Darren MacFarland

Hydrochalarones: A Novel Endohedral Metallofullerene Platform for Enhancing Magnetic Resonance Imaging Contrast

Targeted imaging requires contrast agents that remain in the vasculature for extended periods of time. A new contrast agent is described in which gadolinium is encapsulated within an extremely stable carbon sphere, thus allowing for safe extended residence. Water solubility and small particle size is achieved with novel fullerene chemistry, attaching multiple oligoethylene glycol groups through nitrogen chemistry. These new compounds can be used to visualize tissue architecture in vivo with standard MRI techniques.

Fullerene nanomaterials inhibit phorbol myristate acetate-induced inflammation

Abstract:  Inflammation is a natural biological response that occurs when vascular tissues are subjected to harmful stimuli. This process may be beneficial to the host during wound healing and infections but can be detrimental if left unchecked. Oxidative stress, the generation of reactive oxygen species, is thought to be one component of this response. Fullerenes can counteract reactive oxygen species due to their potent antioxidant capabilities. Thus, we hypothesized that these molecules may inhibit inflammation. To test this hypothesis we used an in vivo model of phorbol 12‐myristate 13‐acetate (PMA)‐induced inflammation and examined the effects fullerenes have on mitigating this response. We show that PMA‐induced inflammation and oedema is dramatically inhibited when fullerenes are given prior to challenge. Thus, fullerene derivatives may be a novel way to blunt certain inflammatory conditions and facilitate faster recovery of damaged tissue.

A New Class of Human Mast Cell and Peripheral Blood Basophil Stabilizers that Differentially Control Allergic Mediator Release

Treatments for allergic disease block the effects of mediators released from activated mast cells and blood basophils. A panel of fullerene derivatives was synthesized and tested for their ability to preempt the release of allergic mediators in vitro and in vivo. The fullerene C70‐tetraglycolic acid significantly inhibited degranulation and cytokine production from mast cells and basophils, while C70‐tetrainositol blocked only cytokine production in mast cells and degranulation and cytokine production in basophils. The early phase of FcɛRI inhibition was dependent on the blunted release of intracellular calcium stores, elevations in reactive oxygen species, and several signaling molecules. Gene microarray studies further showed the two fullerene derivatives inhibited late phase responses in very different ways. C70‐tetraglycolic acid was able to block mast cell‐driven anaphylaxis in vivo, while C70‐tetrainositol did not. No toxicity was observed with either compound. These findings demonstrate the biological effects of fullerenes critically depends on the moieties added to the carbon cage and suggest they act on different FcɛRI‐specific molecules in mast cells and basophils. These next generation fullerene derivatives represent a new class of compounds that interfere with FcɛRI signaling pathways to stabilize mast cells and basophils. Thus, fullerene‐based therapies may be a new approach for treating allergic diseases. Clin Trans Sci 2010; Volume 3: 158–169

Abstract LB-383: In vitro and in vivo MRI evaluation of a novel metallofullerene nanoparticle

Some disadvantages of conventional small molecule contrast agents, such as Magnevist® (Gd - DTPA), are that they extravasate rapidly and are quickly eliminated from blood, limiting the viable MRI time. Macromolecular magnetic resonance imaging (MRI) contrast agents, on the other hand, are useful blood-pool agents and have found application in monitoring tumor vasculature and angiogenesis. There is an urgent need for new MRI contrast agents with higher relaxivity and longer blood half-life. Here, we report in vitro and in vivo characterization of a water-soluble derivatized fullerene nanoparticle contrast agent (NCL124) in comparison to the market standard, Magnevist. In comparison to Magnevist, NCL124 had higher R 1 and R2 relaxivities in human plasma at 22° C and 37°C. In vivo MRI imaging was performed on a LS174T dual-flank xenografts following a single intravenous injection of NCL 124 or Magnevist contrast agent (0.2 mmol Gd/Kg) using a 3.0 Tesla clinical whole-body MRI. Based on the relaxivity-time profiles, the Vss for NCL124 was similar to that of albumin (∼ 100 mL/Kg), suggesting high protein binding, while the Vss of Magnevist was similar to that of extracellular tissue water (∼200 mL/Kg), as expected for an extracellular diffusible tracer. NCL124 also had a longer blood half-life (∼ 100 min) than Magnevist (19 min). Taken together, the higher concentration (C max ) and exposure (AUCall) of NCL124 in the blood, coupled with slow elimination, supports the use of NCL124 as a blood-pool contrast agent. Intriguingly, the half-life of NCL124 varied by tumor size, while Magnevist showed similar half-life in both tumors. This suggests NCL124 may have significant utility in predicting differences in tumor vascular and lymphatic permeability, and potentially be useful as a marker for antiangiogenic therapy. Funded by NCI contract # HHSN261200800001E. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-383.