Novel Stealthy Gd(III)-DOTA/polymer Conjugates for Magnetic Resonance Imaging (MRI)

Magnetic resonance imaging (MRI) is a routine diagnostic tool in modern clinical medicine. MRI has many advantages as a diagnostic imaging modality. It is noninvasive, delivers no radiation, and has excellent (submillimeter) spatial resolution. Some Gadolinium(III) complexes are commonly used to enhance the contrast between adjacent tissues when the resolution/sensitivity of MRI is too low. Because free Gd3+ is very toxic in doses required for MRI, Gd(III) is chelated by poly(amino-carboxylate) such as diethylenetriamine pentaacetic acid (DTPA) or 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Although DTPA/Gd3+ and DOTA/Gd3+ are water soluble, they have a very short circulation lifetime in blood, a low molecular weight and a short rotational time that make the contrast poor. To enhance the contrast, the Gd3+/complex doses have to be increased. In order to increase the sensitivity of the technique, while not increasing the concentration of the contrast agent, we were investigating different strategies to improve (i) the circulation lifetime in blood, (ii) the relaxation rate of Gd(III) (and consequently, the contrasting efficiency) and (iii) the targeting of the contrast agent. This presentation aims at reporting how a multifunctional (co)polymer can be designed and exploited for improving the contrasting ability and bioavailability of gadolinium-based complexes

Design and synthesis of novel DOTA(Gd3+)–polymer conjugates as potential MRI contrast agents

Conventional low molecular weight gadolinium based Magnetic Resonance Imaging (MRI) contrast agents such as Magnevist® are very useful for imaging tissues. However, at the high magnetic fields used in modern MRI equipments, their relaxivity (contrasting efficiency) is rather poor. The grafting of the gadolinium complex onto macromolecules is a way to enhance their relaxivity provided that the rotational motion of the complex is decreased significantly. Here we report the design of novel Gd3+ based MRI contrast agents with improved relaxivity and potential long blood circulation life-time. We investigate the grafting of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, 1,4,7-tris(1,1-dimethylethyl) ester (DO3AtBu-NH2; a precursor of Gd3+ ligand) onto well-defined functional copolymers bearing activated esters (succinimidyl esters) and poly(ethylene oxide) (PEO) chains required for stealthiness. The tert-butyl groups of grafted DO3AtBu-NH2 are then deprotected by trifluoroacetic acid followed by complexation of Gd3+. Addition of free DOTA at the end of the reaction is necessary to leave the pure and stable water soluble macrocontrast agent. Importantly it shows a relaxivity at high frequencies that is 300% higher than that of the ungrafted gadolinium complex. These novel functional copolymers are therefore promising candidates as macromolecular contrast agents for MRI applications

Gd(III)-DOTA conjugate with furtive targeting copolymer poly(AMPEO-co-HEA) by click chemistry for magnetic resonance imaging

Background: Model organisms are used for research because they provide a framework on which to develop and optimize methods that facilitate and standardize analysis. Such organisms should be representative of the living beings for which they are to serve as proxy. However, in practice, a model organism is often selected ad hoc, and without considering its representativeness, because a systematic and rational method to include this consideration in the selection process is still lacking. Methodology/Principal Findings: In this work we propose such a method and apply it in a pilot study of strengths and limitations of Saccharomyces cerevisiae as a model organism. The method relies on the functional classification of proteins into different biological pathways and processes and on full proteome comparisons between the putative model organism and other organisms for which we would like to extrapolate results. Here we compare S. cerevisiae to 704 other organisms from various phyla. For each organism, our results identify the pathways and processes for which S. cerevisiae is predicted to be a good model to extrapolate from. We find that animals in general and Homo sapiens in particular are some of the non-fungal organisms for which S. cerevisiae is likely to be a good model in which to study a significant fraction of common biological processes. We validate our approach by correctly predicting which organisms are phenotypically more distant from S. cerevisiae with respect to several different biological processes. Conclusions/Significance: The method we propose could be used to choose appropriate substitute model organisms for the study of biological processes in other species that are harder to study. For example, one could identify appropriate models to study either pathologies in humans or specific biological processes in species with a long development time, such as plants.This work was partially financed by fellowships AP2002-2772 and Beatriu dePinós to EV. HK is funded by a Generalitat de Catalunya Ph. D. fellowship. RA was partially supported by the Ministerio de Ciencia e Innovación (MICINN, Spain through the Ramon y Cajal program and grants BFU2007-62772/BMC and BFU2010-17704) and by the FLAD foundation during a short stay. AS acknowledges financial support from grant BFU2008-0196 from MICINN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Stealth macromolecular platforms for the design of MRI blood pool contrast agents

Stealth macromolecular platforms bearing alkyne groups and poly(ethylene oxide) brushes were synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization. The anchoring of Gd3+-chelates bearing an azide group was then carried out by the Huisgen 1,3-dipolar cycloaddition (“click”) reaction in mild conditions, leading to macrocontrast agents for MRI applications. The gadolinium complex is hidden in the PEO shell that renders the macrocontrast agents free of any cytotoxicity and stealth to proteins of the immune system. Relaxometry measurements have evidenced an improved relaxivity of the macrocontrast agent compared to ungrafted gadolinium chelate. Moreover, this relaxivity is further enhanced when the spacer length between the Gd3+-chelate and the polymer backbone is shorter, as the result of its decreased tumbling rate. These novel products are therefore promising candidates for MRI applications

Polymer micelles decorated by gadolinium complexes as MRI blood contrast agents: design, synthesis and properties

New micellar macrocontrast agents with improved contrast at high frequencies were designed by grafting a gadolinium based contrast agent onto functional stealth micelles formed by poly(ethylene oxide)-b-poly(ε-caprolactone) (PEO-b-PCL) in water. As evidenced by relaxometry measurements and the hemolytic CH50 test, the new contrast agents are of interest as MRI blood pool agents