Chemical exchange saturation transfer (CEST) MRI has been identified as a novel alternative to classical diagnostic imaging. Over the last several decades, many studies have been conducted to determine possible CEST agents, such as endogenously expressed compounds or proteins, that can be utilized to produce contrast with minimally invasive procedures and reduced or non‐existent levels of toxicity. In recent years there has been an increased interest in the generation of genetically engineered CEST contrast agents, typically based on existing proteins with CEST contrast or modified to produce CEST contrast. We have developed an in silico method for the evolution of peptide sequences to optimize CEST contrast and showed that these peptides could be combined to create de novo biosensors for CEST MRI. A single protein, superCESTide, was designed to be 198 amino acids. SuperCESTide was expressed in
At the beginning of the millennium, the first chemical exchange saturation transfer (CEST) contrast agents were bio‐organic molecules. However, later, metal‐based CEST agents (paraCEST agents) took center stage. This did not last too long as paraCEST agents showed limited translational potential. By contrast, the CEST field gradually became dominated by metal‐free CEST agents. One branch of research stemming from the original work by van Zijl and colleagues is the development of CEST agents based on polypeptides. Indeed, in the last 2 decades, tremendous progress has been achieved in this field. This includes the design of novel peptides as biosensors, genetically encoded recombinant as well as synthetic reporters. This was a result of extensive characterization and elucidation of the theoretical requirements for rational designing and engineering of such agents. Here, we provide an extensive overview of the evolution of more precise protein‐based CEST agents, review the rationalization of enzyme‐substrate pairs as CEST contrast enhancers, discuss the theoretical considerations to improve peptide selectivity, specificity and enhance CEST contrast. Moreover, we discuss the strong influence of synthetic biology on the development of the next generation of protein‐based CEST contrast agents.
more » « less- Award ID(s):
- 2027113
- NSF-PAR ID:
- 10363380
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- NMR in Biomedicine
- Volume:
- 36
- Issue:
- 6
- ISSN:
- 0952-3480
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
more » « less
Abstract E. coli -
Co( ii ) complexes of 1,4,7,10-tetraazacyclododecane (CYCLEN) or 1,4,8,11-tetraazacyclotetradecane (CYCLAM) with 2-hydroxypropyl or carbamoylmethyl (amide) pendants are studied with the goal of developing paramagnetic chemical exchange saturation transfer (paraCEST) agents. Single-crystal X-ray diffraction studies show that two of the coordination cations with hexadentate ligands, [Co(DHP)] 2+ and [Co(BABC)] 2+ , form six-coordinate complexes; whereas two CYCLEN-based complexes with potentially octadentate ligands, [Co(THP)] 2+ and [Co(HPAC)] 2+ , are seven-coordinate with only three of the four pendant groups bound to the metal center. 1 H NMR spectra of these complexes suggest that the six-coordinate complexes are present as a single isomer in aqueous solution. For the complexes which are seven-coordinate in the solid state, one is highly fluxional in aqueous solution on the NMR time scale ([Co(HPAC)] 2+ ), whereas the NMR spectrum of [Co(THP)] 2+ is consistent with an eight-coordinate complex with all pendants bound. Co( ii ) complexes of CYCLEN derivatives show CEST effects of low intensity that are assigned to NH or OH groups of the pendants. One complex, [Co(DHP)] 2+ , shows a highly-shifted CEST peak at 113 ppm versus bulk water, attributed to OH protons. However, the CEST effect is largest for two Co( ii ) CYCLAM-based complexes with coordinated amide groups that undergo NH proton exchange. All five complexes are inert towards dissociation in buffered solutions containing carbonate and phosphate and towards trans-metalation by excess Zn( ii ). These data give insight into the production of an intense CEST effect for tetraazamacrocyclic complexes with pendant groups containing NH or OH exchangeable protons. The intense and highly shifted CEST peak(s) of the CYCLAM-based complexes suggest that they are promising for further development as paraCEST agents.more » « less
-
Abstract Deep learning (DL) is one of the fastest-growing topics in materials data science, with rapidly emerging applications spanning atomistic, image-based, spectral, and textual data modalities. DL allows analysis of unstructured data and automated identification of features. The recent development of large materials databases has fueled the application of DL methods in atomistic prediction in particular. In contrast, advances in image and spectral data have largely leveraged synthetic data enabled by high-quality forward models as well as by generative unsupervised DL methods. In this article, we present a high-level overview of deep learning methods followed by a detailed discussion of recent developments of deep learning in atomistic simulation, materials imaging, spectral analysis, and natural language processing. For each modality we discuss applications involving both theoretical and experimental data, typical modeling approaches with their strengths and limitations, and relevant publicly available software and datasets. We conclude the review with a discussion of recent cross-cutting work related to uncertainty quantification in this field and a brief perspective on limitations, challenges, and potential growth areas for DL methods in materials science.more » « less
-
more » « less
Abstract X‐ray imaging is the most widely used diagnostic imaging method in modern medicine and several advanced forms of this technology have recently emerged. Iodinated molecules and barium sulfate suspensions are clinically approved X‐ray contrast agents and are widely used. However, these existing contrast agents provide limited information, are suboptimal for new X‐ray imaging techniques and are developing safety concerns. Thus, over the past 15 years, there has been a rapid growth in the development of nanoparticles as X‐ray contrast agents. Nanoparticles have several desirable features such as high contrast payloads, the potential for long circulation times, and tunable physicochemical properties. Nanoparticles have also been used in a range of biomedical applications such as disease treatment, targeted imaging, and cell tracking. In this review, we discuss the principles behind X‐ray contrast generation and introduce new types of X‐ray imaging modalities, as well as potential elements and chemical compositions that are suitable for novel contrast agent development. We focus on the progress in nanoparticle X‐ray contrast agents developed to be renally clearable, long circulating, theranostic, targeted, or for cell tracking. We feature agents that are used in conjunction with the newly developed multi‐energy computed tomography and mammographic imaging technologies. Finally, we offer perspectives on current limitations and emerging research topics as well as expectations for the future development of the field.
This article is categorized under:
Diagnostic Tools > in vivo Nanodiagnostics and Imaging
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
-
more » « less
Abstract Three paramagnetic CoIImacrocyclic complexes containing 2‐hydroxypropyl pendant groups, 1,1′,1′′,1′′′‐(1,4,8,11‐tetraazacyclotetradecane‐1,4,8,11‐tetrayl)tetrakis‐ (propan‐2‐ol) ([Co(L1)]2+, 1,1′‐(4,11‐dibenzyl‐1,4,8,11‐tetraazacyclotetradecane‐1,8‐diyl)bis(propan‐2‐ol) ([Co(L2)]2+), and 1,1′‐(4,11‐dibenzyl‐1,4,8,11‐tetraazacyclotetradecane‐1,8‐diyl)bis(octadecan‐2‐ol) ([Co(L3)]2+) were synthesized to prepare transition metal liposomal chemical exchange saturation transfer (lipoCEST) agents. In solution, ([Co(L1)]2+) forms two isomers as shown by1H NMR spectroscopy. X‐ray crystallographic studies show one isomer with 1,8‐pendants in
cis ‐configuration and a second isomer with 1,4‐pendants intrans ‐configuration. The [Co(L2)]2+complex has 1,8‐pendants in acis ‐configuration. Remarkably, the paramagnetic‐induced shift of water1H NMR resonances in the presence of the [Co(L1)]2+complex is as large as that observed for one of the most effective LnIIIwater proton shift agents. Incorporation of [Co(L1)]2+into the liposome aqueous core, followed by dialysis against a solution of 300 mOsm L−1produces a CEST peak at 3.5 ppm. Incorporation of the amphiphilic [Co(L3)]2+complex into the liposome bilayer produces a more highly shifted CEST peak at −13 ppm. Taken together, these data demonstrate the feasibility of preparing CoIIlipoCEST agents.
