Gadolinium-diethylenetriamine Pentaacetic Acid Research Articles

Theranostic Design of Angiopep-2 Conjugated Hyaluronic Acid Nanoparticles (Thera-ANG-cHANPs) for Dual Targeting and Boosted Imaging of Glioma Cells.

Simple SummaryGlioblastoma multiforme is the most aggressive malignant brain tumor with poor patient prognosis. The presence of the blood-brain barrier and the complex tumor microenvironment impair the efficient accumulation of drugs and contrast agents, causing late diagnosis, inefficient treatment and monitoring. Functionalized theranostic nanoparticles are a valuable tool to modulate biodistribution of active agents, promoting their active delivery and selective accumulation for an earlier diagnosis and effective treatment, and provide simultaneous therapy and imaging for improved evaluation of treatment efficacy. In this work, we developed angiopep-2 functionalized crosslinked hyaluronic acid nanoparticles encapsulating gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and irinotecan (Thera-ANG-cHANPs) that were shown to boost relaxometric properties of Gd-DTPA by the effect of Hydrodenticity, improve the uptake of nanoparticles by the exploitation of angiopep-2 improved transport properties, and accelerate the therapeutic effect of Irinotecan.Glioblastoma multiforme (GBM) has a mean survival of only 15 months. Tumour heterogeneity and blood-brain barrier (BBB) mainly hinder the transport of active agents, leading to late diagnosis, ineffective therapy and inaccurate follow-up. The use of hydrogel nanoparticles, particularly hyaluronic acid as naturally occurring polymer of the extracellular matrix (ECM), has great potential in improving the transport of drug molecules and, furthermore, in facilitatating the early diagnosis by the effect of hydrodenticity enabling the T1 boosting of Gadolinium chelates for MRI. Here, crosslinked hyaluronic acid nanoparticles encapsulating gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and the chemotherapeutic agent irinotecan (Thera-cHANPs) are proposed as theranostic nanovectors, with improved MRI capacities. Irinotecan was selected since currently repurposed as an alternative compound to the poorly effective temozolomide (TMZ), generally approved as the gold standard in GBM clinical care. Also, active crossing and targeting are achieved by theranostic cHANPs decorated with angiopep-2 (Thera-ANG-cHANPs), a dual-targeting peptide interacting with low density lipoprotein receptor related protein-1(LRP-1) receptors overexpressed by both endothelial cells of the BBB and glioma cells. Results showed preserving the hydrodenticity effect in the advanced formulation and internalization by the active peptide-mediated uptake of Thera-cHANPs in U87 and GS-102 cells. Moreover, Thera-ANG-cHANPs proved to reduce ironotecan time response, showing a significant cytotoxic effect in 24 h instead of 48 h.

Study on Establishing Reference Safe Concentrations of MRI Contrast Agents for Optimized Images: Paramagnetic Gd-DTPA-BMEA and Superparamagnetic Ferucarbotran

The purpose of this study is to establish the minimal injection doses of magnetic resonance imaging (MRI) contrast agents that can achieve optimized images while improving the safety of injectable MRI drugs. Gadolinium-diethylenetriamine penta-acetic acid (Gd-DTPA) and ferucarbotran, commonly used in clinical practice, were selected and evaluated with in vitro and in vivo experiments. MRI was acquired using T1-weighted (T1W) and T2-weighted (T2W) sequences, and the results were quantitatively analyzed. For in vitro experiments, results showed that T1W and T2W images were optimal when Gd-DTPA-bisamide (2-oxoethyl) (Gd-DTPA-BMEA) and ferucarbotran were diluted to a volume percentage of 0.6% and 0.05%; all comparisons were significant differences in grayscale statistics using one-way analysis of variance (ANOVA). For in vivo experiments, the contrast agent with optimal concentration percentages determined from in vitro experiments were injected into mice with an injection volume of 100 μL, and the images of brain, heart, liver, and mesentery before and after injection were compared. The statistical results showed that the p values of both T1W and T2W were less than 0.001, which were statistically significant. Under safety considerations for MRI contrast agent injection, optimized MRI images could still be obtained after reducing the injection concentration, which can provide a reference for the safety concentrations of MRI contrast agent injection in the future.

Magnetic resonance colonography with intestine-absorbable nanoparticle contrast agents in evaluation of colorectal inflammation

ObjectivesTo develop a nanoparticle-based MRI protocol based on transrectal administration of intestine-absorbable nanoparticle contrast agents to evaluate ulcerative colitis (UC).MethodsSolid lipid nanoparticles (SLNs) were synthesized by loading gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) and octadecylamine-fluorescein isothiocyanate to produce Gd-FITC-SLNs as T1 contrast agents. Twenty mice with acute UC were divided into four groups: enema with Gd-FITC-SLNs, intravenous injection of Gd-FITC-SLNs, enema with Gd-DTPA, and intravenous injection of Gd-DTPA. Five mice with chronic UC and five mice without UC underwent enema with Gd-FITC-SLNs. Axial T1- and T2-weighted MR images were obtained before and 20, 40, 60, 80,100, and 120 min after enema or intravenous injection of the contrast agent. The signal-to-noise ratios (SNRs) of the colorectal wall were measured in both groups. The MRI findings were correlated with subsequent histological confirmation.ResultsAt 20 min after enema with Gd-FITC-SLNs, MRI showed the following contrast enhancement pattern: acute UC > normal intestinal wall > chronic UC. A continuous enhancement effect was observed in mice with acute UC, whereas a slight continuous enhancement of the colorectal wall was observed in mice with chronic UC. The normal intestinal wall rapidly metabolized the contrast agent, and the enhancement decreased on sequential scans. There was no significant difference between the SNRs of the intestinal wall at 20 min after intravenous Gd-DTPA and transrectal Gd-FITC-SLN administration.ConclusionsEnema with Gd-FITC-SLNs may be helpful for the diagnosis and differential diagnosis of acute and chronic UC and can confer the same or better results than with intravenous Gd-DTPA.Key Points• Enema with Gd-FITC-SLNs may be helpful for the diagnosis and differential diagnosis of acute and chronic UC.• Enema with Gd-FITC-SLNs can achieve the same or better result than that with intravenous Gd-DTPA.• SLN-based MR colonography enhances the colorectal wall inflammation, based on the colonic absorption of the nanoparticle contrast agents.

Rational design of high performance nanotheranostics for NIR-II fluorescence/magnetic resonance imaging guided enhanced phototherapy.

Nanotheranostics, which can provide great insight into cancer therapy, has been deemed as a promising technology to settle the unmet medical needs. The rational design of high performance nanotheranostics with multiple complementary imaging features and satisfactory therapeutic efficacy is particularly valuable. Herein, versatile nanotheranostic agents DPPB-Gd-I NPs were fabricated by using gadolinium-diethylenetriaminepentaacetic acid chelates and an iodine-decorated copolymer as encapsulation matrixes to encapsulate a polymer DPPB through one-step nanoprecipitation. We have demonstrated that such nanoagents are able to efficiently damage tumors under single dose injection and NIR laser illumination conditions due to the enhanced photodynamic therapy and enhanced photothermal therapy (the tumor inhibition rate was as high as 94.5%). Moreover, these nanoagents can be utilized as dual-modal NIR-II fluorescence/magnetic resonance imaging probes for tumor diagnosis with high sensitivity, deep tissue penetration, and excellent spatial resolution. Overall, this work offers a powerful tactic to fabricate high performance nanotheranostics for clinical application.

Assessing In Vivo Bladder Urothelial Hyper-Permeability: Preclinical and Clinical Implications

To provide an update on the detection and evaluation of bladder hyper-permeability related to interstitial cystitis/painful bladder syndrome (IC/PBS) and inflammatory bowel disorders (e.g., inflammatory bowel syndrome). We developed a contrast-enhanced magnetic resonance imaging (CE-MRI) approach to assess in vivo bladder hyper-permeability by instilling a MRI contrast agent, Gd-DTPA (gadolinium diethylenetriamine pentaacetic acid), by intravesical injection through a catheter into the bladder. Molecular-targeted MRI (mt-MRI) was also used to assess in vivo bladder hyper-permeability-associated biomarker expressions (e.g., claudin-2, vascular endothelial growth factor receptor-1, and decorin) in preclinical models. An example of evaluating the effect of a therapy against bladder hyper-permeability is also discussed. The CE-MRI approach to detect in vivo bladder hyper-permeability not only serves as a measure of disease severity for IC/PBS and cross-talk complications associated with IBS but also be used to monitor therapeutic response.

Radical Dendrimers Based on Biocompatible Oligoethylene Glycol Dendrimers as Contrast Agents for MRI.

Finding alternatives to gadolinium (Gd)-based contrast agents (CA) with the same or even better paramagnetic properties is crucial to overcome their established toxicity. Herein we describe the synthesis and characterization of entirely organic metal-free paramagnetic macromolecules based on biocompatible oligoethylene glycol dendrimers fully functionalized with 5 and 20 organic radicals (OEG Gn-PROXYL (n = 0, 1) radical dendrimers) with the aim to be used as magnetic resonance imaging (MRI) contrast agents. Conferring high water solubility on such systems is often a concern, especially in large generation dendrimers. Our approach to overcome such an issue in this study is by synthesizing dendrimers with highly water-soluble branches themselves. In this work, we show that the highly water-soluble OEG Gn-PROXYL (n = 0, 1) radical dendrimers obtained showed properties that convert them in good candidates to be studied as contrast agents for MRI applications like diagnosis and follow-up of infectious diseases, among others. Importantly, with the first generation radical dendrimer, a similar r1 relaxivity value (3.4 mM−1s−1) in comparison to gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) used in clinics (3.2 mM−1s−1, r.t. 7T) has been obtained, and it has been shown to not be cytotoxic, avoiding the toxicity risks associated with the unwanted accumulation of Gd in the body.

Time to peak enhancement of malignant hypervascular hepatic tumors versus that of the aorta evaluating by test bolus sequence of magnetic resonance imaging

PurposeTo determine the relationship between time to peak enhancement (TPE) of malignant hypervascular hepatic tumors and that of the aorta. MethodSixty patients with malignant hypervascular hepatic tumors (48 with hepatocellular carcinoma and 12 with metastatic neuroendocrine tumor) who received abdominal MRI with test bolus sequence between January 2015 and May 2019 were enrolled. The test bolus images were monitored every 3 s after the injection of 2 mL gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and 10 mL saline flush, to evaluate the TPE of the tumors and aorta. We used linear regression with a least squares approach to show the relationship between TPE of the malignant hypervascular hepatic tumors and that of the aorta. ResultsTPE of malignant hypervascular hepatic tumors and abdominal aorta were 43.4 ± 12.9 and 23.3 ± 7.4 s, respectively (mean ± standard deviation). In univariate regression analysis, the TPE of malignant hypervascular hepatic tumors have a positively linear correlation with that of the aorta by the following equation: (TPE of malignant hypervascular hepatic tumor) = 1.4 X (TPE of the aorta) + 10.6 s (r = 0.65, p < 0.005). ConclusionsTPE of malignant hypervascular hepatic tumors can be predicted by a simple linear transformation from that of the aorta.

Three-dimensional printing of diamagnetic microparticles in paramagnetic and diamagnetic media

We present an analytical model that explains the motion of finite-size diamagnetic particles in paramagnetic or diamagnetic fluid media. Our model problem is the magnetic field-assisted three-dimensional assembly of carboxylate microspheres in a gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) solution that is placed in a cuboid. The trajectory of each microparticle is determined through a time marching solution of its equation of motion. The effects of the (1) magnetic field distribution and (2) magnetic susceptibility of the paramagnetic solution, which depends on the Gd-DTPA concentration, on the dynamics of particle assembly are identified. Validation of the analytical model is provided through experimental measurements. For the first time, we demonstrate that it is possible to form structures of diamagnetic particles in diamagnetic fluid media, for which we select the assembly of graphene in water.

Contrast-enhanced magnetic resonance (MR) T1 mapping with low-dose gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) is promising in identifying clear cell renal cell carcinoma histopathological grade and differentiating fat-poor angiomyolipoma.

This study aimed to identify clear cell renal cell carcinoma (ccRCC) histopathological grade and differentiate it from fat-poor angiomyolipoma (AML). This was achieved through contrast-enhanced magnetic resonance (MR) T1 mapping with intravenous low-dose gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA). In total, 56 consecutive patients received MR scanning between January 2016 and December 2018 using the pre- and post- contrast-enhanced T1 mapping sequences with low-dose Gd-DTPA (0.036 mmol/kg). RCCs were pathologically proven in 40 patients after surgery and graded according to the International Society of Urological Pathology (ISUP) classification system. Ten AMLs were pathologically proven by surgery histopathology and six AMLs were diagnosed by magnetic resonance imaging (MRI). Patients were followed up for more than half a year. The mean T1 values of the renal lesion and ipsilateral normal renal parenchyma were measured before and after Gd-DTPA administration (T1p and T1e). The reduction of T1 value (T1d) and the ratio of its reduction (T1d %) were calculated and compared. In 40 ccRCCs, higher-grade [International Society of Urologic Pathology (ISUP) grade 3 and 4] and lower-grade (ISUP grade 1 and 2) ccRCCs were noted in 13 and 27 patients, respectively. The mean T1p was 1,514.8±139.4 ms and the mean T1d was 907.7±193.7 ms in the higher-grade ccRCCs, which were significantly higher than in the lower-grade ccRCCs (T1p =1,251.7±151.5 ms and T1d =648.5±218.2 ms, respectively; P<0.001). Fat-poor AMLs had higher T1p (1,677.3±104.8 ms) and T1e (865.6±251.5 ms) as compared to ccRCCs (P<0.001). Combined T1p + T1d showed the highest area under the curve (AUC) (0.912) in the differentiation of higher-grade ccRCCs from lower-grade ccRCCs (P=0.010). Combined T1p + T1e had the highest AUC (0.956) in the differentiation between ccRCCs and fat-poor AMLs (P=0.010). All T1 mapping metrics could discriminate between normal renal parenchyma and renal lesions (P<0.001). No significant difference was found in the T1p and T1e at different parts of the ipsilateral normal renal parenchyma. Interobserver agreement for quantitative longitudinal relaxation time in the T1 maps was excellent. Contrast-enhanced T1 mapping with low-dose Gd-DTPA may provide a more reliable and accurate approach in identifying ccRCCs histopathological grade and differentiating ccRCCs from fat-poor AMLs.

Gadolinium-Loaded Solid Lipid Nanoparticles for Colorectal Tumor in MR Colonography.

The current study aims to investigate the possibility of using solid lipid nanoparticles (SLNs)-enhanced magnetic resonance (MR) colonography to diagnose colorectal cancer. Gd-FITC-SLNs were synthesized by loading gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) and fluorescein isothiocyanate (FITC) simultaneously. Twenty mice received azoxymethane/dextran sulfate sodium (AOM/DSS) to induce adenocarcinoma of the colon and were divided into 4 groups, and 5 in per group. MR colonography were performed at different time periods before and after enema or intravenous injection of Gd-FITC-SLNs or Gd-DTPA. The results demonstrated SNR (signal-to-noise ratio) significantly increased from 1.56- to 1.76-fold within the colorectal tumors after the enema of Gd-FITC-SLNs (p < 0.001). No differences in SNR were observed after the enema of Gd-DTPA (p > 0.05). Besides, SNR increased from 1.54- to 1.72-fold within the colorectal tumors after the intravenous injection of Gd-FITC-SLNs (p < 0.001) while SNR increased from 1.39to 1.57-fold within the colorectal tumors after the injection of Gd-DTPA (p < 0.001). In addition, SNR within colorectal tumors significantly increased ranging from 20th to 140th min, and lasted for about 120 min (p < 0.05) after the enema of Gd-FITC-SLNs and SNR within colorectal tumors also significantly increased ranging from 0th hour to 8th hour, lasted for about 8 hour (p < 0.05) after the injection of Gd-FITC-SLNs. However, after the injection of Gd-DTPA, SNR within colorectal tumors significantly increased only ranging from 0th min to 20th min after administration (p < 0.01). Furthermore, hematoxylin and eosin (H&E) staining revealed that all mice developed adenocarcinoma of the colon. In summary, it is feasible by using Gd-FITC-SLNs in MR colonography to diagnose colorectal cancer. Enema of Gd-FITC-SLNs can provide marked enhancement of colorectal tumors quickly, and safer while intravenous injection of Gd-FITC-SLNs can provide a long-lasting enhancement of colorectal tumors in MR colonography. These findings present a potential clinical application of Gd-FITC-SLNs on MR colonography.

Effect of convection enhanced delivery on the microstructure of brain extracellular space in aged rats

To compare the changes of extracellular space (ECS) structure and local drug distribution in adult brain and aged brain at different drug delivery rates in minimally invasive treatment of encephalopathy by convection enhanced delivery (CED) via ECS pathway. Thirty-six SD male rats were divided into adult rats group (2-8 months, n=18) and aged rats group (18-24 months, n=18) according to the age of the month. According to the drug rates (0.1 μL/min, 0.2 μL/min, and 0.3 μL/min), they were randomly divided into 3 subgroups, 6 in each subgroup. Gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) with a concentration of 10 mmol/L were introduced into the caudate nucleus of each group of rats by stereotactic injection. Tracer-based magnetic resonance imaging (MRI) was used to dynamically monitor the diffusion and distribution images of the Gd-DTPA in the brain interstitial system (ISS). Using the self-developed MRI image measurement and analysis system software to process and analyze the obtained images, the diffusion coefficient, clearance rate, volume fraction, and half-life of each group of rats in the caudate nucleus ECS could be acquired. The effects and differences of drug clearance and ECS structural function in the brain of aged rats and adult rats were compared and analyzed at different drug delivery rates. Magnetic tracer DECS-mapping technique was used to observe the distribution and drainage of tracer in caudate nucleus. At the injection rate of 0.1 μL/min, the volume fraction in the aged rats was increased compared with that in the adult rats (18.20%±0.04% vs. 17.20%±0.03%, t=3.752, P=0.004), and the degree of tortuosity was decreased (1.63±0.04 vs. 1.78±0.09, t=-3.680, P=0.004), the drug clearance rate was decreased [(1.94±0.68) mm2/s vs. (3.25±0.43) mm2/s, t=-3.971, P=0.003], and the molecular diffusion in ECS was increased [(3.99±0.21)×10-4 mm2/s vs. (3.36±0.37)×10-4 mm2/s, t=3.663, P=0.004]. When the rate of injection increased to 0.2 μL/min, the drug clearance in ECS of the aged rats was slowed down [(2.53±0.45) mmol/L vs. (3.37±0.72) mmol/L, t=-1.828, P=0.021]. However, there were no significant differences in volume fraction, molecular diffusion in ECS and macroscopic drug metabolism parameters. When the rate of injection increased to 0.3 μL/min, the volume fraction in the aged rats was decreased (17.20%±0.03% vs. 18.20%±0.05%, t=-0.869, P=0.045), and the drug clearance rate in ECS was significantly accelerated [(4.04±0.76) mmol/L vs. (3.26±0.55) mmol/L, t=1.786, P=0.014], and there was no significant difference in tortuosity and the rate of molecular diffusion in the ECS. The drug clearance and ECS structural parameters of brain ECS in aged brain with CED administration were changed at different rates, and it has the least effect on ECS in the aged brain at the injection rate of 0.2 μL/min. For the application of CED for the treatment of encephalopathy, we should consider the influence of factors such as age and injection rate, and provide reference for the development of individualized clinical treatment plan for minimally invasive treatment of encephalopathy via ECS pathway.

Targeted Delivery of Anti-inflammatory and Imaging Agents to Microglial Cells with Polymeric Nanoparticles.

Insult to the central nervous system (CNS) results in an early inflammatory response, which can be exploited as an initial indicator of neurological dysfunction. Nanoparticle drug delivery systems provide a mechanism to increase the uptake of drugs into specific cell types in the CNS such as microglia, the resident macrophage responsible for innate immune response. In this study, we developed two nanoparticle-based carriers as potential theranostic systems for drug delivery to microglial cells. Poly(lactic-co-glycolic) acid (PLGA)- and l-tyrosine polyphosphate (LTP)-based nanoparticles were synthesized to encapsulate the magnetic resonance imaging (MRI) contrast agent, gadolinium-diethylenetriaminepentaacetic acid (Gd[DTPA]), or the anti-inflammatory drug, rolipram. Robust uptake of both polymer formulations by microglial cells was observed with no evidence of toxicity. In mixed glial cultures, we observed a preferential internalization of nanoparticles by microglia compared to that of astrocytes. Moreover, exposure of our nanoparticles to microglial cells did not induce the release of the proinflammatory cytokines, tumor necrosis factor α (TNF-α), interleukin-1 β (IL-1β), or interleukin-6 (IL-6). These studies provide a foundation for the development of LTP nanoparticles as a platform for the delivery of imaging agents and drugs to the sites of neuroinflammation.

Cyclic RGD functionalized liposomes targeted to activated platelets for thrombosis dual-mode magnetic resonance imaging.

Thrombotic disease is a serious threat to human health. The rapid and accurate detection of thrombosis is still a clinical challenge. To achieve the accurate diagnosis of thrombosis with magnetic resonance imaging (MRI), nanomaterials-based contrast agents have been developed in recent years. In this study, cyclic RGD functionalized liposomes targeted to the activated platelets are developed for thrombosis dual-mode MRI. The cyclic RGD functionalized liposomes (cRGD@MLP-Gd) encapsulated with gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA) and superparamagnetic iron oxide (SPIO) are prepared, and their thrombus-targeted T1 and T2 MRI potential is evaluated in vitro and in vivo. Results show that cRGD@MLP-Gd could actively bind to the activated platelets and gradually accumulate at the thrombus site with a T1 - T2 contrast enhancement imaging effect in vitro. In in vivo MRI experiments, cRGD@MLP-Gd exhibits a T2 contrast enhancement at 1 h after intravenous administration, followed by a visibly larger T1 contrast enhancement at the thrombus site. This dynamic property showed that cRGD@MLP-Gd could actively bind to thrombus and possessed an enhanced T1 and T2 dual-mode MRI effect in vivo. Our results establish the characterization, feasibility and superiority of cRGD@MLP-Gd for the rapid identification of thrombosis, showing great potential to improve diagnostic accuracy and sensitivity to thrombosis of the MRI technique.

Rat mandibular condyle and fossa grew separately then unified as a single joint at 20 days old, which was the weaning age.

Magnetic resonance imaging (MRI) was used to observe growth of the mandibular condyle, mandibular fossa, and articular disc as a single unit. Changes in each component's relative position and size were observed using 7-tesla MRI. Mandibular condyle chondrocytes' growth was evaluated with immunohistochemistry, using the expression of zinc transporter ZIP13. Three-dimensional T1-weighted (T1w) MRI was used to obtain images of the TMJ of Sprague Dawley rats at 4-78 days old (P4-78) with a voxel resolution of 65 μm. Two-dimensional T1w MR images were acquired after a subcutaneous injection of the contrast reagent gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA). The T1w MR images showed that the mandibular condyle was located posterior to the mandibular fossa until P20; however, it then moved to a location underneath the mandibular fossa. In the Gd-DTPA enhanced images, the articular disc was identified as a region with lower signal intensity from P20. The number of ZIP13-positive chondrocytes at P6 was larger than the number at P24. In conclusion, the mandibular condyle with cartilage and disc grows on the posterior side of the mandibular fossa until P20, which was the weaning age. Then, the condyle fit into the mandibular fossa and completed the functional unit.

Dynamic contrast-enhanced MRI of brown and beige adipose tissues.

The vascular blood flow in brown adipose tissue (BAT) is important for handling triglyceride clearance, increased blood flow and oxygenation. We used dynamic contrast-enhanced (DCE)-MRI and fat fraction (FF) imaging for investigating vascular perfusion kinetics in brown and beige adipose tissues with cold exposure or treatment with β3-adrenergic agonist. FF imaging and DCE-MRI using gadolinium-diethylenetriaminepentaacetic acid were performed in interscapular BAT (iBAT) and beige tissues using male Wister rats (n = 38). Imaging was performed at thermoneutral condition and with either cold exposure, treatment with pharmacological agent CL-316,243, or saline. DCE-MRI and FF data were co-registered to enhance the understanding of metabolic activity. Uptake of contrast agent in activated iBAT and beige tissues were significantly (P < .05) higher than nonactivated iBAT. The Ktrans and kep increased significantly in iBAT and beige tissues after treatment with either cold exposure or β3-adrenergic agonist. The FF decreased in activated iBAT and beige tissues. The Ktrans and FF from iBAT and beige tissues were inversely correlated (r = 0.97; r = 0.94). Significant increase in vascular endothelial growth factor expression and Ktrans in activated iBAT and beige tissues were in agreement with the increased vasculature and vascular perfusion kinetics. The iBAT and beige tissues were validated by measuring molecular markers. Increased Ktrans and decreased FF in iBAT and beige tissues were in agreement with the vascular perfusion kinetics facilitating the clearance of free fatty acids. The methodology can be extended for the screening of browning agents.

The Role of Endolymphatic Hydrops in Patients with Pantonal Idiopathic Sudden Sensorineural Hearing Loss: A Cause or Secondary Reaction

The purpose of this study was to investigate the presence of endolymphatic hydrops (EH) in both affected and unaffected ears of patients with pantonal unilateral idiopathic sudden sensorineural hearing loss (ISSNHL) using three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging (3D-FLAIR MRI) and further evaluate the significance of EH in this disorder. Twenty-seven ISSHL patients were enrolled in this study. 3D-FLAIR MRI was performed 24 h after intratympanic injection of gadolinium-diethylenetriaminepentaacetic acid (Gd-DPTA). The incidences of EH in the affected ears and contralateral unaffected ears were compared and the correlations of EH with vertigo or prognosis were analyzed using the Chi-square test. The results showed that the incidence of EH was 68.0% (17/25) in the affected ears and 34.8% (8/23) in the unaffected ears. There was a statistically significant difference between affected ears and unaffected ears in regard to the incidence of EH (P&lt;0.05). There were no significant correlations of EH with vertigo (P=1.000) or with prognosis (P=0.359) in the affected ears. In conclusion, there is EH in the inner ear of patients with pantonal ISSNHL; EH is not related to vertigo, a concomitant symptom of ISSNHL, and the prognosis of this condition. The presence of EH may be a secondary reaction following the impairment of the inner ears with pantonal ISSNHL.

Accuracy of Tumor Perfusion Assessment in Rat C6 Gliomas Model with USPIO.

Detailed characterization of the permeability and vascular volume of brain tumor vasculature can provide essential insights into tumor physiology. In this study, we evaluated the consistency of measurements in tumor blood volume and examined the feasibility of using ultrasmall superparamagnetic iron oxide (USPIO) versus gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) as contrast agents for MR perfusion imaging of brain gliomas in C6 Rats. Eighteen rats were intracerebrally implanted with C6 glioma cells, randomly divided into two groups and examined by 3.0T perfusion MR imaging with Gd-DTPA and USPIO. Tumor relative cerebral blood volume (rCBV) and relative maximum signal reduction ratio (rSRRmax) were created based on analysis of MR perfusion images. The mean values for rCBV were 2.09 and 1.57 in the USPIO and the Gd-DTPA groups, respectively, and rSRRmax values were 1.92 and 1.02 in the USPIO and the Gd-DTPA groups, respectively, showing signifi cant differences in both rCBV and rSRRmax between the USPIO and the Gd-DTPA groups (P < 0.05). The results showed that early vascular leakage occurred with gadolinium rather than USPIO in perfusion assessment, revealing that USPIO was useful in perfusion MR imaging for the assessment of tumor vasculature.

Polymeric Hybrid Nanomicelles for Cancer Theranostics: An Efficient and Precise Anticancer Strategy for the Codelivery of Doxorubicin/miR-34a and Magnetic Resonance Imaging.

To realize precise tumor therapy, a versatile oncotherapy nanoplatform integrating both diagnostic and therapeutic functions is necessary. Herein, we fabricated a hybrid micelle (HM) utilizing two amphiphilic diblock copolymers, polyethylenimine-polycaprolactone (PEI-PCL) and diethylenetriaminepentaacetic acid gadolinium(III) (Gd-DTPA)-conjugated polyethyleneglycol-polycaprolactone (Gd-PEG-PCL), to codeliver the small-molecule chemotherapy drugs doxorubicin (Dox) and microRNA-34a (miR-34a), denoted as Gd-HM-Dox/34a. Conjugating Gd-DTPA on the surface of hybrid micelles, leading the relaxation rate of Gd-DTPA increased more than 1.4 times (13.6 mM-1 S-1). Furthermore, hybrid micelles enhanced the ability of miR-34a to escape from lysosomes/endosomes and Dox release to the nucleus. In addition, the released miR-34a subsequently downregulates Bcl-2, cyclin D1, CDK6, and Bax expression and inhibits proliferation and migration of MDA-MB-231 breast cancer cells. Moreover, the suitable micelle size improved the penetration of Dox into three-dimensional (3D) multicellular spheroids compared with Gd-HM-Dox and Free Dox, generating efficient cell killing in the 3D multicellular spheroids. Furthermore, the Gd-HM-Dox/34a exhibited augmented accumulation in the tumor tissue, which improved the magnetic resonance (MR) imaging contrast of solid tumors and enhanced the combined efficiency of chemotherapeutic drugs Dox and therapeutic gene miR-34a in suppressing tumor growth on MDA-MB-231 tumor-bearing mice. Therefore, we established a hybrid micelle to offer a promising theranostic approach that inhibits tumor growth and enhances MR imaging.

Engineering the surface of Gd2O3 nanoplates for improved T1-weighted magnetic resonance imaging

The oleic acid (OA) and oleylamine (OM)-capped Gd2O3 nanoplates were encapsulated into N-Dodecyl-PEI-PEG polymer to synthesize the hydrophilic clusters for T1-weighted magnetic resonance imaging (MRI). The obtained Gd2O3@N-Dodecyl-PEI-PEG clusters showed a hydrodynamic size of 95 nm and a r1 value of 14.13 mM−1 s−1, which was approximately 4 times greater than that of the commercial product gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) (r1 = 3.40 mM−1 s−1). The in vitro toxicity demonstrated that the obtained clusters were biocompatible. The MRI experiments on SCC-7 cells/xenograft tumors indicated that the clusters had obvious T1-enhancement ability. These clusters have great potential application as T1-weighted MRI contrast agents.

Convection-Enhanced Delivery of Muscimol Into the Bilateral Subthalamic Nuclei of Nonhuman Primates.

Muscimol is a gamma-aminobutyric acid receptor agonist that selectively and temporarily inhibits neurons. Local bolus injection of muscimol has been used experimentally to inhibit neuronal populations within discrete anatomical structures and discern their physiological function. To determine the safety and behavioral effects of convection-enhanced delivery of muscimol into the bilateral subthalamic nuclei (STN) of nonhuman primate rhesus macaques (NHPs). Six awake NHPs underwent co-infusion of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), a surrogate magnetic resonance imaging (MRI) tracer, with increasing concentrations of muscimol for behavioral and histological assessment. Three other NHPs were co-infused with Gd-DTPA and 3H-muscimol into the STN to determine muscimol distribution by MRI and autoradiography. Two NHPs underwent microcatheter implantation without muscimol infusion for control comparison. MRI revealed selective and complete perfusion of the bilateral STN in animals infused with Gd-DTPA and muscimol. No abnormal movements occurred at 0.125 mM. Muscimol doses between 0.25 and 4.4 mM resulted in transient, dose-dependent hyperkinesia. Muscimol (8.8 mM) resulted in severe bilateral dyskinesias, ballistic movements, and sedation. An 88.8 mM dose produced unresponsiveness in 1 animal. Infusion-related pathological abnormities or toxicity was not present on histological examination. MRI distribution of co-infused Gd-DTPA was similar to autoradiographic distribution of 3H-muscimol (Vd; R=0.94). Mean Vd of infused animals was 37.9 mm3±11.7 mm3 and mean Vd: Vi 7.6±2.3. Bilateral convection-enhanced delivery of muscimol into the primate STN resulted in dose-related hyperkinetic movements that resolved after stopping the infusion. Muscimol was not toxic to brain tissue. Gd-DTPA accurately tracked muscimol distribution.