CT Imaging of Enzymatic Activity in Cancer Using Covalent Probes Reveal a Size-Dependent Pattern
Autor: | Yael Ben-Nun, Galia Blum, Tommy Weiss-Sadan, Emmanuelle Merquiol, Darya Tsvirkun, Karen Meir, Ilan Matok, Ivan Zlotver, Rachela Popovtzer |
---|---|
Rok vydání: | 2018 |
Předmět: |
Male
genetic structures Metal Nanoparticles 02 engineering and technology Biochemistry Article Catalysis Cathepsin B Polyethylene Glycols Mice 03 medical and health sciences 0302 clinical medicine Colloid and Surface Chemistry Cell Line Tumor Neoplasms medicine Animals Humans Enzyme Inhibitors chemistry.chemical_classification Mice Inbred BALB C Biomolecule Cancer Dipeptides General Chemistry 021001 nanoscience & nanotechnology medicine.disease Small molecule 3. Good health Enzyme chemistry Covalent bond Colloidal gold 030220 oncology & carcinogenesis NIH 3T3 Cells Gold Tomography Molecular imaging Lysosomes Tomography X-Ray Computed 0210 nano-technology Biomedical engineering |
Zdroj: | Journal of the American Chemical Society |
ISSN: | 1520-5126 0002-7863 |
Popis: | X-ray CT instruments are among the most available, efficient, and cost-effective imaging modalities in hospitals. The field of CT molecular imaging is emerging which relies mainly on the detection of gold nanoparticles and iodine-containing compounds directed to tagging a variety of abundant biomolecules. Here for the first time we attempted to detect enzymatic activity, while the low sensitivity of CT scanners to contrast reagents made this a challenging task. Therefore, we developed a new class of nanosized cathepsin-targeted activity-based probes (ABPs) for functional CT imaging of cancer. ABPs are small molecules designed to covalently modify enzyme targets in an activity-dependent manner. Using a CT instrument, these novel probes enable detection of the elevated cathepsin activity within cancerous tissue, thus creating a direct link between biological processes and imaging signals. We present the generation and biochemical evaluation of a library of ABPs tagged with different sized gold nanoparticles (GNPs), with various ratios of cathepsin-targeting moiety and a combination of different polyethylene glycol (PEG) protective layers. The most potent and stable GNP-ABPs were applied for noninvasive cancer imaging in mice. Surprisingly, detection of CT contrast from the tumor had reverse correlation to GNP size and the amount of targeting moiety. Interestingly, TEM images of tumor sections show intercellular lysosomal subcellular localization of the GNP-ABPs. In conclusion, we demonstrate that the covalent linkage is key for detection using low sensitive imaging modalities and the utility of GNP-ABPs as a promising tool for enzymatic-based CT imaging. |
Databáze: | OpenAIRE |
Externí odkaz: |