Sophie Gaillard

In Vivo Imaging of Carbon Nanotube Biodistribution Using Magnetic Resonance Imaging

As novel engineered nanoparticles such as carbon nanotubes (CNTs) are extensively used in nanotechnology due to their superior properties, it becomes critical to fully understand their biodistribution and effect when accidently inhaled. A noninvasive follow-up study would be beneficial to evaluate the biodistribution and effect of nanotube deposition after exposure directly in vivo. Combined helium-3 and proton magnetic resonance resonance (MRI) were used in a rat model to evaluate the biodistribution and biological impact of raw single-wall CNTs (raw-SWCNTs) and superpurified SWCNTs (SP-SWCNTs). The susceptibility effects induced by metal impurity in the intrapulmonary instilled raw-SWCNT samples were large enough to induce a significant drop in magnetic field homogeneity detected in 3He MR image acquired under spontaneous breathing conditions using a multiecho radial sequence. No MRI susceptibility variation was observed with SP-SWCNT exposition even though histological analysis confirmed their presence in instilled lungs. Proton MRI allowed detection of intravenously injected raw-SWCNTs in spleen and kidneys using gradient echo sequence sensitive to changes of relaxation time values. No signal modifications were observed in the SP-SWCNT injected group. In instilled groups, the contrast-to-noise ratio in liver, spleen, and kidneys stayed unchanged and were comparable to values obtained in the control group. Histological analysis confirms the absence of SWCNTs in systemic organs when SWCNTs were intrapulmonary instilled. In conclusion, the presence of SWCNTs with associated metal impurities can be detected in vivo by noninvasive MR techniques. Hyperpolarized 3He can be used for the investigation of CNT pulmonary biodistribution while standard proton MR can be performed for systemic investigation following injection of CNT solution.

Safety and Tolerability of Ultrasmall Superparamagnetic Iron Oxide Contrast Agent: Comprehensive Analysis of a Clinical Development Program

Background:Because of its cellular uptake pattern, ferumoxtran-10 may be potentially useful for the imaging of a variety of diseases (eg, atheroma, multiple sclerosis, stroke, renal graft rejection, glomerulonephritis and brain tumors, in addition to differentiation of metastatic and nonmetastatic lymph nodes). The aim of this article is to present a comprehensive review of the safety and tolerability of ferumoxtran-10 as reported during clinical development of the compound as an ultrasmall superparamagnetic iron oxide contrast agent for use in magnetic resonance imaging. Materials and Methods:The safety profile of ferumoxtran-10 was assessed using pooled data from 37 phase I to III clinical studies in 1777 adults (1663 received the contrast agent [1527 patients and 136 healthy volunteers], 75 received placebo, and 39 patients were enrolled but did not receive study medication). Results:At least one adverse event was reported in 23.2% of patients who received ferumoxtran-10. Adverse events were of mild-to-moderate severity in 86.3% of patients in the ferumoxtran-10 group. At least 1 event considered by the investigator to be related to study treatment was reported in 18.2% of patients in the ferumoxtran-10 group. The most commonly reported treatment-related adverse events were back pain, pruritus, headache, and urticaria. A total of 44 patients (2.6%) in the ferumoxtran-10 group reported 76 serious adverse event (SAE). Only 7 SAEs (0.42%) were considered to be treatment-related (anaphylactic shock, chest pain, dyspnea, skin rash, oxygen saturation decreased, and 2 cases of hypotension). There were 12 deaths, only one of which (anaphylactic shock) was considered to be related to ferumoxtran-10 which was administered by bolus injection of undiluted product, a mode of administration that is no longer recommended. Results in high-risk groups of patients including the elderly and those with hepatic, renal or cardiovascular disease seemed to show no cause for special clinical concern in these groups. Conclusions:Clinical experience to date therefore shows ferumoxtran-10 to be a well tolerated contrast agent.

Hyperpolarized 3He MR for Sensitive Imaging of Ventilation Function and Treatment Efficiency in Young Cystic Fibrosis Patients with Normal Lung Function

PURPOSE To assess the sensitivity of hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging for the detection of peripheral airway obstruction in younger cystic fibrosis (CF) patients showing normal spirometric results (mean forced expiratory volume in 1 second [FEV(1)], 112% +/- 14.5 [standard deviation]) and to observe the immediate effects of a single chest physical therapy (CPT) session, thereby comparing two image quantification techniques. MATERIALS AND METHODS Ten pediatric CF patients (age range, 8-16 years) with normal spirometric results were included in this study after approval from the local research ethics committee. Spirometry followed by proton and hyperpolarized (3)He three-dimensional lung imaging were performed with a 1.5-T MR unit before and after 20 minutes of CPT. The number of ventilation defects per image (VDI) and the ventilated lung fraction (VF), defined as the ratio of ventilated lung volume divided by total lung volume, were quantified. RESULTS Ventilation defects were found in all patients (mean VDI, 5.1 +/- 1.9; mean global VF, 78.5% +/- 12.3; and mean peripheral VF, 75.5% +/- 17.1) despite normal spirometric results. After CPT, disparate changes in the distribution of ventilation defects were observed but the average VDI and VF did not change significantly (mean VDI, 5.1 +/- 1.1; mean global VF, 83.5% +/- 12.2; and mean peripheral VF, 80.3% +/- 12.2). There was no correlation between FEV(1) and VDI (rho = -0.041, P = .863) or global VF (rho = -0.196, P = .408) values but peripheral VF and VDI were correlated (rho = -0.563, P = .011). CONCLUSION Although spirometric results indicate normal lung function, the mean VDI in patients (5.1) found in this study is well above the VDI in healthy subjects (1.6) reported in the literature. A single CPT session induces disparate changes in the distribution and extent of ventilation defects.

Cardiovascular safety of gadoterate meglumine (Gd-DOTA)

Objectives:Gadolinium complexes are not considered to be a drug class at high risk for prolonging cardiac repolarization, which can lead to potentially life-threatening arrhythmias such as torsade de pointes. However, only limited robust data are available on these compounds despite their extensive use as contrast enhancers in magnetic resonance imaging. We present an overview of recent cardiovascular safety data obtained on gadoterate meglumine (Gd-DOTA). Materials and Methods:Cardiovascular safety was evaluated by “state-of-the-art” nonclinical ex vitro (dog Purkinje fibers) and in vivo studies in both normal (dogs) and sensitized animal models (rabbits) and in patients with various diseases in a specific clinical trial. Results:In all of these studies, Gd-DOTA did not show any direct deleterious effect on cardiac electrophysiology and especially on ventricular repolarization. Conclusion:These results confirmed the good safety profile of Gd-DOTA derived from postmarketing evaluations. Nonspecific gadolinium complexes used for magnetic resonance contrast enhancement do not constitute a class-at-risk for drug-related arrhythmias.

Longitudinal 3He and proton imaging of magnetite biodistribution in a rat model of instilled nanoparticles

Epidemiological and toxicological studies have provided evidence that accidentally inhaled nanosize ultrafine particles can induce chronic or acute health damage. MRI, being noninvasive, is able to assess the biodistribution and clearance of magnetically labeled nanoparticles induced by instillation or inhalation. We report 3He and proton MRI follow‐up of lung, liver, spleen, and kidney distribution of USPIO (ultrasmall superparamagnetic iron oxide) in a rat model. The sensitivity of the imaging technique to various concentrations of instilled magnetite suspension was first assessed in vivo (n = 12). A 2‐week longitudinal imaging study was then performed on animals (n = 7) instilled with a 0.5 mg magnetite solution. Hypointense and void signal regions associated with intrapulmonary USPIO were observed in the 3He ventilation images throughout the study, whereas no USPIO‐related proton signal intensity changes were found. Intrapulmonary magnetite nanoparticle confinement was confirmed by ex vivo iron assay and histological analysis. This study demonstrates that combined 3He and proton MRI enables noninvasive assessment of the distribution and clearance of magnetically labeled instilled nanoparticles. Magn Reson Med 59:1298–1303, 2008.

Free breathing hyperpolarized 3He lung ventilation spiral MR imaging.

Objectives:Current clinical hyperpolarized 3He lung ventilation MR imaging protocols rely on the patients ability to control inhalation and exhalation and hold their breath on demand. This is impractical for intensive care unit patients under ventilation or for pediatric populations under the age of 3 to 4 years. To address this problem, we propose a free-breathing protocol for hyperpolarized 3He lung ventilation spiral imaging. This approach was evaluated in vitro and on rabbits. Materials and Methods:The protocol was implemented on a clinical 1.5-T magnetic resonance imaging scanner. Ventilation images were acquired using a spiral sequence, in vitro on a lung phantom and in vivo on rabbits, the animal breathing freely from a gas reservoir. Dynamic spiral ventilation images were reconstructed using retrospective Cine synchronization. Magnetic resonance (MR) signal dynamics was modeled taking account of gas inflow and outflow, radiofrequency depolarization and oxygen-induced relaxation. Results:Cine ventilation images acquired in spontaneously breathing rabbits were reconstructed with a temporal resolution of 50 milliseconds. Gas volume variations and time-to-maximum maps were obtained. The numerical model was validated in vitro and in vivo with various gas mixtures. Ventilation parameters (functional residual capacity, tidal volume, and alveolar pO2) were extracted from the MR signal dynamics. Conclusions:Ventilation imaging can be performed at tidal volume using a simple experimental protocol, without any ventilation device or breath-hold period. Acquisition time, SNR and pO2 decay can be optimized using the developed numerical model. Free-breathing ventilation images can be obtained without artifacts related to motion or gas flow. Lastly, parametric maps can be derived from the time-resolved ventilation images and physiological parameters extracted from the global signal dynamics.

Hepatic lentiviral gene transfer prevents the long-term onset of hepatic tumours of glycogen storage disease type 1a in mice

Glycogen storage disease type 1a (GSD1a) is a rare disease due to the deficiency in the glucose-6-phosphatase (G6Pase) catalytic subunit (encoded by G6pc), which is essential for endogenous glucose production. Despite strict diet control to maintain blood glucose, patients with GSD1a develop hepatomegaly, steatosis and then hepatocellular adenomas (HCA), which can undergo malignant transformation. Recently, gene therapy has attracted attention as a potential treatment for GSD1a. In order to maintain long-term transgene expression, we developed an HIV-based vector, which allowed us to specifically express the human G6PC cDNA in the liver. We analysed the efficiency of this lentiviral vector in the prevention of the development of the hepatic disease in an original GSD1a mouse model, which exhibits G6Pase deficiency exclusively in the liver (L-G6pc(-/-) mice). Recombinant lentivirus were injected in B6.G6pc(ex3lox/ex3lox). SA(creERT2/w) neonates and G6pc deletion was induced by tamoxifen treatment at weaning. Magnetic resonance imaging was then performed to follow up the development of hepatic tumours. Lentiviral gene therapy restored glucose-6 phosphatase activity sufficient to correct fasting hypoglycaemia during 9 months. Moreover, lentivirus-treated L-G6pc(-/-) mice presented normal hepatic triglyceride levels, whereas untreated mice developed steatosis. Glycogen stores were also decreased although liver weight remained high. Interestingly, lentivirus-treated L-G6pc(-/-) mice were protected against the development of hepatic tumours after 9 months of gene therapy while most of untreated L-G6pc(-/-) mice developed millimetric HCA. Thus the treatment of newborns by recombinant lentivirus appears as an attractive approach to protect the liver from the development of steatosis and hepatic tumours associated to GSD1a pathology.

Highly constrained backprojection for improving dynamic 3He MR ventilation imaging in rats

The highly constrained backprojection algorithm (HYPR) has recently been shown to allow accelerated acquisition in various fields of MRI, including angiography, perfusion and diffusion imaging as well as hyperpolarized gas imaging. Increase in temporal resolution is of particular interest in the case of small animal ventilation imaging due to the high respiration rate. In the present study, the two-dimensional HYPR technique and its iterative version (I-HYPR) were applied to (3)He ventilation imaging in rats. Two imaging protocols were used for two separate groups of animals. A single inspiration protocol consisted of (3)He imaging of the lungs during gas inflow and a following apnea. A multiple inspiration protocol involved spontaneous breathing of (3)He contained in a gas reservoir. Series of HYPR frames with four-fold increase in the temporal resolution were obtained in the case of the single inspiration experiment. For the multiple inspiration protocol, series of HYPR images corresponding to four different echo times were obtained and were used to reconstruct T(2)(*) maps at the inspiration and the expiration phases of the breathing cycle. The feasibility of using the two-dimensional HYPR technique for different (3)He ventilation protocols in small animals is demonstrated. Image quality and signal kinetics representations are compared for two variants of the HYPR algorithm.