importance in early-stage cancer diagnoses and monitoring the efficacy of therapies. Small-molecule fluorescent probes have become a powerful tool for the detection and imaging of enzymatic activities in biological systems by virtue of their higher sensitivity, nondestructive fast analysis, and real-time detection abilities. Moreover, due to their structural tailorability, numerous small-molecule enzymatic fluorescent probes have been developed to meet various demands involving real-time tracking and visualizing different enzymes in live cancer cells or in vivo. In this review, we provide an overview of recent advances in small-molecule enzymatic fluorescent probes mainly during the past decade, including the design strategies and applications for various enzymes in live cancer cells. We also highlight the challenges and opportunities in this rapidly developing field of small-molecule fluorescent probes for interventional surgical imaging, as well as cancer diagnosis and therapy.

Recent progresses in small-molecule enzymatic fluorescent probes for cancer imaging

Cathepsins are the most abundant lysosomal proteases that are mainly found in acidic endo/lysosomal compartments where they play a vital role in intracellular protein degradation, energy metabolism, and immune responses among a host of other functions. The discovery that cathepsins are secreted and remain functionally active outside of the lysosome has caused a paradigm shift. Contemporary research has unraveled many versatile functions of cathepsins in extralysosomal locations including cytosol and extracellular space. Nevertheless, extracellular cathepsins are majorly upregulated in pathological states and are implicated in a wide range of diseases including cancer and cardiovascular diseases. Taking advantage of the differential expression of the cathepsins during pathological conditions, much research is focused on using cathepsins as diagnostic markers and therapeutic targets. A tailored therapeutic approach using selective cathepsin inhibitors is constantly emerging to be safe and efficient. Moreover, recent development of proteomic-based approaches for the identification of novel physiological substrates offers a major opportunity to understand the mechanism of cathepsin action. In this review, we summarize the available evidence regarding the role of cathepsins in health and disease, discuss their potential as biomarkers of disease progression, and shed light on the potential of extracellular cathepsin inhibitors as safe therapeutic tools.

/pdf/the-ins-and-outs-of-cathepsins-physiological-function-and-1eobx02453.pdf

The Ins and Outs of Cathepsins: Physiological Function and Role in Disease Management.

For a long time, cysteine cathepsins were considered primarily as proteases crucial for nonspecific bulk proteolysis in the endolysosomal system. However, this view has dramatically changed, and cathepsins are now considered key players in many important physiological processes, including in diseases like cancer, rheumatoid arthritis, and various inflammatory diseases. Cathepsins are emerging as important players in the extracellular space, and the paradigm is shifting from the degrading enzymes to the enzymes that can also specifically modify extracellular proteins. In pathological conditions, the activity of cathepsins is often dysregulated, resulting in their overexpression and secretion into the extracellular space. This is typically observed in cancer and inflammation, and cathepsins are therefore considered valuable diagnostic and therapeutic targets. In particular, the investigation of limited proteolysis by cathepsins in the extracellular space is opening numerous possibilities for future break-through discoveries. In this review, we highlight the most important findings that establish cysteine cathepsins as important players in the extracellular space and discuss their roles that reach beyond processing and degradation of extracellular matrix (ECM) components. In addition, we discuss the recent developments in cathepsin research and the new possibilities that are opening in translational medicine.

Cysteine Cathepsins and Their Extracellular Roles: Shaping the Microenvironment

Infectious diseases can be transmitted and they cause a significant burden on public health globally. They are the greatest world killers and it is estimated that they are responsible for the demise of over 17 million people annually. The impact of these diseases is greater in the developing countries. People with compromised immune systems and children are the most affected. Infectious diseases may be caused by bacteria, viruses, and protozoa. The treatment of infectious diseases is hampered by simultaneous resistance to multiple drugs, indicating that there is a serious and pressing need to develop new therapeutics that can overcome drug resistance. This review will focus on the recent reports of metal-based nanoparticles that are potential therapeutics for the treatment of infectious diseases and their biological efficacy (in vitro and in vivo).

Metal-Based Nanoparticles for the Treatment of Infectious Diseases

https://www.cell.com/cell-chemical-biology/pdf/S2451-9456(15)00469-9.pdf

A Bright Future for Precision Medicine: Advances in Fluorescent Chemical Probe Design and Their Clinical Application

The Future of Cysteine Cathepsins in Disease Management.

Intensive research in the area of medical nanotechnology, especially to cope with the bacterial resistance against conventional antibiotics, has shown strong antimicrobial action of metallic and metal-oxide nanomaterials towards a wide variety of bacteria. However, the important remaining problem is that nanomaterials with highest antibacterial activity generally express also a high level of cytotoxicity for mammalian cells. Here we present gallium nanoparticles as a new solution to this problem. We developed a nanocomposite from bioactive hydroxyapatite nanorods (84 wt %) and antibacterial nanospheres of elemental gallium (16 wt %) with mode diameter of 22 ± 11 nm. In direct comparison, such nanocomposite with gallium nanoparticles exhibited better antibacterial properties against Pseudomonas aeruginosa and lower in-vitro cytotoxicity for human lung fibroblasts IMR-90 and mouse fibroblasts L929 (efficient antibacterial action and low toxicity from 0.1 to 1 g/L) than the nanocomposite of hydroxyapatite and silver nanoparticles (efficient antibacterial action and low toxicity from 0.2 to 0.25 g/L). This is the first report of a biomaterial composite with gallium nanoparticles. The observed strong antibacterial properties and low cytotoxicity make the investigated material promising for the prevention of implantation-induced infections that are frequently caused by P. aeruginosa.

Biocompatible nano-gallium/hydroxyapatite nanocomposite with antimicrobial activity.

The synthesis and evaluation of two cathepsin S-specific probes is described. For long-term retention of the probe at the target site and a high signal-to-noise ratio, we introduced a lipidation approach via the simple attachment of palmitoic acid to the reporter. After cathepsin S-specific cleavage in cultured cells and in a grafted tumor mouse model, fluorescence increased owing to dequenching and we observed an intracellular accumulation of the fluorescence in the target tissue. The lipidated probe provided a prolonged and strongly fluorescent signal in tumors when compared to the very similar non-lipidated probe, demonstrating that non-invasive tumor identification is feasable. The homing principle by probe lipidation might also work for selective administration of cytotoxic compounds to specifically reduce tumor mass.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.201310979

In Vivo Imaging of Mouse Tumors by a Lipidated Cathepsin S Substrate

Cysteine cathepsins often contribute to cancer progression due to their overexpression in the tumour microenvironment and therefore present attractive targets for non-invasive diagnostic imaging. However, the development of highly selective and versatile small molecule probes for cathepsins has been challenging. Here, we targeted tumour-associated cathepsin B using designed ankyrin repeat proteins (DARPins). The selective DARPin 8h6 inhibited cathepsin B with picomolar affinity (Ki = 35 pM) by binding to a site with low structural conservation in cathepsins, as revealed by the X-ray structure of the complex. DARPin 8h6 blocked cathepsin B activity in tumours ex vivo and was successfully applied in in vivo optical imaging in two mouse breast cancer models, in which cathepsin B was bound to the cell membrane or secreted to the extracellular milieu by tumour and stromal cells. Our approach validates cathepsin B as a promising diagnostic and theranostic target in cancer and other inflammation-associated diseases.

https://www.zora.uzh.ch/id/eprint/139762/1/Kramer_et_al._2017.pdf

Non-invasive in vivo imaging of tumour-associated cathepsin B by a highly selective inhibitory DARPin.

Modified hydroxyapatite with antibacterial properties and high biocompatibility with mammalian cells is very desirable in many biomedical applications. Here we study the incorporation of Ga3+ ions into hydroxyapatite to achieve such an effective biological response. Antibacterial action against P. aeruginosa and cytocompatibility with L929 mouse fibroblasts was examined in vitro for different hydroxyapatites with incorporated Ga3+ ions (HAp(Ga)). Different Ga(III) contents and HAp(Ga) morphologies were obtained by adding Ga3+ ions at different stages of the hydroxyapatite synthesis and varying the Ga3+ concentration. Ga3+ ions were incorporated into the hydroxyapatite precursor phases at the early stages of the hydroxyapatite synthesis and into the amorphous surface layer of the apatite crystals at the late stages or after the synthesis, which yielded a mixed Ca/Ga amorphous phosphate surface layer. Their incorporation into the precursor nuclei before crystal formation and growth reduced the size of the final HAp(Ga) to small apatite nanocrystals with a large fraction of the mixed Ca/Ga amorphous phosphate surface layer. The release of Ga3+ ions from the HAp(Ga) depended on the overall amount of Ga in the material, while the biological response was mediated by the composition of the amorphous surface layer. The mainly Ca-phosphate amorphous surface layer resulted in a low antibacterial efficiency, while the mainly Ga-phosphate amorphous surface layer resulted in a high antibacterial efficiency, but also cytotoxicity. Ga(III)-containing hydroxyapatite can be designed for an effective biological response by varying the HAp(Ga) size and the overall Ga content to achieve the desired composition of the amorphous surface layer. The optimum HAp(Ga) in this study contained 4 wt% of Ga(III) and was obtained by adding Ga3+ ions during transformation of the precursor octacalcium phosphate/hydroxyapatite crystals to the final hydroxyapatite crystals. It provides excellent control over the release of the Ga3+ ions, and joins together the high efficacy of the antimicrobial action and non-toxicity over a wide concentration range (from 0.3 g L−1 to at least 1 g L−1).

Designing Ga(III)-containing hydroxyapatite with antibacterial activity

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