Frequency dependence of MR relaxation times. I. Paramagnetic ions

T1 and T2 of paramagnetic ions in free and chelated form were measured over the range of clinical magnetic resonance imaging field strengths (0.02-1.5 T). T1 values agreed with published data; however, to our knowledge, the field dependence of T2 has not been systematically studied before Mn2+, Cr3+, and Fe3+ all showed T2 reduction at high field strengths, although reduction due to Fe3+ was minimal. This is believed to be due to "contact" interactions, which have been previously noted for manganese. No such T2 reduction was seen in the chelates, except that dysprosium chelate (but not free ion) showed an anomalous decrease in T2 at high field strengths, which may possibly be explained by a dephasing effect caused by the large magnetic moment of Dy3+.     

In Vivo Micro‐CT Imaging of Human Mesenchymal Stem Cells Labeled with Gold‐Poly‐l‐Lysine Nanocomplexes

Developing in vivo cell tracking is an important prerequisite for further development of cell‐based therapy. So far, few computed tomography (CT) cell tracking studies have been described due to its notoriously low sensitivity and lack of efficient labeling protocols. A simple method is presented to render human mesenchymal stem cells (hMSCs) sufficiently radiopaque by complexing 40 nm citrate‐stabilized gold nanoparticles (AuNPs) with poly‐l ‐lysine (PLL) and rhodamine B isothiocyanate (RITC). AuNP‐PLL‐RITC labeling does not affect cellular viability, proliferation, or downstream cell differentiation into adipocytes and osteocytes. Labeled hMSCs can be clearly visualized in vitro and in vivo with a micro‐CT scanner, with a detection limit of ≈2 × 10⁴ cells per µL in vivo. Calculated Hounsfield unit values are 2.27 per pg of intracellular Au, as measured with inductively coupled plasma mass spectrophotometry, and are linear over a wide range of cell concentrations. This linear CT attenuation is observed for both naked AuNPs and those that were taken up by hMSCs, indicating that the number of labeled cells can be quantified similar to the use of radioactive or fluorine tracers. This approach for CT cell tracking may find applications in CT image‐guided interventions and fluoroscopic procedures commonly used for the injection of cellular therapeutics.     

The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function

Tetracycline antibiotics act by inhibiting bacterial protein translation. Given the bacterial ancestry of mitochondria, we tested the hypothesis that doxycycline—which belongs to the tetracycline class—reduces mitochondrial function, and results in cardiac contractile dysfunction in cultured H9C2 cardiomyoblasts, adult rat cardiomyocytes, in Drosophila and in mice. Ampicillin and carbenicillin were used as control antibiotics since these do not interfere with mitochondrial translation. In line with its specific inhibitory effect on mitochondrial translation, doxycycline caused a mitonuclear protein imbalance in doxycycline-treated H9C2 cells, reduced maximal mitochondrial respiration, particularly with complex I substrates, and mitochondria appeared fragmented. Flux measurements using stable isotope tracers showed a shift away from OXPHOS towards glycolysis after doxycycline exposure. Cardiac contractility measurements in adult cardiomyocytes and Drosophila melanogaster hearts showed an increased diastolic calcium concentration, and a higher arrhythmicity index. Systolic and diastolic dysfunction were observed after exposure to doxycycline. Mice treated with doxycycline showed mitochondrial complex I dysfunction, reduced OXPHOS capacity and impaired diastolic function. Doxycycline exacerbated diastolic dysfunction and reduced ejection fraction in a diabetes mouse model vulnerable for metabolic derangements. We therefore conclude that doxycycline impairs mitochondrial function and causes cardiac dysfunction.     

MRI/SPECT/Fluorescent Tri‐Modal Probe for Evaluating the Homing and Therapeutic Efficacy of Transplanted Mesenchymal Stem Cells in a Rat Ischemic Stroke Model

Quantitatively tracking engraftment of intracerebrally or intravenously transplanted stem cells and evaluating their concomitant therapeutic efficacy for stroke has been a challenge in the field of stem cell therapy. In this study, first, an MRI/SPECT/fluorescent tri‐modal probe (¹²⁵I‐fSiO4@SPIOs) is synthesized for quantitatively tracking mesenchymal stem cells (MSCs) transplanted intracerebrally or intravenously into stroke rats, and then the therapeutic efficacy of MSCs delivered by both routes and the possible mechanism of the therapy are evaluated. It is demonstrated that ⁽¹²⁵⁾I‐fSiO4@SPIOs have high efficiency for labeling MSCs without affecting their viability, differentiation, and proliferation capacity , and found that 35% of intracerebrally injected MSCs migrate along the corpus callosum to the lesion area, while 90% of intravenously injected MSCs remain trapped in the lung at 14 days after MSC transplantation. However, neurobehavioral outcomes are significantly improved in both transplantation groups, which are accompanied by increases of vascular endothelial growth factor, basic fibroblast growth factor, and tissue inhibitor of metalloproteinases‐3 in blood, lung, and brain tissue (p < 0.05). The study demonstrates that ¹²⁵I‐fSiO4@SPIOs are robust probe for long‐term tracking of MSCs in the treatment of ischemic brain and MSCs delivered via both routes improve neurobehavioral outcomes in ischemic rats.     

The application of nanoparticles in gene therapy and magnetic resonance imaging

The combination of nanoparticles, gene therapy, and medical imaging has given rise to a new field known as gene theranostics, in which a nanobioconjugate is used to diagnose and treat the disease. The process generally involves binding between a vector carrying the genetic information and a nanoparticle, which provides the signal for imaging. The synthesis of this probe generates a synergic effect, enhancing the efficiency of gene transduction and imaging contrast. We discuss the latest approaches in the synthesis of nanoparticles for magnetic resonance imaging, gene therapy strategies, and their conjugation and in vivo application.     

In Vivo Imaging of Composite Hydrogel Scaffold Degradation Using CEST MRI and Two‐Color NIR Imaging

Hydrogel scaffolding of stem cells is a promising strategy to overcome initial cell loss and manipulate cell function post‐transplantation. Matrix degradation is a requirement for downstream cell differentiation and functional tissue integration, which determines therapeutic outcome. Therefore, monitoring of hydrogel degradation is essential for scaffolded cell replacement therapies. It is shown here that chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) can be used as a label‐free imaging platform for monitoring the degradation of crosslinked hydrogels containing gelatin (Gel) and hyaluronic acid (HA), of which the stiffness can be fine‐tuned by varying the ratio of the Gel:HA. By labeling Gel and HA with two different near‐infrared (NIR) dyes having distinct emission frequencies, it is shown here that the HA signal remains stable for 42 days, while the Gel signal gradually decreases to <25% of its initial value at this time point. Both imaging modalities are in excellent agreement for both the time course and relative value of CEST MRI and NIR signals (R² = 0.94). These findings support the further use of CEST MRI for monitoring biodegradation and optimizing of gelatin‐containing hydrogels in a label‐free manner.     

Relaxometry and magnetometry of ferritin

To characterize the nature of kainate (KA) receptors distinct in the CA3 region of the hippocampus, properties of depolarizations induced by pulses of KA or AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) applied to dendrites of CA3 neurons with micropipettes were studied in thin transverse slices of the guinea pig hippocampus. KA induced depolarizations at negligible latencies only when administered to the most proximal dendritic areas. The depolarization was unaffected by tetrodotoxin or by a decrease in Ca2+ and an increase in Mg2+ concentrations. The declining slope of the KA-induced depolarization was significantly slower than that of the AMPA-induced depolarization. In comparison with the AMPA-induced depolarization, the KA-induced depolarization was much less susceptible to antagonists such as 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX) and 1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI52466). 6, 7,8,9-Tetrahydro-5-nitro-1H-benz[g]indole-2,3-dione-3-oxime (NS-102) and (2S,4R)-4-methylglutamate (SYM 2081) were without effects. The threshold concentration of pressure-ejected KA to induce depolarizations was about 200 nM. Excitatory postsynaptic potentials elicited by mossy fiber stimulation were more potently suppressed by CNQX than by GYKI52466. These results indicate that receptors responsible for the slow KA depolarization in the CA3 region of the hippocampus are not AMPA receptors but KA receptors. They are localized in the most proximal part of the apical dendrite and distinct from those observed in primary cultures of hippocampal neurons.     

Study of relapsing remitting experimental allergic encephalomyelitis SJL mouse model using MION-46L enhanced in vivo MRI: early histopathological correlation

Constitutive expression of VEGF after implantation of genetically engineered myoblasts into non-ischemic muscle led to an increase in vascular structures. Previously, effects of VEGF delivery to adult muscle have only been reported in ischemic tissues. The resulting vascular structures were reminiscent of those formed during embryonic vasculogenesis, rather than angiogenesis, sprouting from preexisting vessels. Initially, VEGF caused an accumulation of endothelial cells and macrophages, followed by networks of vascular channels and hemangiomas with locally high serum VEGF levels. No effects were evident in adjacent tissue or contralateral legs, where low serum VEGF was detected. These data suggest that the induction by VEGF of angiogenesis or vasculogenesis may be dose-dependent. Furthermore, VEGF expression must be carefully modulated, as overexpression is deleterious.