Magnetic Resonance Imaging Tracer Research Articles

Greatly improved neuroprotective efficiency of citicoline by stereotactic delivery in treatment of ischemic injury

Limited penetration of neuroprotective drug citicoline into the central nervous system (CNS) by systemic administration led to poor efficiency. A novel method of stereotactic drug delivery was explored to make citicoline bypass the blood brain barrier (BBB) and take effect by direct contact with ischemic neurons. A permanent middle cerebral artery occlusion (pMCAO) model of rats was prepared. To get the optimal conditions for citicoline administration by the novel stereotactic delivery pathway, magnetic resonance imaging (MRI) tracer method was used, and a dose-dependent effect was given. Examinations of MRI, behavior evaluation, infarct volume assessment and histological staining were performed to evaluate the outcome. This MRI-guided stereotactic delivery of citicoline resulted in a notable reduction (>80%) in infarct size and a delayed ischemic injury in cortex 12 hours after onset of acute ischemia when compared with the systematic delivery. The improved neuroprotective efficiency was realized by a full distribution of citicoline in most of middle cerebral artery (MCA) territory and an adequate drug reaction in the involved areas of the brain. Brain lesions of treated rats by stereotactic delivery of citicoline were well predicted in the lateral ventricle and thalamus due to a limited drug deposition by MRI tracer method. Our study realized an improved neuroprotective efficiency of citicoline by stereotactic delivery, and an optimal therapeutic effect of this administration pathway can be achieved under MRI guidance.

Abstract LB-293: Perfluorocarbon labeling of human α-type-1-polarized dendritic cells and conventional dendritic cells for in vivo trafficking by fluorine MRI

Abstract Human dendritic cells (DC) have yet to live up to their clinical promise as an immunotherapeutic intervention against cancer, in spite of their in vitro profiles of their ability to effectively prime tumor-specific T cell responses. It is still unclear which is the best route of administration for the most efficient interaction of DC with tumor-specific T cells in patients, and whether the migratory capacity and localization of DC in patients correlates with clinical responsiveness. Here we utilize a perfluorocarbon (PFC) magnetic resonance imaging (MRI) tracer agent which may enable the assessment of the migration and localization of α-type-1-polarized dendritic cells (αDC1) in the clinic. αDC1 producing high levels of interleukin-12p70 with putative strong lymph node homing capabilities, are currently being evaluated clinically for anti-cancer activity. In vivo results demonstrate the capability of 19F MRI to detect and quantify labeled cells with moderate sensitivity, detecting fewer than 1×104 cells per voxel. The lack of endogenous fluorine in the body allows highly-specific 19F MR detection of label and when paired with proton MRI provides clear and quantitative cell localization within their anatomical context. The inertness of this tracking agent on the functional capacity of DC was examined in a panel of in vitro studies. The use of the MRI tracer with both conventional DC and αDC1 indicated similar labeling efficiencies with no observed effect on the DC's ability to stimulate T cell expansion, produce IL-12p70, process antigen or express co-stimulatory and polarizing factors. These data support the clinical translation of this tracer agent to safely track and quantify the administration and migration of human αDC1 by non-invasive 19F MRI in the treatment of cancer patients. An imminent clinical trial of PFC-labeled αDC1 will provide cell tracking data in patients, facilitating advances in greater efficacy in the next generation of DC-based cellular vaccines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-293. doi:10.1158/1538-7445.AM2011-LB-293

Evaluation of cellular therapies utilizing a fluorine-based magnetic resonance imaging (MRI) tracer agent (131.40)

Abstract Natural killer cells (NK), T cells and dendritic cells (DC) are increasingly being used in the clinic to adjust patient immune function in response to cancer. One of the current limitations of such therapies is the inability to track the therapeutic cells once they are administered to a patient. Here we utilize a novel, non-radioactive fluorine-based (19F) MRI tracer agent to label clinically relevant cells ex-vivo and to non-invasively detect the transferred cells in vivo over time. We demonstrate that human NK, T cells and DC (immature and mature) can be effectively labeled without effect on their health, phenotype or function. Using a murine xenograft model as a pre-clinical “proof of principle” assay, we visualized and tracked the migration of human DC in-vivo. Following injection, the 19F labeled cells were detected and anatomically located by MRI. Mature DC but not immature DC were observed to migrate into the region of draining lymph nodes 18h post injection by MRI. Isolation and flow cytometric analysis of cells from draining lymph nodes confirmed the presence of human DC as well as the efficacy of this method. The application of this tracer agent across several cell types, along with non-invasive highly specific detection of 19F labeled cells by MRI, demonstrates the potential use of 19F in translational and clinical applications of cellular therapies. Ultimately, this technology may expedite a therapy’s transition from bench to bedside.

Real-time, Image-Guided, Convection-Enhanced Delivery of Interleukin 13 Bound to Pseudomonas Exotoxin

To determine if the tumor-targeted cytotoxin interleukin 13 bound to Pseudomonas exotoxin (IL13-PE) could be delivered to the brainstem safely at therapeutic doses while monitoring its distribution in real-time using a surrogate magnetic resonance imaging tracer, we used convection-enhanced delivery to perfuse rat and primate brainstems with IL13-PE and gadolinium-bound albumin (Gd-albumin). Thirty rats underwent convective brainstem perfusion of IL13-PE (0.25, 0.5, or 10 microg/mL) or vehicle. Twelve primates underwent convective brainstem perfusion of either IL13-PE (0.25, 0.5, or 10 microg/mL; n = 8), co-infusion of 125I-IL13-PE and Gd-albumin (n = 2), or co-infusion of IL13-PE (0.5 microg/mL) and Gd-albumin (n = 2). The animals were permitted to survive for up to 28 days before sacrifice and histologic assessment. Rats showed no evidence of toxicity at all doses. Primates showed no toxicity at 0.25 or 0.5 microg/mL but showed clinical and histologic toxicity at 10 microg/mL. Quantitative autoradiography confirmed that Gd-albumin precisely tracked IL13-PE anatomic distribution and accurately showed the volume of distribution. IL13-PE can be delivered safely and effectively to the primate brainstem at therapeutic concentrations and over clinically relevant volumes using convection-enhanced delivery. Moreover, the distribution of IL13-PE can be accurately tracked by co-infusion of Gd-albumin using real-time magnetic resonance imaging.

Radiation improves the distribution and uptake of liposomal doxorubicin (caelyx) in human osteosarcoma xenografts.

Liposomal drug delivery appears to improve the antitumor effect and reduce toxicity compared with the free drug. The therapeutic index may be improved further by combining cytotoxic drugs and radiotherapy. Successful therapy requires that the cytotoxic agents reach the tumor cells. Therefore, we studied tumor growth and the microdistribution of liposomal doxorubicin (Caelyx) with and without additional ionizing radiation in human osteosarcoma xenografts in athymic mice. Caelyx was injected i.v. 1 day before single or fractionated radiotherapy. Both chemoirradiation regimens induced significant tumor growth delays and worked synergistically. Confocal laser scanning microscopy showed that intact liposomes were located in close proximity to endothelial cells, and the distribution of released doxorubicin was heterogeneous. Before radiotherapy, hardly any doxorubicin was localized in the central parts of the tumor. Radiotherapy increased the tumor uptake of doxorubicin by a factor of two to four, with drug being redistributed farther from the vessels in the tumor periphery and located around vessels in the central parts of the tumor. Colocalization of doxorubicin and hypoxic cells showed no distribution of drug into hypoxic areas. Dynamic contrast-enhanced magnetic resonance imaging (MRI) 1 day before the injection of Caelyx and 2 days after treatment start showed that the combined treatment reduced the vascular volume and the vascular transfer rate of the MRI tracer. The results show that chemoirradiation with Caelyx induces synergistic treatment effects. Improved intratumoral drug uptake and distribution are responsible to some extent for the enhanced antitumor effect.

MRI measurement of blood-brain barrier permeability following spontaneous reperfusion in the starch microsphere model of ischemia

Quantification of the acute increases in blood-brain barrier (BBB) permeability that occur subsequent to experimental ischemic injury has been limited to single time-point, invasive methodologies. Although permeability can be qualitatively assessed to visualise regional changes during sequential studies on the same animal using contrast-enhanced magnetic resonance imaging (MRI), quantitative information on the magnitude of change is required to compare barrier function during sequential studies on the same animal or between different animals. Recently, improvements in MRI tracer kinetic models and in MR hardware design mean that an estimate of permeability in vivo can now be obtained with acceptable accuracy and precision. We report here the use of such methods to study acute changes following spontaneous reperfusion in an animal model of ischemia. We have obtained estimates of BBB permeability following spontaneous reperfusion, subsequent to forebrain ischemia by unilateral carotid injection of starch microspheres in the rat. T2∗-weighted and diffusion-trace imaging were used to monitor the initial reduction in CBF and the time-course of ischemia, respectively. Following reperfusion, an intraveneous bolus of dimeglumine gadopentetate (Gd-DTPA) and horseradish peroxidase (HRP) was given during a continuous acquisition of T1 maps with a 48s temporal resolution. Permeability maps were constructed using a 4-compartment model; K trans, the permeability-surface area product of the capillary walls was estimated to be 9.2 ± 0.6 × 10 −4 min −1 in the cortex. Visualisation of the regional extent of HRP extravasation on histological sections following termination of the experiment demonstrated very little correspondence to the region of Gd-DTPA leakage. Quantitative MRI assessment of BBB permeability following ischemia-reperfusion is consistent with published values obtained by invasive methods. Differences between Gd-DTPA-enhancement and HRP may reflect differences in the molecular size of the tracers.