Paramagnetic Agent Research Articles

Neuromelanin-sensitive magnetic resonance imaging: a promising technique for depicting tissue characteristics containing neuromelanin.

Idiopathic Parkinson's disease (IPD) is a progressive, neurodegenerative movement disorder characterized by bradykinesia, muscular rigidity, postural instability and tremor. IPD is usually diagnosed based on clinical findings, but diagnoses are only 75–90% accurate when compared with autopsy results. Improving diagnostic accuracy is critical for the early differentiation of IPD from other Parkinsonism-related disorders because of differences in their prognoses and treatment. Furthermore, IPD is clinically heterogeneous, with variable prognosis. Although the biological function of neuromelanin has not yet been determined, the selective vulnerability of neuromelanin-containing neurons in patients with IPD suggests a role for this pigment in neurodegeneration. Recently developed ultra-high-field magnetic resonance imaging (MRI) systems produce T1-weighted neuromelanin-sensitive images with very high spatial resolution, enabling the depiction of tissue containing neuromelanin. Here we review recent advances in neuromelanin-sensitive MRI in IPD and related conditions suggesting that neuromelanin may be a potential diagnostic biomarker for IPD. Neuromelanin is a dark polymer produced in specific populations of catecholaminergic neurons in the brain. Three main regions of the brain contain neuromelanin-producing cells: the substantia nigra (SN) of the midbrain, the locus coeruleus (LC) within the pons and the ventrolateral reticular formation and nucleus of the solitary tract in the medulla oblongata. Moreover, two of these regions, the SN and the LC, contain large clusters of pigmented neurons that appear macroscopically as darkened areas (Fedorow et al., 2005). Parkinsonian syndrome is a heterogeneous group of movement disorders, which can be subdivided into IPD, genetic forms of Parkinson's disease (PD) and atypical parkinsonian syndrome. In addition, several other neurodegenerative disorders may show clinical signs of parkinsonism. The etiology, histopathology, clinical manifestation and disease course of these disorders vary significantly. The loss of neuromelanin-containing cells within the SN and LC is a primary pathological diagnostic criterion for IPD. The presence of neuromelanin in these vulnerable cells suggests a role for this pigment in the neurodegenerative process of IPD. The amount of neuromelanin contained within the dopaminergic neurons of the midbrain has been reported to be inversely related to the relative vulnerability of these cells to IPD (Hirsch et al., 1988). In addition to the degree of neuromelanin pigmentation, the position of neuromelanin-containing cells within the nigral complex was also found to be a key factor for neuronal survival in IPD (Damier et al., 1999). Neuromelanin has a high chelating ability for iron, and has been shown to bind neurotoxic and toxic metals that could promote neurodegeneration, such as pesticides and MPP +, suggesting a neuroprotective role of neuromelanin (Zecca et al., 2001). Cell death observed in IPD may be partly due to oxidative stress. This oxidation may also be relieved by neuromelanin. Following its binding of iron, neuromelanin acts as a paramagnetic agent. Recently developed ultra-high-field magnetic resonance imaging (MRI) systems produce T1-weighted neuromelanin-sensitive images of very high spatial resolution (Enochs et al., 1997; Sasaki et al., 2006; Bolding et al., 2013). On these images, neuromelanin-containing tissues appear as foci of high signal intensity, with the intensity proportional to the neuromelanin concentration. Neuromelanin-sensitive MRI can be used to directly measure the volume or concentration of neuromelanin in the SN and LC, suggesting that this modality may be able to distinguish IPD from other related conditions. We review here the usefulness of neuromelanin MRI for the diagnosis of parkinsonian syndrome, with special reference to neuropathological findings.

¹⁹F NMR indicator displacement assay using a synthetic receptor with appended paramagnetic relaxation agent.

An admixture of zinc(II)-bis(dipicolylamine) receptor with covalently attached paramagnetic relaxation agent and fluorine-labeled phosphate indicator enables (19)F NMR detection of phosphorylated analytes with amplified switched-on signal intensity.

Micellar self-assemblies of gadolinium(iii)/europium(iii) amphiphilic complexes as model contrast agents for bimodal imaging

The synthesis and characterization of two novel DTPA bisamide derivatives DTPA-BC12PheA and DTPA-BC14PheA functionalized with p-dodecylaniline and p-tetradecylaniline are described. The ligands were coordinated to Gd(iii) and Eu(iii), resulting in highly paramagnetic and luminescent complexes, respectively. Mixed micelles consisting of Gd/Eu-DTPA-BC12PheA and DTPA-BC14PheA with a homogeneous size distribution (33-40 nm) were prepared by the assembly of the amphiphilic complexes with phospholipid DPPC and a surfactant Tween 80®. Taking into account the sensitivity difference between magnetic resonance and optical imaging techniques, the ratios of Gd and Eu complexes (Gd/Eu) 1 : 1, 2 : 1, 3 : 1, 20 : 1 and 50 : 1 were combined in one single micelle and their optical and relaxometric properties were characterized in detail. Upon excitation at 290 nm, the micelles display characteristic red emission bands due to the (5)D0→(7)FJ (J = 0-4) transitions of Eu(iii). The number of water molecules in the first coordination sphere of Eu(iii) (qEu = 0.1-0.2) was calculated from the lifetime measurements performed in H2O and D2O solutions. Micelles composed of exclusively europium complexes display quantum yields in the range of 1.0%, decreasing with the europium concentration when going from 1 : 1 to 50 : 1 Gd/Eu contents. The ligand-to-lanthanide sensitization efficiency for micelles consisting of Eu-DTPA-BC12PheA and Eu-DTPA-BC14PheA equals 3.8% and 4.1%, respectively. The relaxivity r1 per Gd(iii) ion at 40 MHz and 310 K reaches a maximum value of 14.2 s(-1) mM(-1) for the Gd-DTPA-BC12PheA assemblies and 16.0 s(-1) mM(-1) for the micellar Gd-DTPA-BC14PheA assemblies compared to a value of 3.5 s(-1) mM(-1) for Gd-DTPA (Magnevist®). Theoretical fitting of the (1)H NMRD profiles results in τR values of 4.2 to 6.6 ns. The optimal concentration ratio of Gd/Eu compounds in the micelles in order to provide the required bimodal performance has been determined to be 20 : 1. In the search for other bimodal systems, this discovery can be used as a guideline concerning the load of paramagnetic agents with respect to luminescent probes.

Paramagnetic doping of a 7TM membrane protein in lipid bilayers by Gd3+-complexes for solid-state NMR spectroscopy

A considerable limitation of NMR spectroscopy is its inherent low sensitivity. Approximately 90 % of the measuring time is used by the spin system to return to its Boltzmann equilibrium after excitation, which is determined by (1)H-T1 in cross-polarized solid-state NMR experiments. It has been shown that sample doping by paramagnetic relaxation agents such as Cu(2+)-EDTA accelerates this process considerably resulting in enhanced sensitivity. Here, we extend this concept to Gd(3+)-complexes. Their effect on (1)H-T1 has been assessed on the membrane protein proteorhodopsin, a 7TM light-driven proton pump. A comparison between Gd(3+)-DOTA, Gd(3+)-TTAHA, covalently attached Cu(2+)-EDTA-tags and Cu(2+)-EDTA reveals a 3.2-, 2.6-, 2.4- and 2-fold improved signal-to-noise ratio per unit time due to longitudinal paramagnetic relaxation enhancement. Furthermore, Gd(3+)-DOTA shows a remarkably high relaxivity, which is 77-times higher than that of Cu(2+)-EDTA. Therefore, an order of magnitude lower dopant concentration can be used. In addition, no line-broadening effects or peak shifts have been observed on proteorhodopsin in the presence of Gd(3+)-DOTA. These favourable properties make it very useful for solid-state NMR experiments on membrane proteins.

Paramagnetic Relaxation of Long‐Lived Coherences in Solution NMR

Long-lived coherences (LLCs) are known to have lifetimes much longer than transverse magnetization or single quantum coherences (SQCs). The effect of paramagnetic ions on the relaxation of LLCs is not known. This is particularly important, as LLCs have potential applications in various fields like analytical NMR, in vivo NMR and MR imaging methods. We study here the behaviour of LLCs in the presence of paramagnetic relaxation agents. The stepwise increase in the concentration of the metal ion is followed by measuring various relaxation rates. The effect of paramagnetic ions is analysed in terms of the external random field's contribution to the relaxation of two coupled protons in 2,3,6-trichlorobenzaldehyde. The LLCs relax faster than ordinary SQCs in the presence of paramagnetic ions of varying character. This is explained on the basis of an increase in the contribution of the external random field to relaxation due to a paramagnetic relaxation mechanism. Comparison is also made with ordinary Zeeman relaxation rates like R1, R2, R1ρ and also with rate of relaxation of long-lived states RLLS which are known to be less sensitive to paramagnetically induced relaxation. Also, the extent of correlation of random fields at two proton sites is studied and is found to be strongly correlated with each other. The obtained correlation constant is found to be independent of the nature of added paramagnetic impurities.

Design and testing of paramagnetic liposome-based CEST agents for MRI visualization of payload release on pH-induced and ultrasound stimulation

The development of nanomedicines in cancer therapy is constantly growing because of the advantages associated with the use of nanosized drug delivery systems. Among them, the possibility of accurate spatiotemporal control of the release of the chemotherapeutic from the carrier is one of the most interesting and clinically relevant. To further improve the therapy outcome, the clinical translation of imaging protocols for the in vivo visualization of the release step is of paramount importance. In this work, the combination of the great chemical versatility of liposomes and the outstanding potential of MRI chemical exchange saturation transfer agents has been successfully harnessed to image the selective release of the liposomal content stimulated by endogenous (variation of pH) and externally applied (nonfocused ultrasound) stimuli. The use of clinically safe components (both liposomes and MRI agents) and the good results obtained in vitro hold promise for a successful future in vivo translation.

Release of a Paramagnetic Magnetic Resonance Imaging Agent from Liposomes Triggered by Low Intensity Non-Focused Ultrasound

Release of a Paramagnetic Magnetic Resonance Imaging Agent from Liposomes Triggered by Low Intensity Non-Focused Ultrasound

Improved Quality and Diagnostic Confidence Achieved by Use of Dose-Reduced Gadolinium Blood-Pool Agents for Time-Resolved Intracranial MR Angiography

Time-resolved MRA with the use of bolus injection of paramagnetic agents has proved valuable in neurovascular imaging. Standard contrast agents have limited blood-pool residence times, motivating the development of highly protein-bound blood-pool agents with greater relaxivity and longer intravascular residence, affording improved image quality at lesser doses. This study represents the first comparison of blood-pool agents to standard agents in time-resolved cerebral MRA. One hundred datasets were acquired at 1.5 T by use of a standardized, time-resolved MRA protocol. Patients received either unit dosing of a standard extracellular agent at 0.1 mmol/kg or a blood-pool agent at 0.03 mmol/kg. Peak arterial and venous enhancement phases were identified and subsequently scored qualitatively by use of a 4-point Likert scale, with attention to 6 vascular segments: 1) intracranial ICA; 2) MCA M1; 3) MCA M2; 4) MCA M3; 5) deep cerebral veins; and 6) dural venous sinuses. Fifty MR angiographies were acquired with each agent. No significant differences were found between agents in generation of uncontaminated arteriograms. Blood-pool agents, at 67% dose reduction, were of significantly greater quality across most vascular segments, including ICA (P = .019), M2 (P = .003), and M3 (P < .01). Superiority in the M1 segment approached significance (P = .059). Significantly better venographic quality was noted for deep venous structures (P = .016) with the use of blood-pool agents. Blood-pool agents provide superior demonstration of most intracranial vessels in time-resolved MRA compared with standard agents, at reduced doses. The greater relaxation enhancement and more favorable dosing profile make blood-pool agents superior to standard agents for use in cerebral time-resolved MRA.

In vivo three‐dimensional molecular imaging with Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) at high spatiotemporal resolution

Spectroscopic signals which emanate from complexes between paramagnetic lanthanide (III) ions (e.g. Tm(3+)) and macrocyclic chelates (e.g. 1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate, or DOTMA(4-)) are sensitive to physiology (e.g. temperature). Because nonexchanging protons from these lanthanide-based macrocyclic agents have relaxation times on the order of a few milliseconds, rapid data acquisition is possible with chemical shift imaging (CSI). Thus, Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) which originate from nonexchanging protons of these paramagnetic agents, but exclude water proton detection, can allow molecular imaging. Previous two-dimensional CSI experiments with such lanthanide-based macrocyclics allowed acquisition from ~12-μL voxels in rat brain within 5 min using rectangular encoding of k space. Because cubical encoding of k space in three dimensions for whole-brain coverage increases the CSI acquisition time to several tens of minutes or more, a faster CSI technique is required for BIRDS to be of practical use. Here, we demonstrate a CSI acquisition method to improve three-dimensional molecular imaging capabilities with lanthanide-based macrocyclics. Using TmDOTMA(-), we show datasets from a 20 × 20 × 20-mm(3) field of view with voxels of ~1 μL effective volume acquired within 5 min (at 11.7 T) for temperature mapping. By employing reduced spherical encoding with Gaussian weighting (RESEGAW) instead of cubical encoding of k space, a significant increase in CSI signal is obtained. In vitro and in vivo three-dimensional CSI data with TmDOTMA(-), and presumably similar lanthanide-based macrocyclics, suggest that acquisition using RESEGAW can be used for high spatiotemporal resolution molecular mapping with BIRDS.

Nanoparticle‐based chemical exchange saturation transfer (CEST) agents

The frequency-encoding property of chemical exchange saturation transfer (CEST) agents places them in a unique position among the MRI contrast agents, as it allows the visualization of more agents in the same MR image, as well as making it possible to set up innovative MRI-responsive agents. The sensitivity issue shown by molecular CEST agents (either diamagnetic or paramagnetic) has been tackled with the design of nanoparticle-based CEST agents endowed with a large number of exchangeable protons that ensure large saturation transfer levels. Several systems have been considered, namely supramolecular adducts, dendrimers, micelles and liposomes loaded with CEST agents (in most cases, paramagnetic CEST agents). A particularly sensitive system is represented by lipoCEST agents, consisting of liposomes whose inner water resonance is shifted by the co-presence of paramagnetic lanthanide complexes. The exchangeable pool of protons is represented by all the water molecules contained in the inner liposome cavity (10(6) -10(8) ). Although in vitro work has provided excellent results, in vivo translation appears to be hampered to some extent by the peculiar behavior shown by these particles on administration to living animals.

Evaluation of the effect of homogenization energy input on the enclosed water volume of concentrated W/O/W emulsions by low-resolution T2-relaxometry

The usefulness of low-resolution NMR for W/O/W double emulsion characterization was evaluated. Whereas pfg-NMR diffusion experiments enabled the detection of phase inversion and water droplet diameter distribution in the primary W/O emulsion, T2 relaxation measurements allowed discriminating internal and external water when a paramagnetic agent, such as manganese dichloride was added to the W/O/W emulsion.The study aimed to entrap a maximal amount of water in the W/O emulsion in order to obtain a concentrated W/O/W emulsion. In addition, the impact of homogenization duration and intensity on the enclosed water volume of the double emulsion was investigated. The results indicated that high-intensity process conditions drastically decreased the yield of the W/O/W emulsion.

Orientation of Phospholamban in Lipid Bicelles Detected by Electron Paramagnetic Resonance

We have used electron paramagnetic resonance (EPR) to probe the structural dynamics of the integral membrane protein phospholamban (PLB), as a function of phosphorylation and addition of its regulatory target, the sarcoplasmic reticulum calcium ATPase (SERCA). We found previously that PLB remains bound to SERCA after phosphorylation, suggesting that a structural transition within the SERCA-PLB complex is responsible for relief of inhibition. Our current goal is to elucidate this mechanism through orientation and accessibility EPR, in order to support rational design of therapies to improve calcium transport in muscle cells. We used the monomeric mutant AFA-PLB, with the rigid electron spin label TOAC incorporated within the transmembrane domain, and reconstituted the protein in lipid bicelles and vesicles. EPR showed that the accessibilities of PLB spin labels to paramagnetic relaxation agents changed upon phosphorylation, indicating vertical (parallel to the membrane normal) movement of PLB. EPR on aligned bicelles showed that PLB changes its tilt relative to the membrane upon phosphorylation. Results will also be reported on structural changes in the presence of SERCA. This work was funded by grants from NIH (R01 GM27906 and T32 AR007612).View Large Image | View Hi-Res Image | Download PowerPoint Slide

Exchange‐dependent relaxation in the rotating frame for slow and intermediate exchange – modeling off‐resonant spin‐lock and chemical exchange saturation transfer

Chemical exchange observed by NMR saturation transfer (CEST) and spin-lock (SL) experiments provide an MRI contrast by indirect detection of exchanging protons. The determination of the relative concentrations and exchange rates is commonly achieved by numerical integration of the Bloch-McConnell equations. We derive an analytical solution of the Bloch-McConnell equations that describes the magnetization of coupled spin populations under radiofrequency irradiation. As CEST and off-resonant SL are equivalent, their steady-state magnetization and dynamics can be predicted by the same single eigenvalue: the longitudinal relaxation rate in the rotating frame R1ρ . For the case of slowly exchanging systems, e.g. amide protons, the saturation of the small proton pool is affected by transverse relaxation (R2b ). It turns out, that R2b is also significant for intermediate exchange, such as amine- or hydroxyl-exchange or paramagnetic CEST agents, if pools are only partially saturated. We propose a solution for R1ρ that includes R2 of the exchanging pool by extending existing approaches, and verify it by numerical simulations. With the appropriate projection factors, we obtain an analytical solution for CEST and SL for nonzero R2 of the exchanging pool, exchange rates in the range 1-10(4) Hz, B1 from 0.1 to 20 μT and arbitrary chemical shift differences between the exchanging pools, whilst considering the dilution by direct water saturation across the entire Z-spectra. This allows the optimization of irradiation parameters and the quantification of pH-dependent exchange rates and metabolite concentrations. In addition, we propose evaluation methods that correct for concomitant direct saturation effects. It is shown that existing theoretical treatments for CEST are special cases of this approach.

Mapping Molecular Perturbations by a New Form of Two-Dimensional Spectroscopy

We propose a new general form of two-dimensional spectroscopy where the indirect "evolution" dimension is derived using the Radon transform. This idea is applicable to several types of spectroscopy but is illustrated here for the case of NMR spectroscopy. This "projection spectroscopy" displays characteristic correlation peaks that highlight perturbations of chemical shifts caused by temperature, pressure, solvent, molecular binding, chemical exchange, hydrogen bonding, pH variations, conformational changes, or paramagnetic agents. The results are displayed in a convenient format that allows the chemist to see all of the chemical shift perturbations at a glance and assess their rates of change and directions. As a proof of principle, we present two simple, practical examples that display two-dimensional representations of the effects of temperature and solvent on NMR spectra.

Intracystic Gadolinium-Enhanced MRI in the Evaluation of Residual Giant-Cystic Craniopharyngiomas in Children: Report of Four Cases

Residual giant-cystic craniopharyngiomas are amenable to intracavitary bleomycin treatment. Radiologic identification of potential cyst leaks is of paramount for treatment decisions. This report describes our experience in the use of intracystic Gadolinium (Gd)-enhanced MR imaging to determine potential communications between the tumoral cysts and other intra-axial spaces in 4 pediatric patients with residual giant-cystic craniopharyngiomas in whom intracavitary bleomycin treatment was planned after the injection of .1-.2 mL of gadopentetate dimeglumine (Gd-DTPA). In three cases no leaks were found. In one case, whose previous water-soluble iodinated contrast-enhanced CT cystography was negative for leaks, intracystic Gd-enhanced MR showed intraventricular Gd enhancement. We conclude that MR imaging after intracystic administration of Gd-based contrast paramagnetic agents is useful in the detection of potential leaks in cases of giant residual craniopharyngiomas.

In Vivo Imaging of Neurovascular Remodeling After Stroke

Stroke is one of the leading causes of adult disability throughout the world and, even though neural mechanisms of loss of function have been extensively studied, many aspects of poststroke cerebral responses remain poorly understood. Of particular interest is the mounting evidence of the capacity of the adult brain to reorganize after injury, which is believed to contribute to limitation of the extent of neural dysfunction and to restoration of affected neural functions. Processes such as neuronal plasticity, glial proliferation, and neovascularization may be essential for preservation or recovery of function after stroke and may conceivably go hand-in-hand at nearby and remote sites of active tissue reorganization.1,2 Specifically, the acute initiation of neurovascular remodeling, stimulating the proliferation and growth of existing arteries/arterioles (ie, arteriogenesis) or new capillaries (ie, angiogenesis), may be critical to facilitate the survival and restructuring of neural tissue, which ultimately may contribute to functional recovery at later stages.3 A variety of vascular imaging strategies is available for in vivo detection, characterization, and quantification of these processes, which can significantly aid in elucidation of the role of neurovascular remodeling after stroke, as discussed in this review. Because most of the described imaging modalities are present in experimental and clinical settings, this raises significant opportunities for translational studies. Growth and remodeling of existing and nascent vascular networks in health and disease involve a number of critical steps that have been comprehensively described by Risau4 and Carmeliet.5 Arteriogenesis involves adaptive growth and proliferation of preexisting (collateral) arteries and arterioles in response to increase in intravascular shear forces. The increased shear stress leads to upregulation of cell adhesion molecules, followed by accumulation of monocytes and other leukocytes that release cytokines and growth factors around the proliferating and maturating arteries.6 Although arteriogenic growth of collateral …

Rapid Mapping of Active Site of KSI by Paramagnetic NMR

N HSQC spectra using 4-hydroxyl-2,2,6,6-tetramethylpiperidinyl-1-oxy (HyTEMPO) and an intermediateanalog (equilenin). Our result revealed that residues in hydrophobic cavity of KSI, particularly active siteregion, mainly experienced a high line-broadening effect of NMR signal with HyTEMPO, while theyexperienced full recovery of a lineshape upon the addition of equilenin. The mapped region was very similarto the active site of KSI as described by the crystal structure. These observations indicate that a combined useof paramagnetic reagent and substrate (or analog) could rapidly identify the residues in potential active site ofKSI, and can be applied to the analysis of both active site and function in unknown protein.Key Words : NMR, Ketosteroid isomerase, Active site, Paramagnetic agent, EquileninIntroductionIt has been known that the protein active site plays asignificant role in various physiological processes. Thecatalytic process is a binding reaction of protein similar to alock and key model where the substrate behaves like a keyfitting in the lock by interaction between substrate andresidues of active site in the protein. The active site of theprotein fits to the substrate conformation in size, shape,charge, and hydrophobic or hydrophilic character, or a littleconformational change is induced in order to ensure precisebinding to the substrate.

In vivo MRI visualization of different cell populations labeled with PARACEST agents

Conventional T1- or T2-MRI contrast agents do not allow to track the distribution of different cell populations simultaneously because the effects of relaxation enhancers are additive. Herein, it is shown that paramagnetic chemical exchange saturation transfer agents offer the opportunity to visualize different cell populations in vitro and in vivo by 1H-MRI. Yb- and Eu-HPDO3A complexes have been used to label murine macrophages (J774.A1) and melanoma cells (B16-F10), respectively. By selective irradiation of the highly-shifted OH resonances of the two chemical exchange saturation transfer agents, it has been shown that tracking of the two cell types is possible. These PARAmagnetic Chemical Exchange Saturation Transfer agents have a tremendous potential for clinical translation as they share the same stability and in vivo pharmacokinetic properties of Gd-HPDO3A (ProHance®), which is a widely used clinically approved MRI agent.

Myelin mapping in the central nervous system of living mice using contrast-enhanced magnetization transfer MRI

This work compares magnetization transfer (MT) MRI of living mice with contrast-enhanced MT MRI using intraventricular administration of gadopentetate dimeglumine (Gd-DTPA), systemic administration of MnCl2, and both. In MT MRI at 9.4 T, the contrast-to-noise ratio (CNR) between white matter (WM) and gray matter (GM) increased by 85% after Gd-DTPA injection into the lateral ventricle. When applied in conjunction with manganese-enhanced MT MRI (117 μm isotropic resolution, 6 min measuring time), Gd-DTPA boosted the CNR increase from +56% to +117%. Additional T1 measurements at 2.35 T revealed that intraventricular Gd-DTPA shortens the T1 of GM much more than that of WM, which corresponds to estimated extracellular spaces of 26% in GM and only 15% in WM. These results explain the additional MT contrast enhancement by Gd-DTPA and demonstrate that the T1 shortening by intracellular Mn2+ is well complemented by extracellular Gd-DTPA. The data suggest a high myelin and low water content to hinder access of hydrophilic paramagnetic agents, so that the resulting differential accumulation effectively reduces the MT saturation in water-rich tissues and thereby facilitates the mapping of myelin-rich tissues. Finally, a 156% CNR increase between GM and WM for contrast-enhanced MT MRI at 9.4T using both Gd-DTPA and manganese allowed for 60μm isotropic resolution (102 min measuring time), which delineated myelinated fibers and layers even within GM areas such as the thalamus and cerebellar cortex. Improved MT contrasts were also seen in the cervical spinal cord.

Cancer Therapy Utilizing Molecular Layer Deposition and Self-Organized Lightwave Network: Proposal and Theoretical Prediction

Cancer therapy utilizing the molecular layer deposition (MLD) and the self-organized lightwave network (SOLNET) is proposed. The MLD is a growth method, in which different kinds of molecules are sequentially provided to a substrate to synthesize organic tailored materials with designated molecular arrangements. The first proposal is the selective delivery of multifunctional materials, containing luminescent molecules for imaging, sensitizers for photodynamic therapy, paramagnetic agent, and so on, to cancer cells by the MLD. The second proposal is the in situ synthesis of drugs, especially, large and toxic ones, at cancer cell sites by the MLD to deliver the drugs efficiently deep inside the cancer without attacking normal cells. The third proposal is the SOLNET-assisted laser surgery. After luminescent molecules are adsorbed in cancer cells by the MLD, a write beam is introduced from an optical fiber into the area containing cancer cells through photoinduced refractive index increase materials to construct self-aligned optical waveguides of the SOLNET connecting the optical fiber to the cancer cells. Surgery laser beams are guided to cancer cells by the SOLNET. A proof-of-concept, which indicates that the surgery laser beams are guided toward cancer cell targets selectively, is presented by a simulation using the finite-difference time-domain method and a preliminary experimental observation.