The new functionalized trimetallic nitride endohedral metallofullerene species Gd(3)N@C(80)[DiPEG5000(OH)(x)] is an effective proton relaxation agent, as demonstrated with in vitro relaxivity and MR imaging studies, in infusion experiments with agarose gel and in vivo rat brain studies simulating clinical conditions of direct intraparenchymal drug delivery for the treatment of brain tumors.

The contribution of brain edema to brain swelling in cases of traumatic brain injury remains a critical problem. The authors believe that cellular edema, the result of complex neurotoxic events, is the major contributor to brain swelling and that vasogenic edema, secondary to blood-brain barrier compromise, may be overemphasized. The objective of this study, therefore, was to quantify temporal water content changes and document the type of edema that forms during the acute and late stages of edema development following closed head injury (CHI). The measurement of brain water content was based on magnetic resonance imaging-determined values of tissue longitudinal relaxation time (T1-weighted imaging) and their subsequent conversion to percentage of water, whereas the differentiation of edema formation (cellular vs. vasogenic) was based on the measurement of the apparent diffusion coefficient (ADC) by diffusion-weighted imaging. A new impact-acceleration model was used to induce CHI. Thirty-six adult Sprague-Dawley rats were separated into two groups: Group I, control (six animals); and Group II, trauma (30 animals). Fast ADC measurements (localized, single-voxel) were obtained sequentially (every minute) up to 1 hour postinjury. The T1-weighted images, used for water content determination, and the diffusion-weighted images (ADC measurement with conventional diffusion-weighted imaging) were obtained at the end of the 1st hour postinjury and on Days 1, 3, 7, 14, 28, and 42 in animals from the trauma and control groups. In the animals subjected to trauma, the authors found a significant increase in ADC (10 +/- 5%) and brain water content (1.3 +/- 0.9%) during the first 60 minutes postinjury. This is consistent with an increase in the volume of extracellular fluid and vasogenic edema formation as a result of blood-brain barrier compromise. This transient increase, however, was followed by a continuing decrease in ADC that began 40 to 60 minutes postinjury and reached a minimum value on Days 7 to 14 (10 +/- 3% reduction). Because the water content of the brain continued to increase during the first 24 hours postinjury (1.9 +/- 0.9%), it is suggested that the decreased ADC indicated cellular edema formation, which started to develop soon after injury and became dominant between 1 and 2 weeks postinjury. The study provides supportive evidence that cellular edema is the major contributor to posttraumatic swelling in diffuse CHI and defines the onset and duration of the increase in cellular volume.

Agarose gel (0.6%) is a useful surrogate for in vivo brain in exploratory studies of convection-enhanced delivery.

A new magnetic resonance imaging (MRI) contrast agent based on the trimetallic nitride templated (TNT) metallofullerene, Gd 3 N@C 80 , was synthesized by a facile method in high yield. The observed longitudinal and transverse relaxivities, r 1 and r 2 , for water hydrogens in the presence of the watersoluble gadofullerene 2, Gd 3 N@C 80 (OH)~2 6 (CH 2 CH 2 COOM)~1 6 (M = Na or H), are 207 and 282 mM -1 s -1 (per C 80 cage) at 2.4 T, respectively; these values are 50 times larger than those of Gd 3+ poly(aminocarboxylate) complexes, such as commercial Omniscan ® and Magnevist ® . This high 1 H relaxivity for this new hydroxylated and carboxylated gadofullerene derivative provides high signal enhancement at significantly lower Gd concentration as demonstrated by in vitro and in vivo MRI studies. Dynamic light scattering data reveal a unimodal size distribution with an average hydrodynamic radius of ca. 78 nm in pure water (pH = 7), which is significantly different from other hydroxylated or carboxylated fullerene and metallofullerene derivatives reported to date. Agarose gel infusion results indicate that the gadofullerene 2 displayed diffusion properties different from that of commercial Omniscan ® and those of PEG5000 modified Gd 3 N@C 80 . The reactive carboxyl functionality present on this highly efficient contrast agent may also serve as a precursor for biomarker tissue-targeting purposes.

The objective of this study was to use diffusion-weighted magnetic resonance imaging (DWI) to help detect the type of edema that develops after experimental trauma and trauma coupled with hypotension and hypoxia (THH). Reduction in the apparent diffusion coefficients (ADCs) is thought to represent cytotoxic edema. In a preliminary series of experiments, the infusion edema model and middle cerebral artery occlusion models were used to confirm the direction of ADC change in response to purely extracellular and cytotoxic edema, respectively. The ADCs increased (p<0.05) in the case of extracellular edema and decreased (p<0.001) in cytotoxic edema. Following these initial experiments, a new impact acceleration model was used to induce traumatic brain injury. Thirty-six adult Sprague-Dawley rats were separated into four groups; sham, trauma alone, hypoxia and hypotension (HH), and THH. Following trauma, a 30-minute insult of hypoxia (PaO2 of 40 mm Hg) and hypotension (mean arterial blood pressure (MABP) of 30 mm Hg) were imposed and the animals were resuscitated. The DWI was carried out at four 1-hour intervals postinjury, and MABP, intracranial pressure (ICP), cerebral perfusion pressure (CPP), and cerebral blood flow (CBF) were monitored. The ADCs in the control and HH groups remained unchanged. The ADCs in the THH group rapidly decreased from a control level of 0.68 +/- 0.05 x 10(-3) mm2/second to 0.37 +/- 0.09 x 10(-3) mm2/second by 3 hours posttrauma (p < 0.001). In this group, the decreased CBF and CPP during secondary insult remained low despite resuscitation, with the ICP increasing to 56 +/- 7 mm Hg by 3 hours. In the trauma alone group, the rise in ICP reached a maximum value (28 +/- 3 mm Hg) at 30 minutes with a significant and sustained increase in CBF despite a gradual decrease in CPP. The ADCs in this group were not significantly reduced. The data lead the authors to suggest that the rise in ICP following severe trauma coupled with secondary insult in this model is predominately caused by cytotoxic edema and that ischemia plays a major role in the development of brain edema after head injury.

The water soluble poly(ethylene glycol) (PEG) functionalized and hydroxylated endohedral trimetallic nitride metallofullerene derivatives, Gd 3 N@C 80 [DiPEG(OH)

These studies demonstrate that IL-13 peptide-conjugated gadolinium metallofullerenes could serve as a platform to deliver imaging and therapeutic agents to tumor cells.

The authors posit that cellular edema is the major contributor to brain swelling in diffuse head injury and that the contribution of vasogenic edema may be overemphasized. The objective of this study was to determine the early time course of blood-brain barrier (BBB) changes in diffuse closed head injury and to what extent barrier permeability is affected by the secondary insults of hypoxia and hypotension. The BBB disruption was quantified and visualized using T1-weighted magnetic resonance (MR) imaging following intravenous administration of the MR contrast agent gadolinium-diethylenetriamine pentaacetic acid. To avoid the effect of blood volume changes, the maximum signal intensity (SI) enhancement was used to calculate the difference in BBB disruption. A new impact-acceleration model was used to induce closed head injury. Forty-five adult Sprague-Dawley rats were separated into four groups: Group I, sham operated (four animals), Group II, hypoxia and hypotension (four animals), Group III, trauma only (23 animals), and Group IV, trauma coupled with hypoxia and hypotension (14 animals). After trauma was induced, a 30-minute insult of hypoxia (PaO2 40 mm Hg) and hypotension (mean arterial blood pressure 30 mm Hg) was imposed, after which the animals were resuscitated. In the trauma-induced animals, the SI increased dramatically immediately after impact. By 15 minutes permeability decreased exponentially and by 30 minutes it was equal to that of control animals. When trauma was coupled with secondary insult, the SI enhancement was lower after the trauma, consistent with reduced blood pressure and blood flow. However, the SI increased dramatically on reperfusion and was equal to that of control by 60 minutes after the combined insult. In conclusion, the authors suggest that closed head injury is associated with a rapid and transient BBB opening that begins at the time of the trauma and lasts no more than 30 minutes. It has also been shown that addition of posttraumatic secondary insult-hypoxia and hypotension-prolongs the time of BBB breakdown after closed head injury. The authors further conclude that MR imaging is an excellent technique to follow (time resolution 1-1.5 minutes) the evolution of trauma-induced BBB damage noninvasively from as early as a few minutes up to hours or even longer after the trauma occurs.