Development of Novel Collagen-targeted Protein-based MRI Contrast Agent for Imaging of Chronic Liver and Heart Diseases

Chronic diseases and conditions such as liver and heart diseases are among the most common, costly, and preventable of all health problems. As of 2012 in the U.S., about half of all adults—117 million people—had one or more chronic health conditions. Aortic aneurysm and liver fibrosis are among the most common chronic diseases which are generated by the formation and deposition of excess extracellular matrix proteins (largely type I collagen) as a result of a reparative process, represents one of the most major global health problems. Collagen type I is one of the major diagnostic biomarkers and therapeutic targets for many chronic diseases including heart and liver diseases. Early diagnosis, noninvasive detection and staging of these diseases, remain as one of the major clinical barriers which can lead to effective treatment and stop further progression toward major clinical consequences. MRI as one the popular imaging modalities has several unique advantages for monitoring slow progression and detection of disease with high resolution without using radiation, however, there is an unmet medical need to develop MRI contrast agents with desired sensitivity and collagen specificity. In this dissertation, the successful design of a protein-based contrast agent with collagen type I targeting capability (ProCA32.collagen1) is reported to diagnose and stage liver and heart diseases in many mouse models of caner, fibrosis and aortic aneurysm. ProCA32.collagen1 exhibits the highest relaxivity values for r1 (34 ± 0.12 mM-1.s-1) and r2 (50 ± 0.16 mM-1.s-1) per Gd3+ at 1.4 T and r1 (21.3 ± 0.5 mM-1.s-1) and r2 (108.5 ± 1.2 mM-1.s-1) at 7.0 T. ProCA32.collagen1 can detect both early (Ishak 3 of 6) and late stage mouse liver fibrosis as well as early stage nonalcoholic steatohepatitis (Ishak 1 of 6) in different models with strong metal binding affinity and selectivity. The targeted contrast agent is also capable of detecting disease heterogeneity with high collagen type I binding affinity with dissociation constant of Kd=1.42 ± 0.2 mM. ProCA32.collagen1 has largely reduced dose and strong resistance against transmetallation (104-1012-fold higher metal selectivity for Gd3+ over Ca2+ and Zn2+) compared to existing contrast agents. ProCA32.collagen1 is expected to have strong translational potential to improve detection of different diseases at early stages with high confidence, and subsequently monitor disease progression and patient response to treatment

Use of nanomaterials in the pretreatment of water samples for environmental analysis

The challenge of providing clean drinking water is of enormous relevance in today’s human civilization, being essential for human consumption, but also for agriculture, livestock and several industrial applications. In addition to remediation strategies, the accurate monitoring of pollutants in water sup-plies, which most of the times are present at low concentrations, is a critical challenge. The usual low concentration of target analytes, the presence of in-terferents and the incompatibility of the sample matrix with instrumental techniques and detectors are the main reasons that renders sample preparation a relevant part of environmental monitoring strategies. The discovery and ap-plication of new nanomaterials allowed improvements on the pretreatment of water samples, with benefits in terms of speed, reliability and sensitivity in analysis. In this chapter, the use of nanomaterials in solid-phase extraction (SPE) protocols for water samples pretreatment for environmental monitoring is addressed. The most used nanomaterials, including metallic nanoparticles, metal organic frameworks, molecularly imprinted polymers, carbon-based nanomaterials, silica-based nanoparticles and nanocomposites are described, and their applications and advantages overviewed. Main gaps are identified and new directions on the field are suggested.publishe

Hydroxamate-Based Selective Macrophage Elastase (MMP-12) Inhibitors and Radiotracers for Molecular Imaging

International audienceMacrophage elastase [matrix metalloproteinase (MMP)-12] is the most upregulated MMP in abdominal aortic aneurysm (AAA) and, hence, MMP-12-targeted imaging may predict AAA progression and rupture risk. Here, we report the design, synthesis, and evaluation of three novel hydroxamate-based selective MMP-12 inhibitors (CGA, CGA-1, and AGA) and the methodology to obtain MMP-12 selectivity from hydroxamate-based panMMP inhibitors. Also, we report two 99mTc-radiotracers, 99mTc-AGA-1 and 99mTc-AGA-2, derived from AGA. 99mTc-AGA-2 displayed faster blood clearance in mice and better radiochemical stability compared to 99mTc-AGA-1. Based on this, 99mTc-AGA-2 was chosen as the lead tracer and tested in murine AAA. 99mTc-AGA-2 uptake detected by autoradiography was significantly higher in AAA compared to normal aortic regions. Specific binding of the tracer to MMP-12 was demonstrated through ex vivo competition. Accordingly, this study introduces a novel family of selective MMP-12 inhibitors and tracers, paving the way for further development of these agents as therapeutic and imaging agents