The clinical applications of multimodal probes are numerous since a few decades. 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) has played an important role in diagnostic and therapeutic areas. The vast applications of DOTA as chelator have been explored in magnetic resonance imaging (MRI) and in radioisotope chemistry. Moreover, the possibility to functionalize the macrocycle with pendant arms has allowed to explore new functionalities as bimodal imaging agents. Different combinations are possible between the different possible imaging techniques like Magnetic Resonance Imaging, Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), and Optical imaging (OI). The main use of DOTA and its derivatives was for MRI as gadolinium complexes. It was then further extended to the complexation with europium or terbium for optical imaging. Although other chelates are available such as DTPA or NOTA, derivatives of DOTA were often the primary choice due to their versatility. DOTA derivatives can indeed also be complexed with radioisotopes and conjugated to peptides which leads to targeted contrast agents for PET or SPECT. Depending on the chosen imaging modality, a variety of radiometals can be complexed with DOTA, e.i. 64Cu and 68Ga for PET, or 111In and 90Y for SPECT. Conjugation of chromophores to gadolinium complexes of DOTA derivatives can also lead to bimodal agents for MRI and OI. In this review, we will provide the applications of DOTA and its derivatives in different imaging modalities and their clinical applications.
Non-invasive imaging and quantification of human beta cell mass remains a major challenge. We performed pre-clinical in vivo validation of a peptide previously discovered by our group, namely, P88 that targets a beta cell specific biomarker, FXYD2γa. We conjugated P88 with DOTA and then complexed it with GdCl3 to obtain the MRI (magnetic resonance imaging) contrast agent (CA) Gd-DOTA-P88. A scrambled peptide was used as a negative control CA, namely Gd-DOTA-Scramble. The CAs were injected in immunodeficient mice implanted with EndoC-βH1 cells, a human beta cell line that expresses FXYD2γa similarly to primary human beta cells. The xenograft-bearing mice were analyzed by MRI. At the end, the mice were euthanized and the CA biodistribution was evaluated on the excised tissues by measuring the Gd concentration with inductively coupled plasma mass spectrometry (ICP-MS). The MRI and biodistribution studies indicated that Gd-DOTA-P88 accumulates in EndoC-βH1 xenografts above the level observed in the background tissue, and that its uptake is significantly higher than that observed for Gd-DOTA-Scramble. In addition, the Gd-DOTA-P88 showed good xenograft-to-muscle and xenograft-to-liver uptake ratios, two potential sites of human islets transplantation. The CA shows good potential for future use to non-invasively image implanted human beta cells.
Reactive extrusion and magnesium (II) N-heterocyclic carbene catalyst are successfully employed in continuous polylactide synthesis. The possibility of using six-membered N-heterocyclic carbene adducts to act as efficient catalysts towards the sustainable synthesis of poly(l-lactide) through ring-opening polymerization of l-lactide (LA) is first investigated in bulk batch reactions. Under optimized solvent-free conditions, polylactide (PLA) of moderate to high molecular weights and excellent optical activities are successfully achieved. These promising results are further applied in the continuous production of PLA in an extruder.
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