Magnetic Resonance Imaging Probes Research Articles

Disentangling micro from mesostructure by diffusion MRI: A Bayesian approach

Diffusion-sensitized magnetic resonance imaging probes the cellular structure of the human brain, but the primary microstructural information gets lost in averaging over higher-level, mesoscopic tissue organization such as different orientations of neuronal fibers. While such averaging is inevitable due to the limited imaging resolution, we propose a method for disentangling the microscopic cell properties from the effects of mesoscopic structure. We further avoid the classical fitting paradigm and use supervised machine learning in terms of a Bayesian estimator to estimate the microstructural properties. The method finds detectable parameters of a given microstructural model and calculates them within seconds, which makes it suitable for a broad range of neuroscientific applications.

Gadolinium-doped carbon dots with high quantum yield as an effective fluorescence and magnetic resonance bimodal imaging probe

It is highly desired to develop the dual-modality fluorescence and magnetic resonance imaging (MRI) probes in medical imaging because it can provide high-resolution macroscopical anatomical information and high-sensitivity microscopical optical signal simultaneously. In this study, harmless gadolinium-doped carbon dots (Gd-CDs) were prepared via a convenient one-pot hydrothermal approach for fluorescence/MR bimodal imaging. The derived Gd-CDs exhibit enhanced blue photoluminescence with a quantum yield as high as 69.86% and significantly improved longitudinal relaxivity (r1 = 14.33 mM−1 s−1, 0.5 T) in comparison with commercial Magnevist (Gd-DTPA, r1 = 4.5 mM−1 s−1, 0.5 T). Here Gd3+ ions are simply chelated onto CDs by carboxyl groups. Moreover, unlike the previous reports, Gd3+ chelation does not perturb core optical properties of CDs. Excellent water solubility, good cell-membrane permeability and negligible cytotoxicity make Gd-CDs an ideal dual-modal fluorescence/MR imaging nanoprobe, suggesting its potential and significance in practical biological and clinic applications in the future.

Optical Nuclear Spin Polarization of Divacancies in SiC

We demonstrate optically pumped dynamic nuclear polarization (DNP) of 29Si nuclear spins that are strongly coupled to paramagnetic color centers in 4H- and 6H-SiC. We observe 99%±1% degree of polarization. By combining ab initio theory with the experimental identification of the color centers’ optically excited states, we quantitatively model how the polarization derives from hyperfine-mediated level anticrossings. In addition, we developed a general model for these optical DNP processes that allows the effects of many microscopic processes to be integrated. Applying this theory, we gain a deeper insight into dynamic nuclear spin polarization. In particular, our findings show that the defect electron spin coherence times and excited state lifetimes are crucial factors in the entire DNP process. These results lay a foundation for SiC-based quantum memories, nuclear gyroscopes, and hyperpolarized probes for magnetic resonance imaging.

Biopolymers coated superparamagnetic Nickel Ferrites: Enhanced biocompatibility and MR imaging probe for breast cancer

We report evidence for the promising application of bovine serum albumin (BSA), chitosan (CS) or carboxymethyl cellulose (CMC) coated NiFe2O4 cores for improved biocompatibility and enhanced T2 relaxivity, through a single combinatorial approach. Pure nickel-ferrite nano cores (NFs) successfully synthesized by thermolysis, were immobilize with BSA, CS or CMC layer employing a simple cross linking procedure to avoid any significant influence of these biopolymers on the morphology and crystal structure of the cores. Phase, morphology, magnetic hysteresis and surface chemistry were characterized by X-ray diffraction (XRD), Field emission scanning electron microscopy (FE-SEM), vibrating sample magnetometer (VSM) and Fourier transform infrared (FTIR) spectroscopy.The preliminary haemolysis and cell viability experiments show that biopolymers conjugation mitigates the haemolytic effect of the NFs on erythrocytes as the haemolytic index is less than 2% and cell viability is up to 100%, when normalized with the nontreated cells. The relaxivity value of coated NFs is 351±2.6 when compared to 84±0.22 of NFs without biopolymer conjugation. The results demonstrate that BSA, CS or CMC covering on NFs provide a single combinatorial approach to improve the biocompatibility and enhance the relaxivity value. Thus addressing the current challenge of the same with very good contrast for targeting MCF-7 without any further vectorization.

Functional Hyperbranched Polylysine as Potential Contrast Agent Probes for Magnetic Resonance Imaging.

Researchers have never stopped questing contrast agents with high resolution and safety to overcome the drawbacks of small-molecule contrast agents in clinic. Herein, we reported the synthesis of gadolinium-based hyperbranched polylysine (HBPLL-DTPA-Gd), which was prepared by thermal polymerization of l-lysine via one-step polycondensation. After conjugating with folic acid, its potential application as MRI contrast agent was then evaluated. This contrast agent had no obvious cytotoxicity as verified by WST assay and H&E analysis. Compared to Gd(III)-diethylenetriaminepentaacetic acid (Gd-DTPA) (r1 = 4.3 mM(-1) s(-1)), the FA-HBPLL-DTPA-Gd exhibited much higher longitudinal relaxivity value (r1 = 13.44 mM(-1) s(-1)), up to 3 times higher than Gd-DTPA. The FA-HBPLL-DTPA-Gd showed significant signal intensity enhancement in the tumor region at various time points and provided a long time window for MR examination. The results illustrate that FA-HBPLL-DTPA-Gd will be a potential candidate for tumor-targeted MRI.

In Vivo Magnetic Resonance and Fluorescence Dual-Modality Imaging of Tumor Angiogenesis in Rats Using GEBP11 Peptide Targeted Magnetic Nanoparticles.

Angiogenesis is an essential process for tumor progression. Tumor vasculature-targeting peptides have shown great potential for use in cancer imaging and therapy. Our previous studies have shown that GEBP11, a novel vasculature-specific binding peptide that exhibits high affinity and specificity to tumor angiogenesis, is a promising candidate for the diagnosis and targeted radiotherapy of gastric cancer. In the present study, we developed a novel magnetic resonance and fluorescence (MR/Fluo) dual-modality imaging probe by covalently coupling 2,3-dimercaptosuccinnic acid-coated paramagnetic nanoparticles (DMSA-MNPs) and Cy5.5 to the GEBP11 peptide. The probe Cy5.5-GEBP11-DMSA-MNPs (CGD-MNPs), with a hydrodynamic diameter of 82.8 ± 6.5 nm, exhibited good imaging properties, high stability and little cytotoxicity. In vivo MR/Fluo imaging revealed that CGD-MNPs were successfully applied to visualize tumor angiogenesis in SGC-7901 xenograft mouse models. Prussian blue and CD31 immunohistochemical staining confirmed that CGD-MNPs co-localized with tumor blood vessels. In conclusion, CGD-MNPs are promising candidates for use as MR and fluorescence imaging probes for visualizing gastric cancer angiogenesis in vivo.

Magnetic barcode imaging for contrast agents.

To demonstrate a new MR imaging approach that unambiguously identifies and quantitates contrast agents based on intrinsic agent properties such as r1 , r2 , r2*, and magnetic susceptibility. The approach is referred to as magnetic barcode imaging (MBI). Targeted and bioresponsive contrast agents were imaged in agarose phantoms to generate T1 , T2 , T2*, and quantitative susceptibility maps. The parameter maps were processed by a machine learning algorithm that is trained to recognize the contrast agents based on these parameters. The output is a quantitative map of contrast agent concentration, identity, and functional state. MBI allowed the quantitative interpretation of intensities, removed confounding backgrounds, enabled contrast agent multiplexing, and unambiguously detected the activation and binding states of bioresponsive and targeted contrast agents. MBI has the potential to overcome significant limitations in the interpretation, quantitation, and multiplexing of contrast enhancement by MR imaging probes. Magn Reson Med 77:970-978, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Life Sciences Discovery and Technology Highlights

Life Sciences Discovery and Technology Highlights

11B NMR Probes of Copper(II): Finding and Implications of the Cu2+‐Promoted Decomposition of ortho‐Carborane Derivatives

AbstractThe development of noninvasive methodologies for the detection of d‐block metal ions such as copper (Cu2+), zinc (Zn2+), and manganese (Mn2+) is important for understanding their biological roles and relationship with diseases. We have been interested in the use of 11B NMR probes for the detection of d‐block metal ions, because 11B is an ultratrace element in living systems. o‐Carboranes, which consist of ten boron and two carbon atoms, have been applied to numerous drugs and biological active agents. In this work, we found that the o‐carborane‐pendant cyclens (L3–L5) (cyclen = 1,4,7,10‐tetraazacyclododecane) are decomposed in the presence of Mn2+ or Cu2+ in aqueous solution at neutral pH, accompanied by the release of 4–9 equiv. of B(OH)3. Furthermore, it was found that o‐carborane derivatives that contain hydroxyl groups instead of a cyclen unit also undergo decomposition in the presence of Cu2+ and the corresponding complexes such as Cu(bpy) to afford 10 equiv. of B(OH)3, as confirmed by 11B NMR spectroscopic analysis and an azomethine‐H assay. These reactions are applied to 11B MRI (magnetic resonance imaging) probes for Cu2+.

Smart Contrast Agents for Magnetic Resonance Imaging.

By visualizing bioactive molecules or biological parameters in vivo, molecular imaging is searching for information at the molecular level in living organisms. In addition to contributing to earlier and more personalized diagnosis in medicine, it also helps understand and rationalize the molecular factors underlying physiological and pathological processes. In magnetic resonance imaging (MRI), complexes of paramagnetic metal ions, mostly lanthanides, are commonly used to enhance the intrinsic image contrast. They rely either on the relaxation effect of these metal chelates (T(1) agents), or on the phenomenon of paramagnetic chemical exchange saturation transfer (PARACEST agents). In both cases, responsive molecular magnetic resonance imaging probes can be designed to report on various biomarkers of biological interest. In this context, we review recent work in the literature and from our group on responsive T(1) and PARACEST MRI agents for the detection of biogenic metal ions (such as calcium or zinc), enzymatic activities, or neurotransmitter release. These examples illustrate the general strategies that can be applied to create molecular imaging agents with an MRI detectable response to biologically relevant parameters.

Magnetic nanocomposites as MRI probes: Design and applications

Magnetic resonance imaging (MRI) probes are the important tools for discovering small pathological changes with functionality analysis. Probe structural design, functionality, multimodality, and applications will be covered in this talk. The focus of probe structural design is mainly aimed on how to improve the imaging sensitivity, including one important feature: the relaxivity of probes. Superparamagnetic nanoparticles are efficient proton enhancers. In our approach, magnetic nanoparticles are usually delivered by polymeric carriers with improved biocompatibility and sensitivity. Design of small moleucle paramagnetic probes and conjugation to polymeric carriers will also be discussed. Short BIOGRAPHY Hua Ai, PhD, Professor of Biomaterials, National Engineering Research Center for Biomaterials, Sichuan University. Dr. Ai is focusing on design and applications of nanobiomaterials for molecular imaging and drug delivery. He has developed ultrasensitive MRI probes based on self-assembly of amphiphilic polymers and magnetic nanocrystals. His work has been published on academic journals including Acc Chem Res, Adv Drug Deliv Rev, Adv Mater, Biomaterials, Nano Letters, Small, J Control Release, etc. Dr. Ai is in the editorial boards of Biomaterials, BioNanoScience, J Pharm Sci, and Pharmaceutical Nanotechnology. Dr. Ai is the current Secretary-General of Chinese Society for Biomaterials (www.csbm.org.cn).

Folic acid-conjugated chitosan derivative for tumor-targeted magnetic resonance imaging

Contrast agents with high efficiency and safety are excellent candidates as magnetic resonance imaging probes. In this study, a nanoparticle contrast agent based on chitosan was synthesized. The backbone was chitosan, and the side chains were low molecular oligoethylenimine, which possessed multiple primary amines to increase the grafting number of Gd-DTPA per glucose ring. This macromolecular chitosan derivative covalently conjugated with folic acid offers a high loading density of Gd-DTPA with targeting capacity. The r1 value was found to be 25.9 mM s, which was 5.4 times higher than Magnevist. The higher r1 value was mainly due to the increased rotational correlation time (τR) after conjugation of DTPA-Gd onto chitosan chain and the increased loading density of Gd permolecule. No obvious cytotoxicitywas observed fromWSTassay,which illustrated that the chitosan derivative exhibited excellent biocompatibility. During in vivo animal studies, the probe provided better signal intensity enhancement in the tumor after 5 h post-injection. This study demonstrated that the developed oligoethylenimine grafted chitosan route was effective to increase the loading density of Gd and then significantly enhanced the relaxivity of the macromolecular contrast probes. Such an oligoethylenimine-grafted chitosan derivative has great potential for developing sensitive and biocompatible MRI probe with targeting capability.

A Theranostic Agent Combining a Two-Photon-Absorbing Photosensitizer for Photodynamic Therapy and a Gadolinium(III) Complex for MRI Detection.

The convergent synthesis and characterization of a potential theranostic agent, [DPP-ZnP-GdDOTA](-), which combines a diketopyrrolopyrrole-porphyrin component DPP-ZnP as a two-photon photosensitizer for photodynamic therapy (PDT) with a gadolinium(III) DOTA complex as a magnetic resonance imaging probe, is presented. [DPP-ZnP-GdDOTA](-) has a remarkably high longitudinal water proton relaxivity (19.94 mm(-1) s(-1) at 20 MHz and 25 °C) for a monohydrated molecular system of this size. The Nuclear Magnetic Relaxation Dispersion (NMRD) profile is characteristic of slow rotation, related to the extended and rigid aromatic units integrated in the molecule and to self-aggregation occurring in aqueous solution. The two-photon properties were examined and large two-photon absorption cross-sections around 1000 GM were determined between 910 and 940 nm in DCM with 1 % pyridine and in DMSO. Furthermore, the new conjugate was able to generate singlet oxygen, with quantum yield of 0.42 and 0.68 in DCM with 1 % pyridine and DMSO, respectively. Cellular studies were also performed. The [DPP-ZnP-GdDOTA](-) conjugate demonstrated low dark toxicity and was able to induce high one-photon and moderate two-photon phototoxicity on cancer cells.

PH-Responsive biodegradable polymeric micelles with anchors to interface magnetic nanoparticles for MR imaging in detection of cerebral ischemic area.

A novel type of pH-responsive biodegradable copolymer was developed based on methyloxy-poly(ethylene glycol)-block-poly[dopamine-2-(dibutylamino) ethylamine-l-glutamate] (mPEG-b-P(DPA-DE)LG) and applied to act as an intelligent nanocarrier system for magnetic resonance imaging (MRI). The mPEG-b-P(DPA-DE)LG copolymer was synthesized by a typical ring opening polymerization of N-carboxyanhydrides (NCAs-ROP) using mPEG-NH2 as a macroinitiator, and two types of amine-terminated dopamine groups and pH-sensitive ligands were grafted onto a side chain by a sequential aminolysis reaction. This design greatly benefits from the addition of the dopamine groups to facilitate self-assembly, as these groups can act as high-affinity anchors for iron oxide nanoparticles, thereby increasing long-term stability at physiological pH. The mPEG moiety in the copolymers helped the nanoparticles to remain well-dispersed in an aqueous solution, and pH-responsive groups could control the release of hydrophobic Fe3O4 nanoparticles in an acidic environment. The particle size of the Fe3O4-loaded mPEG-b-P(DPA-DE)LG micelles was measured by dynamic light scattering (DLS) and cryo-TEM. The superparamagnetic properties of the Fe3O4-loaded mPEG-b-P(DPA-DE)LG micelles were confirmed by a superconducting quantum interference device (SQUID). T2-weighted magnetic resonance imaging (MRI) of Fe3O4-loaded mPEG-b-P(DPA-DE)LG phantoms exhibited enhanced negative contrast with an r2 relaxivity of approximately 106.7 mM(-1) s(-1). To assess the ability of the Fe3O4-loaded mPEG-P(DE-DPA)LG micelles to act as MRI probes, we utilized a cerebral ischemia disease rat model with acidic tissue. We found that a gradual change in contrast in the cerebral ischemic area could be visualized by MRI after 1 h, and maximal signal loss was detected after 24 h post-injection. These results demonstrated that the Fe3O4-loaded mPEG-b-P(DPA-DE)LG micelles can act as pH-triggered MRI probes for diagnostic imaging of acidic pathological tissues.

Development and Characterization of Novel LipoCEST Agents Based on Thermosensitive Liposomes.

Purpose:To develop a novel probe for chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) based on thermosensitive liposomes (lipoCEST) for theranostics, in which diagnostics and therapy are integrated into a single platform.Methods:We developed two kinds of lipoCEST agents. The first kind encapsulated dysprosium (Dy)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-Na·3NaCl, terbium-DOTA-Na·3NaCl, or thulium-DOTA-Na·3NaCl into the inner cavity of thermosensitive liposomes, while the second kind encapsulated Dy-DOTA-Na and incorporated amphiphilic metal complex [thulium-diethylenetriamine pentaacetic acid-bis (stearylamide) (Tm-DTPA-BSA)] as a membrane constituent. The nuclear magnetic resonance (NMR)- and Z-spectra of these lipoCEST agents were acquired at various temperatures on a 9.4T MRI scanner. To investigate their applicability to the drug release induced by hyperthermia, we also encapsulated a fluorescent dye (calcein) into the inner cavity of liposomes and measured calcein release after warming them.Results:The intra- and extraliposomal water signals could be differentiated in all agents from their NMR- and Z-spectra. The agent incorporating Tm-DTPA-BSA showed the largest chemical shift (approximately 15 ppm) derived from the intraliposomal water protons. The calcein retained in this agent was successfully released at 44°C. The agent incorporating 30 mol% of Tm-DTPA-BSA in its membrane released more calcein at 42–44°C than that of the agent incorporating 10 mol%.Conclusion:We developed novel thermosensitive lipoCEST agents and characterized them. Our preliminary results suggest that they are useful and can be applied to theranostics.

Gadolinium(iii) based nanoparticles for T1-weighted magnetic resonance imaging probes

This review summarized the recent progress on Gd(iii)-based nanoparticles asT1-weighted MRI contrast agents and multimodal contrast agents.

Biocleavable Oligolysine-Grafted Poly(disulfide amine)s as Magnetic Resonance Imaging Probes.

To develop safe and effective macromolecular MRI contrast agents, a macromolecular contrast agent (mCA) containing biocleavable disulfide bonds in the main chain and oligolysine in the side chain is prepared, and its applicability as a MRI contrast agent is demonstrated both in vitro and in vivo. This brush-like mCA possesses a high T1 relaxivity (11.8 mM(-1) s(-1)), up to 3 times higher than the commercial Gd-DTPA (4.2 mM(-1) s(-1)), along with very low toxicity as determined by WST assay and histological analysis. Meanwhile, the disulfide bond can be broken under appropriate reducing conditions, followed by degradation into small fragments. Furthermore, the mCA is functionalized with folic acid to improve the target specificity. In vivo experiments show that FA-labeled mCA can efficiently enhance the resolution between the tumor and surrounding tissues compared to the mCA without FA. This study may provide helpful insights for the further development of sensitive and biocompatible MRI probes.

Towards An Advanced Graphene-Based Magnetic Resonance Imaging Contrast Agent: Sub-acute Toxicity and Efficacy Studies in Small Animals.

Current clinical Gd3+-based T1 magnetic resonance imaging (MRI) contrast agents (CAs) are suboptimal or unsuitable, especially at higher magnetic fields (>1.5 Tesla) for advanced MRI applications such as blood pool, cellular and molecular imaging. Herein, towards the goal of developing a safe and more efficacious high field T1 MRI CA for these applications, we report the sub-acute toxicity and contrast enhancing capabilities of a novel nanoparticle MRI CA comprising of manganese (Mn2+) intercalated graphene nanoparticles functionalized with dextran (hereafter, Mangradex) in rodents. Sub-acute toxicology performed on rats intravenously injected with Mangradex at 1, 50 or 100 mg/kg dosages 3 times per week for three weeks indicated that dosages ≤50 mg/kg could serve as potential diagnostic doses. Whole body 7 Tesla MRI performed on mice injected with Mangradex at a potential diagnostic dose (25 mg/kg or 455 nanomoles Mn2+/kg; ~2 orders of magnitude lower than the paramagnetic ion concentration in a typical clinical dose) showed persistent (up to at least 2 hours) contrast enhancement in the vascular branches (Mn2+ concentration in blood at steady state = 300 ppb, per voxel = 45 femtomoles). The results lay the foundations for further development of Mangradex as a vascular and cellular/ molecular MRI probe.

Synthesis of an Amphiphilic Bis-Aqua Gd(OBETA) Complex for the Preparation of High-Relaxivity Supramolecular Magnetic Resonance Imaging Probes.

Prompted by the favourable relaxometric, thermodynamic and kinetic properties of the bis-hydrated Gd(OBETA) (OBETA=2,2'-oxybis(ethylamine)-N,N,N',N'-tetraacetic acid) complex, a novel derivative tailored with an n-hexadecyl chain was synthesised. The amphiphilic gadolinium complex was designed and prepared with the aim of obtaining high relaxivity supramolecular aggregates by self-assembly in micelles and liposomes. Thus, lipidic nanoparticles were prepared and characterised by dynamic light scattering and 1 H NMR relaxometry. Relaxivity values of up to 48.3 mm-1 s-1 (20 MHz and 298 K) were registered in liposomal aggregates. The binding to human serum albumin (HSA), evaluated both in terms of affinity and relaxometric properties of the supramolecular adduct, yielded exceptionally high relaxivity values (71.4 mm-1 s-1 at 30 MHz and 298 K).

CMC-coated Fe3O4 nanoparticles as new MRI probes for hepatocellular carcinoma

Pure Fe3O4 nanoparticles and Fe3O4 magnetic nanoparticles (MNPs) coated with carboxymethyl cellulose (CMC) were successfully prepared by co-precipitating of FeCl2·4H2O and FeCl3·6H2O in the solutions containing ammonia at 80°C for 3h. Phase, morphology, particle-sized distribution, surface chemistry, and weight loss were characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), transmission electron microscopy (TEM) including high-resolution transmission electron microscopy (HRTEM) and selected area electron diffraction (SAED), thermogravimetric analysis (TGA), and Fourier transform infrared (FTIR) spectroscopy. In this research, CMC-coated Fe3O4 MNPs consisting of Fe2+ and Fe3+ ions with 543.3-mM−1s−1 high relaxivity were detected and were able to be used for magnetic resonance imaging (MRI) application with very good contrast for targeting hepatocellular carcinoma (HCC) without any further vectorization.