Significant Contrast Enhancement Research Articles

An enzyme-activatable and cell-permeable MnIII-porphyrin as a highly efficient T1 MRI contrast agent for cell labeling.

Magnetic resonance imaging (MRI) is a preferred technique for noninvasively monitoring the fate of implanted cells, such as stem cells and immune cells in vivo. Cellular MRI requires contrast agents (CAs) to label the cells of interest. Despite promising progress made in this emerging field, highly sensitive, stable and biocompatible T1 CAs with high cell permeability and specificity remains an unmet challenge. To address this need, a novel MnIII-porphyrin, MnAMP was designed and synthesized based on the modification of MnIIItetra(carboxy-porphyrin) (MnTCP), a small and highly stable non-Gd extracellular CA with good biocompatibility and high T1 relaxivity (r1 = 7.9 mM-1 s-1) at clinical field of 3 Tesla (T). Cell permeability was achieved by masking the polar carboxylates of MnTCP with acetoxymethyl-ester (AM) groups, which are susceptible to hydrolysis by intracellular esterases. The enzymatic cleavage of AM groups led to disaggregation of the hydrophobic MnAMP, releasing activated MnTCP with significant increase in T1 relaxivity. Cell uptake of MnAMP is highly efficient as tested on two non-phagocytic human cell lines with no side effects observed on cell viability. MRI of labeled cells exhibited significant contrast enhancement with a short T1 of 161 ms at 3 T, even though a relatively low concentration of MnAMP and short incubation time was applied for cell labeling. Overall, MnAMP is among the most efficient T1 cell labeling agents developed for cellular MRI.

Compact plane illumination plugin device to enable light sheet fluorescence imaging of multi-cellular organisms on an inverted wide-field microscope.

We developed a compact plane illumination plugin (PIP) device which enabled plane illumination and light sheet fluorescence imaging on a conventional inverted microscope. The PIP device allowed the integration of microscope with tunable laser sheet profile, fast image acquisition, and 3-D scanning. The device is both compact, measuring approximately 15 by 5 by 5 cm, and cost-effective, since we employed consumer electronics and an inexpensive device molding method. We demonstrated that PIP provided significant contrast and resolution enhancement to conventional microscopy through imaging different multi-cellular fluorescent structures, including 3-D branched cells in vitro and live zebrafish embryos. Imaging with the integration of PIP greatly reduced out-of-focus contamination and generated sharper contrast in acquired 2-D plane images when compared with the stand-alone inverted microscope. As a result, the dynamic fluid domain of the beating zebrafish heart was clearly segmented and the functional monitoring of the heart was achieved. Furthermore, the enhanced axial resolution established by thin plane illumination of PIP enabled the 3-D reconstruction of the branched cellular structures, which leads to the improvement on the functionality of the wide field microscopy.

Sudden onset bilateral lower limb weakness in a female patient with no significant past medical history: question

Spinal cord infarction is a relatively rare condition, with the most common type being anterior spinal artery syndrome, presenting with acute bilateral weakness/paraparesis, impaired spinothalamic sensation and usually preserved deep sensation with or without respiratory dysfunction [1]. Common aetiologies include atherosclerosis, aortic aneurysm, surgery or dissection, and hypercoagulability states. Hence, spinal cord infarction arising from an atherosclerotic pathogenesis has a propensity to occur in elderly and vasculopath patients [1–3]. The classical MRI features of spinal cord infarction are central T2 hyperintensity without significant cord expansion or contrast enhancement. Although usually technically difficult to image, if possible, diffusion-weighted imaging demonstrates corresponding abnormal restricted diffusion, as in acute cerebral infarction [2]. These MRI changes were evident in our patient with H-shaped T2 hyperintensity demonstrated on the axial image (Fig. 1A of Images in Neuroscience: Question) which was confined to the grey matter of the cord, consistent with the known particular sensitivity of the neuronal perikaryon to hypoxia. The striking diffuse apparent diffusion coefficient hypointensity along the cord which was congruent with increased signal intensity demonstrated on diffusion weighted imaging, is also consistent with abnormal restricted diffusion indicative of an acute ischaemic process (Fig. 1B, Fig. 1C from Images in Neuroscience: Question). The CT aortogram (Fig. 1A) demonstrates severe calcific atherosclerosis throughout the aorta and its major abdominal branches, which is a common underlying cause of cord infarction in this age group [4]. Our patient had clinical and radiological findings consistent with diffuse cord infarction which is an unfortunate condition with little prospect of recovery, as occurred in this patient [1,5].

PTPS-18APPARENT DIFFUSION COEFFICIENT MEASUREMENT IN PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIIOMA (DIPG): WORK-IN-PROGRESS

BACKGROUND: Pediatric diffuse intrinsic pontine gliomas (DIPG) are pediatric brain tumors with an extremely poor prognosis. Diagnosis has historically been based on magnetic resonance (MR) imaging appearance of the lesion, which demonstrates an expansile pontine lesion; T1 hypo-/T2 hyperintense and without significant contrast enhancement. These imaging findings change during the course of treatment. Efforts have focused on identifying prognostically significant, quantifiable MR characteristics. PURPOSE: Measure the apparent diffusion coefficient (ADC) on serial MR examinations in patients with DIPG. SUBJECTS/METHODS: Medical records of 7 subjects, (2.11 -54.6 years), with the diagnosis of pontine glioma and diffusion imaging were reviewed. MR studies were retrieved from the online Agfa archives. After reviewing the MRIs, images with the most significant enhancing tumor/disease were identified from each patient's most recent/last imaging series. Regions of interest (ROIs) were drawn on the corresponding slices on the ADC maps. Similar ROIs were drawn on the same slices from prior examinations for each patient. Control ROI was obtained from measurements on normal appearing cerebellar white matter bilaterally. ADC values were recorded. Right and left values were combined for the pontine and cerebellar ROIs. Adjusted values were calculated for time points by dividing the pontine by the cerebellar value compensating for differences in the diffusion B-Value and scanner to scanner imaging parameter variability. Adjusted ADC values were plotted against the patient's age at the time of each MRI. A graph with ADC value vs. the number days remaining before patient's death (or last imaging study) was generated, reflecting patient's survival. RESULTS: We identified different patterns of change in the ADC over time for each patient. ADC values were higher than normal in all patients though interpatient variability was noted. Clinical significance of these differences is unclear at present. Correlation with clinical parameters, treatments and survival time is a work-in-progress.

A corrole nanobiologic elicits tissue-activated MRI contrast enhancement and tumor-targeted toxicity

Water-soluble corroles with inherent fluorescence can form stable self-assemblies with tumor-targeted cell penetration proteins, and have been explored as agents for optical imaging and photosensitization of tumors in pre-clinical studies. However, the limited tissue-depth of excitation wavelengths limits their clinical applicability. To examine their utility in more clinically-relevant imaging and therapeutic modalities, here we have explored the use of corroles as contrast enhancing agents for magnetic resonance imaging (MRI), and evaluated their potential for tumor-selective delivery when encapsulated by a tumor-targeted polypeptide. We have found that a manganese-metallated corrole exhibits significant T1 relaxation shortening and MRI contrast enhancement that is blocked by particle formation in solution but yields considerable MRI contrast after tissue uptake. Cell entry but not low pH enables this. Additionally, the corrole elicited tumor-toxicity through the loss of mitochondrial membrane potential and cytoskeletal breakdown when delivered by the targeted polypeptide. The protein–corrole particle (which we call HerMn) exhibited improved therapeutic efficacy compared to current targeted therapies used in the clinic. Taken together with its tumor-preferential biodistribution, our findings indicate that HerMn can facilitate tumor-targeted toxicity after systemic delivery and tumor-selective MR imaging activatable by internalization.

Comparison between computed tomography multislice and high-field magnetic resonance in the diagnostic evaluation of patients with renal masses.

Renal masses are a common finding in diagnostic imaging; these lesions usually are solid or cystic, benign or malignant, and the correct diagnosis may be difficult. The aim of our study was the comparison of multi-slice computed tomography (MSCT) and high-field magnetic resonance (MR) in the diagnostic evaluation of renal masses. We studied 29 patients, 16 men and 13 women aged 8-85 years (mean 61±17 years) with histo-cytological diagnosis of renal masses (n=31), of which the majority (74%; n=23) was represented by malignant lesions [renal cell carcinoma (Ca) =16, chromophobe renal cell Ca =2, squamous cell Ca =1, urothelial Ca =2, lymphoma =1, Wilms tumor =1]; the remaining 8 masses (26%) were benign (pyelonephritis =2, simple cyst =1, hematic cyst =1, lipoma =1 and oncocytoma =3). All patients underwent MSCT and MR (3.0 Tesla) before and after contrast injection; the images were evaluated in double-blind by two expert radiologists. The results of the images were then compared with the histo-cytological data to calculate the values of diagnostic accuracy for both methods in the identification and characterization of renal masses. The benign or malignant nature of the lesions was established according to the regularity of the margins, presence or absence of significant contrast enhancement, infiltration of perirenal fat and vascular invasion. The concordance of the results of the two imaging techniques was then calculated using the coefficient Kappa Cohen. For both identification and characterization of renal masses, MSCT and MR showed comparable values of diagnostic accuracy with a significant concordance (k=1); in particular, the diagnostic accuracy of MSCT/MR was 100%/100% for lesion identification, 90%/90% for lesion characterization in terms of benign or malignant nature, 97%/97% for the evaluation of lesion edges, 90%/90% for the assessment of lesion contrast enhancement, 93%/93% for the evaluation of peri-renal fat infiltration and 96%/96% for the evaluation of vascular infiltration. Only in three cases of oncocytoma the two imaging methods were both inaccurate for diagnosis of benignity classifying the lesions as probably malignant on the basis of the absence of central scar and of dynamic contrast enhancement pattern. The results of our study show comparable diagnostic accuracy of computed tomography (CT) and MR for the identification and characterization of expansive renal lesions. High-field MR is, therefore, a valid alternative to MSCT in the evaluation of renal masses avoiding exposure to ionizing radiation.

Multifunctional magnetic-hollow gold nanospheres for bimodal cancer cell imaging and photothermal therapy

Multifunctional nanocomposites combining imaging and therapeutic functions have great potential for cancer diagnosis and therapy. In this work, we developed a novel theranostic agent based on hollow gold nanospheres (HGNs) and superparamagnetic iron oxide nanoparticles (SPIO). Taking advantage of the excellent magnetic properties of SPIO and strong near-infrared (NIR) absorption property of HGNs, such nanocomposites were applied to targeted magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) of cancer cells. In vitro results demonstrated they displayed significant contrast enhancement for T2-weighted MRI and strong PAI signal enhancement. Simultaneously, the nanocomposites exhibited a high photothermal effect under the irradiation of the near-infrared laser and can be used as efficient photothermal therapy (PTT) agents for selective killing of cancer cells. All these results indicated that such nanocomposites combined with MRI-PAI and PTT functionality can have great potential for effective cancer diagnosis and therapy.

P103 – 2340: Atypical enterovirus encephalitis causing behavioral changes and autism-like clinical manifestations: Case report

Objective Enteroviruses are one of the most common causative agents of aseptic meningitis and viral encephalitis. Autism-like symptoms related to enterovirus encephalitis are extremely rare. Methods Herein, we present a fourteen-year-old female adolescent with a chronic, atypical enterovirus encephalitis, who developed behavioural changes and autistic features such as impairment of communication, mutism and lack of eye contact. Results The patient's general physical examination was normal. On neurological examination, lack of eye contact and communication, bradymimy, gait disturbance, slight rigidity on both upper extremities, dystonia on her right hand were found. Her computed tomography scan of the brain on admission was normal. Laboratory investigations were within normal limits. Cerebrospinal fluid (CSF) cytology and biochemistry including CSF glucose, protein, electrolytes, albumin, immunoglobulin (Ig) G were normal. Cranial MRI showed no significant lesion or contrast enhancement. Further detailed investigations were planned, but at the same time IVIG treatment of 20 mg/kg was administrated. The standard and sleep EEG's showed diffuse background slowing more apparent on the right hemisphere and bilateral posterior halves of the hemispheres. A wide range of serum antibodies (autoimmune and paraneoplastic) were negative. Quantitative serum aminoacids and urine organic acids were negative. Serum IgM and IgG for measles, and CSF fluid bacterial culture were negative. Polymerase chain reaction assay of the CSF was positive for enterovirus. During the hospital stay, the patient's clinical picture gradually improved. At discharge the patient was able to speak and communicate. Six months after discharge, her clinical status was improved. Her bradymimy and rigidity on the upper extremities were totally resolved. Conclusion The autism spectrum disorder or autism-like clinical symptoms are extremely rare, but they may be a clear manifestations of enterovirus encephalitis. There is no specific antiviral treatment for enterovirus encephalitis. The early administration of IVIg is beneficial to achieve better recovery in patients.

High relaxivity Gd(III)-DNA gold nanostars: investigation of shape effects on proton relaxation.

Gadolinium(III) nanoconjugate contrast agents (CAs) have distinct advantages over their small-molecule counterparts in magnetic resonance imaging. In addition to increased Gd(III) payload, a significant improvement in proton relaxation efficiency, or relaxivity (r1), is often observed. In this work, we describe the synthesis and characterization of a nanoconjugate CA created by covalent attachment of Gd(III) to thiolated DNA (Gd(III)-DNA), followed by surface conjugation onto gold nanostars (DNA-Gd@stars). These conjugates exhibit remarkable r1 with values up to 98 mM(-1) s(-1). Additionally, DNA-Gd@stars show efficient Gd(III) delivery and biocompatibility in vitro and generate significant contrast enhancement when imaged at 7 T. Using nuclear magnetic relaxation dispersion analysis, we attribute the high performance of the DNA-Gd@stars to an increased contribution of second-sphere relaxivity compared to that of spherical CA equivalents (DNA-Gd@spheres). Importantly, the surface of the gold nanostar contains Gd(III)-DNA in regions of positive, negative, and neutral curvature. We hypothesize that the proton relaxation enhancement observed results from the presence of a unique hydrophilic environment produced by Gd(III)-DNA in these regions, which allows second-sphere water molecules to remain adjacent to Gd(III) ions for up to 10 times longer than diffusion. These results establish that particle shape and second-sphere relaxivity are important considerations in the design of Gd(III) nanoconjugate CAs.

Folic acid-conjugated superparamagnetic iron oxide nanoparticles for tumor-targeting MR imaging

Superparamagnetic iron oxide nanoparticles (SPIONs) have been the subject of extensive research due to their potential biomedical applications. In the present investigation, superparamagnetic FA-PEI-Fe3O4 were successfully prepared and evaluated as a targeted MRI contrast agent. FTIR characteristics, TGA, VSM, and MR imaging confirmed the composition and magnetic properties of the synthesized nanoparticles. TEM showed that FA-PEI-Fe3O4 were spherical in shape and well dispersed. The nanoparticles were superparamagnetic at room temperature with a saturation magnetization value of 67.1 emu/g. The nanoparticles showed higher uptake efficiency due to receptor-mediated endocytosis. Moreover, specificity of FA-PEI-Fe3O4 to target tumor cells was demonstrated by the increased nanoparticle uptake and significant contrast enhancement of KB cells over MCF7 cells. The competitive inhibition of FA-PEI-Fe3O4 by free FA further confirmed the specific interaction of this conjugate with FA receptors. In vivo MR imaging studies showed a decreased signal intensity and enhanced tumor contrast post-injection of FA-PEI-Fe3O4. These results indicate that FA-PEI-Fe3O4 can be used as a promising tumor-targeting agent as well as a T2 negative-contrast agent in MR imaging applications.

Abstract T P99: Development of Liposomes Loaded With Computed Tomogratphy Contrast Agent for Thrombus Imaging

Introduction: Liposomes are the most established nanocarriers that can be loaded with contrast agents as well as tailored for targeting to the desired tissue. Targeted CT liposomes represent a novel approach for rapid thrombus imaging. They allow specific and selective accumulation in thrombus providing significant contrast enhancement (expressed as HU) over the surrounding tissue. Hypothesis: We hypothesize that preparation technology will produce homogenous liposomes with sufficient level of loaded CT contrast agent. Methods: Liposomes were composed of distearoyl phosphatidylcholine, cholesterol, and distearoyl phosphatidylethanolamine - polyethylene glycol 2000 (molar ratio, 55/45/5). CT liposomes were prepared by lipid film hydration with iohexol (Omnipaque 350, GE Healthcare) followed by freeze-thaw extrusion (100 nm). Subsequently, they were purified by dialysis (Slide-A-Lyzer, cut-off 10 kDa) to remove un-loaded ioxehol. After purification, liposome-associated iohexol was determined by UV/VIS spectrophotometry and CT. Size distribution of final CT liposomes was assessed by dynamic light scattering. Results: Preparation technology produced homogenous liposome population having appropriate size distribution (90-110 nm and PD index, 0.05-0.10). Iohexol that remains associated in final CT liposomes represented only 5% of its initial level entering the preparation process. Almost 95% of iohexol was released and its final content was found to be 5 mg iodine/ml. Conclusions: Liposomal CT formulation was prepared with satisfactory size distribution and homogenity. Although the significant portion of iohexol was released, these CT liposomes were still detectable in vitro by CT. This basic liposomal platform will be optimized to achieve higher iohexol loading and will be further developed for thrombus imaging such as targeted CT liposomes.

Fusion of Fuzzy Enhanced Overexposed and Underexposed Images

Abstract An image fusion algorithm based on DWT is used to combine fuzzy enhanced overexposed images and underexposed images. The proposed method provides fused image containing visual salient information present in both the input images along with significant contrast enhancement. The proposed algorithm is useful for a wide range of applications such as military applications, surveillance, medical diagnosis etc. The fused image obtained from DWT fusion of fuzzy enhanced images is visually better than those obtained from DWT fusion of: unenhanced images, gamma corrected images as well as histogram equalized images. Both subjective and objective assessment is performed to evaluate the performance of the proposed algorithm. The objective image quality measures: entropy and standard deviation, also shows that the proposed method performs better than the other method.

An ultrasmall and metabolizable PEGylated NaGdF4:Dy nanoprobe for high-performance T(1)/T(2)-weighted MR and CT multimodal imaging.

Lanthanide-based multimodal probes with high sensitivity, simple synthesis strategy, and good biocompatibility promise new applications for clinical diagnosis. However, today's challenge is not only to develop high-performance multimodal probes for more accurate and reliable diagnosis, but also to understand the fate of these probes in vivo. In this context, a novel PEGylated Dy-doped NaGdF4 nanoprobe (PEG-NaGdF4:Dy) was designed and fabricated as a T1/T2-weighted MRI/CT imaging agent. This nanoprobe has a distinct longitudinal relaxivity (r1 = 5.17 mM(-1) s(-1)), relatively high transverse relaxivity (r2 = 10.64 mM(-1) s(-1)), and exhibits strong X-ray attenuation properties (44.70 HU L g(-1)) in vitro. Furthermore, T1/T2-weighted MRI/CT imaging in vivo confirmed that this PEG-NaGdF4:Dy nanoprobe could lead to a significant contrast enhancement effect on liver, spleen and kidney at 24 h post injection. The MTT assay, histological analysis, and biodistribution investigation demonstrated that this multifunctional nanoprobe possessed relatively low cytotoxicity, negligible tissue damage and could be completely excreted out of the body of mice as time prolonged. Therefore, the present PEG-NaGdF4:Dy nanoprobe has the potential for the development of multifunctional T1/T2-weighted MRI/CT imaging to provide more comprehensive and accurate diagnosis information.

ICAM-1 as a molecular target for triple negative breast cancer.

Triple negative breast cancers (TNBCs) have a high mortality rate owing to aggressive proliferation and metastasis and a lack of effective therapeutic options. Herein, we describe the overexpression of intercellular adhesion molecule-1 (ICAM-1) in human TNBC cell lines and tissues, and demonstrate that ICAM-1 is a potential molecular target and biomarker for TNBC therapy and diagnosis. We synthesized ICAM-1 antibody-conjugated iron oxide nanoparticles (ICAM-IONPs) as a magnetic resonance imaging (MRI) probe to evaluate tumor targeting. Quantitative analysis of ICAM-1 surface expression predicted the targeting capability of ICAM-IONPs to TNBC cells. MRI of the TNBC xenograft tumor after systemic administration of ICAM-IONPs, coupled with iron quantification and histology, demonstrated a significant and sustained MRI contrast enhancement and probe accumulation in tumors with ICAM-1 overexpression relative to control. Identification of ICAM-1 as a TNBC target and biomarker may lead to the development of a new strategy and platform for addressing a critical gap in TNBC patient care.

Delivery of siRNA by MRI-visible nanovehicles to overcome drug resistance in MCF-7/ADR human breast cancer cells

Multidrug resistance (MDR) is one of the major barriers in cancer chemotherapy. P-glycoprotein (P-gp), a cell membrane protein in MDR, also a member of ATP-Binding cassette (ABC) transporter, can increase the efflux of various hydrophobic anticancer drugs. In this study, polycation/iron oxide nanocomposites, were chosen as small interfering RNA (siRNA) carriers to overcome MDR through silencing of the target messenger RNA and subsequently reducing the expression of P-gp. Amphiphilic low molecular weight polyethylenimine was designed with different alkylation groups and alkylation degree to form various nanocarriers with clustered iron oxide nanoparticles inside and carrying siRNA through electrostatic interaction. A few optimized formulations can form stable nanocomplexes with siRNA and protect them from degradation during delivery, and lead to effective silencing effect that comparable to a commercial golden standard transfection agent, Lipofectamine 2000. Human breast cancer MCF-7/ADR cells can be vulnerable to doxorubicin treatment after the strong downregulation of P-gp through siRNA tranfection. Once transfected with these nanocomplexes, the cells displayed significant contrast enhancement against non-transfected cells under a 3T clinical MRI scanner. These nanocomposites also demonstrated their downregulation efficacy of P-gp in a MCF-7/ADR orthotopic tumor model in mice.

Magnetic Prussian blue nanoparticles for targeted photothermal therapy under magnetic resonance imaging guidance.

This paper reported a core-shell nanotheranostic agent by growing Prussian blue (PB) nanoshells of 3-6 nm around superparamagnetic Fe3O4 nanocores for targeted photothermal therapy of cancer under magnetic resonance imaging (MRI) guidance. Both in vitro and in vivo experiments proved that the Fe3O4@PB core-shell nanoparticles showed significant contrast enhancement for T2-weighted MRI with the relaxivity value of 58.9 mM(-1)·s(-1). Simultaneously, the composite nanoparticles exhibited a high photothermal effect under irradiation of a near-infrared laser due to the strong absorption of PB nanoshells, which led to more than 80% death of HeLa cells with only 0.016 mg·mL(-1) of the nanoparticles with the aid of the magnetic targeting effect. Using tumor-bearing nude mice as the model, the near-infrared laser light ablated the tumor effectively in the presence of the Fe3O4@PB nanoparticles and the tumor growth inhibition was evaluated to be 87.2%. Capabilities of MRI, magnetic targeting, and photothermal therapy were thus integrated into a single agent to allow efficient MRI-guided targeted photothermal therapy. Most importantly, both PB and Fe3O4 nanoparticles were already clinically approved drugs, so the Fe3O4@PB nanoparticles as a theranostic nanomedicine would be particularly promising for clinical applications in the human body due to the reliable biosafety.

Leukocyte mimetic polysaccharide microparticles tracked in vivo on activated endothelium and in abdominal aortic aneurysm

We have developed injectable microparticles functionalized with fucoidan, in which sulfated groups mimic the anchor sites of P-selectin glycoprotein ligand-1 (PSGL-1), one of the principal receptors supporting leukocyte adhesion. These targeted microparticles were combined with a fluorescent dye and a T2∗ magnetic resonance imaging (MRI) contrast agent, and then tracked in vivo with small animal imaging methods. Microparticles of 2.5μm were obtained by a water-in-oil emulsification combined with a cross-linking process of polysaccharide dextran, fluorescein isothiocyanate dextran, pullulan and fucoidan mixed with ultrasmall superparamagnetic particles of iron oxide. Fluorescent intravital microscopy observation revealed dynamic adsorption and a leukocyte-like behaviour of fucoidan-functionalized microparticles on a calcium ionophore induced an activated endothelial layer of a mouse mesentery vessel. We observed 20times more adherent microparticles on the activated endothelium area after the injection of functionalized microparticles compared to non-functionalized microparticles (197±11 vs. 10±2). This imaging tool was then applied to rats presenting an elastase perfusion model of abdominal aortic aneurysm (AAA) and 7.4T in vivo MRI was performed. Visual analysis of T2∗-weighted MR images showed a significant contrast enhancement on the inner wall of the aneurysm from 30min to 2h after the injection. Histological analysis of AAA cryosections revealed microparticles localized inside the aneurysm wall, in the same areas in which immunostaining shows P-selectin expression. The developed leukocyte mimetic imaging tool could therefore be relevant for molecular imaging of vascular diseases and for monitoring biologically active areas prone to rupture in AAA.

Synthesis and characterization of a porphyrazine–Gd(III) MRI contrast agent and in vivo imaging of a breast cancer xenograft model

Porphyrazines (Pz), or tetraazaporphyrins, are being studied for their potential use in detection and treatment of cancer. Here, an amphiphilic Cu-Pz-Gd(III) conjugate has been prepared via azide-alkyne Huisgen cycloaddition or 'click' chemistry between an azide functionalized Pz and alkyne functionalized DOTA-Gd(III) analog for use as an MRI contrast agent. This agent, Cu-Pz-Gd(III), is synthesized in good yield and exhibits solution-phase ionic relaxivity (r1 = 11.5 mM(-1) s(-1)) that is approximately four times higher than that of a clinically used monomeric Gd(III) contrast agent, DOTA-Gd(III). Breast tumor cells (MDA-MB-231) associate with Cu-Pz-Gd(III) in vitro, where significant contrast enhancement (9.336 ± 0.335 contrast-to-noise ratio) is observed in phantom cell pellet MR images. This novel contrast agent was administered in vivo to an orthotopic breast tumor model in athymic nude mice and MR images were collected. The average T1 of tumor regions in mice treated with 50 mg kg(-1) Cu-Pz-Gd(III) decreased relative to saline-treated controls. Furthermore, the decrease in T1 was persistent relative to mice treated with the monomeric Gd(III) contrast agent. An ex vivo biodistribution study confirmed that Cu-Pz-Gd(III) accumulates in the tumors and is rapidly cleared, primarily through the kidneys. Differential accumulation and T1 enhancement by Cu-Pz-Gd(III) in the tumor's core relative to the periphery offer preliminary evidence that this agent would find application in the imaging of necrotic tissue.

Binding of a dimeric manganese porphyrin to serum albumin: towards a gadolinium-free blood-pool T 1 MRI contrast agent

As the first clinically approved gadolinium-based blood-pool MRI contrast agent, gadofosveset was designed to bind to human serum albumin (HSA) reversibly, extending the circulation time in the bloodstream. This valuable pharmacokinetic property required for vasculature imaging, however, raises the risk of release and accumulation of gadolinium in vivo. The binding of gadofosveset to HSA significantly increases the relaxivity at low field, which decreases drastically when the magnetic field increases, limiting the applications of gadofosveset at fields of 3 T and higher. To address those challenges, we evaluated a novel dimeric manganese(III) porphyrin (MnP2) in vitro and in vivo as a potential gadolinium-free blood-pool agent. Through multiple spectroscopic studies, we demonstrated that MnP2 binds to HSA tightly. MnP2 exhibits a moderate relaxivity decrease on HSA binding. Nevertheless, owing to the unique field-dependent relaxation behaviors and the dimeric construct (two Mn(III) ions per complex), MnP2-HSA has a molar relaxivity twice that of the gadofosveset-HSA complex at 3 T. Through intravenous injection in rats, MnP2 exhibits long retention and significant contrast enhancement in the vascular compartment, as tested in a 3-T high-field clinical MRI scanner. Taken together, these data demonstrate that MnP2 represents a new class of gadolinium-free blood-pool agents suitable for both regular and high-field applications.

Highly magnetic iron carbide nanoparticles as effective T2contrast agents

This paper reports that iron carbide nanoparticles with high air-stability and strong saturation magnetization can serve as effective T2 contrast agents for magnetic resonance imaging. Fe5C2 nanoparticles (~20 nm in diameter) exhibit strong contrast enhancement with an r2 value of 283.2 mM(-1) S(-1), which is about twice as high as that of spherical Fe3O4 nanoparticles (~140.9 mM(-1) S(-1)). In vivo experiments demonstrate that Fe5C2 nanoparticles are able to produce much more significant MRI contrast enhancement than conventional Fe3O4 nanoparticles in living subjects, which holds great promise in biomedical applications.