Tens of millions of contrast-enhanced magnetic resonance imaging (MRI) exams are performed annually around the world. The contrast agents, which improve diagnostic accuracy, are almost exclusively small, hydrophilic gadolinium(III) based chelates. In recent years concerns have arisen surrounding the long-term safety of these compounds, and this has spurred research into alternatives. There has also been a push to develop new molecularly targeted contrast agents or agents that can sense pathological changes in the local environment. This comprehensive review describes the state of the art of clinically approved contrast agents, their mechanism of action, and factors influencing their safety. From there we describe different mechanisms of generating MR image contrast such as relaxation, chemical exchange saturation transfer, and direct detection and the types of molecules that are effective for these purposes. Next we describe efforts to make safer contrast agents either by increasing relaxivity, increasing resistance to metal ion release, or by moving to gadolinium(III)-free alternatives. Finally we survey approaches to make contrast agents more specific for pathology either by direct biochemical targeting or by the design of responsive or activatable contrast agents.

Chemistry of MRI Contrast Agents: Current Challenges and New Frontiers

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.

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Imaging biomarker roadmap for cancer studies.

Background: Sediments are massive reservoirs of carbon compounds and host a large fraction of microbial life. Microorganisms within terrestrial aquifer sediments control buried organic carbon turnover, degrade organic contaminants, and impact drinking water quality. Recent 16S rRNA gene profiling indicates that members of the bacterial phylum Chloroflexi are common in sediment. Only the role of the class Dehalococcoidia, which degrade halogenated solvents, is well understood. Genomic sampling is available for only six of the approximate 30 Chloroflexi classes, so little is known about the phylogenetic distribution of reductive dehalogenation or about the broader metabolic characteristics of Chloroflexi in sediment. Results: We used metagenomics to directly evaluate the metabolic potential and diversity of Chloroflexi in aquifer sediments. We sampled genomic sequence from 86 Chloroflexi representing 15 distinct lineages, including members of eight classes previously characterized only by 16S rRNA sequences. Unlike in the Dehalococcoidia, genes for organohalide respiration are rare within the Chloroflexi genomes sampled here. Near-complete genomes were reconstructed for three Chloroflexi. One, a member of an unsequenced lineage in the Anaerolinea, is an aerobe with the potential for respiring diverse carbon compounds. The others represent two genomically unsampled classes sibling to the Dehalococcoidia, and are anaerobes likely involved in sugar and plant-derived-compound degradation to acetate. Both fix CO2 via the Wood-Ljungdahl pathway, a pathway not previously documented in Chloroflexi. The genomes each encode unique traits apparently acquired from Archaea, including mechanisms of motility and ATP synthesis. Conclusions: Chloroflexi in the aquifer sediments are abundant and highly diverse. Genomic analyses provide new evolutionary boundaries for obligate organohalide respiration. We expand the potential roles of Chloroflexi in sediment carbon cycling beyond organohalide respiration to include respiration of sugars, fermentation, CO2 fixation, and acetogenesis with ATP formation by substrate-level phosphorylation.

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Community genomic analyses constrain the distribution of metabolic traits across the Chloroflexi phylum and indicate roles in sediment carbon cycling

Natural biodegradable polymers based nano-formulations for drug delivery: A review.

This review discusses different forms of nanomaterials generated from chitosan and its derivatives for controlled drug delivery. Nanomaterials are drug carriers with multiple features, including target delivery triggered by environmental, pH, thermal responses, enhanced biocompatibility, and the ability to cross the blood-brain barrier. Chitosan (CS), a natural polysaccharide largely obtained from marine crustaceans, is a promising drug delivery vector for therapeutics and diagnostics, owing to its biocompatibility, biodegradability, low toxicity, and structural variability. This review describes various approaches to obtain novel CS derivatives, including their distinct advantages, as well as different forms of nanomaterials recently developed from CS. The advanced applications of CS-based nanomaterials are presented here in terms of their specific functions. Recent studies have proven that nanotechnology combined with CS and its derivatives could potentially circumvent obstacles in the transport of drugs thereby improving the drug efficacy. CS-based nanomaterials have been shown to be highly effective in targeted drug therapy.

Chitosan-Based Nanomaterials for Drug Delivery.

The suitability of paramagnetic complexes as contrast agents depends not only on their relaxivity but also on their stability and inertness towards transmetallation processes by endogenous ions. In this work, we describe a convenient method to study the stability of paramagnetic Gd complexes through the evolution of the paramagnetic longitudinal relaxation rate of water protons at 37 °C. Copyright © 2010 John Wiley & Sons, Ltd.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cmmi.388

How to measure the transmetallation of a gadolinium complex.

Paramagnetic magnetic resonance imaging (MRI) contrast agents are the compounds most used in clinical studies. Among these, the derivatives of Gd-DTPA (gadoliniumdiethylenetriaminepentaacetic acid, Magnevist®, Bayer HealthCare) have been extensively studied. The first part of this work consists of a comparison of various derivatives of Gd-DTPA [mono-, bis- or pentaamides; C-functionalised (C2, C4, C5, N6) or diester derivatives] according to their synthesis and to the most important parameters that regulate their efficacy. The synthesis of bis(amide)s consists of only one step and is thus easier than the synthesis of the C4 derivatives, which needs several steps and requires a tedious purification. These last compounds are, however, more stable against transmetallation with another ion such as zinc [more than 50 % of the gadolinium complex remains after 4300 min while this percentage falls under 40 % for most of the bis(amide) compounds] and generally have higher relaxivities. Moreover, the residence time of the water molecule in the first coordination sphere of the gadolinium complex (τM) is shorter for the C4 derivatives and does not limit the relaxivity. In the second part of this work, an overview of different kinds of recently developed paramagnetic contrast agents is presented: new systems to improve the relaxivity, like fullerenol compounds, apoferritin or zeolite complexes, lipophilic complexes (in structures like micelles or liposomes), macromolecular products as well as small complexes interacting with human serum albumin (HSA).

Synthesis and Physicochemical Characterisation of Gd‐DTPA Derivatives as Contrast Agents for MRI

Knowledge of the longitudinal and transverse relaxation times (T1 and T2) of water protons in an aqueous solution of an MRI contrast agent is essential for its characterization. These parameters can be measured at low field on low resolution spectrometers or at high field on high resolution spectrometers. The reliability and the accuracy of T1 and T2 measurements rely on several experimental settings and on the equation used to fit the data. Examples of the importance of careful adjustment of the most important parameters are illustrated through several measurements performed on a low-resolution, low-magnetic field instrument. In addition, some specificities of T1 and T2 measurements on high-resolution, high-magnetic field spectrometers are pointed out. Copyright © 2009 John Wiley & Sons, Ltd.

How to perform accurate and reliable measurements of longitudinal and transverse relaxation times of MRI contrast media in aqueous solutions

Thanks to their unique properties, inorganic nanostructures have become the center of modern material science. Among existing nanomaterials, magnetic iron oxide nanoparticles (IONP) have attracted a lot of interest. These nanoparticles are suitable for many technological applications such as contrast agent for magnetic resonance imaging. When comparing to molecular MRI probes (Gd-based organic complexes), IONP present many advantages such as a better sensitivity, a poor toxicity, and the possibility to easily modify their surface to develop some properties as multimodality, modulable half-life or specificity. However, one must stress that these properties are related to IONP’s composition, shape and stability (physical and chemical). In that paper, we will introduce some concepts related to IONP’s physico-chemical properties, the synthetic ways to obtain such structures and we will finish with some concepts governing their stability and surface modification.

Céline Henoumont

Papers

How to measure the transmetallation of a gadolinium complex.

Synthesis and Physicochemical Characterisation of Gd‐DTPA Derivatives as Contrast Agents for MRI

How to perform accurate and reliable measurements of longitudinal and transverse relaxation times of MRI contrast media in aqueous solutions

Superparamagnetic Iron Oxide Nanoparticles

MRI Contrast Agents