Biodistribution studies of a water-soluble radioactive metallofullerene compound have been conducted using BALB͞c mice. To this end, a sample containing Ho x @C 82 (x ‫؍‬ 1, 2) was purified and derivatized to prepare the watersoluble metallofullerol, Ho x @C 82 Since the discovery of fullerenes in 1985 (1) and the subsequent incorporation of metal atoms within their carbon cage (2), intense interest has focused on these unique molecules. Research efforts have greatly extended our knowledge of the chemical and biological properties of empty fullerenes (3; for review, see ref. 4), but comparatively little is known about endohedral metallofullerenes because of their low production yields, low solution solubilities, difficult purification, and air sensitivity (5-9). However, advances in HPLC purification procedures (5-9) and chemical derivatization (10-15) of fullerenes have recently expanded research possibilities into applications for metallofullerenes when relatively small amounts of material are required.One potential application for metallofullerenes is in the field of nuclear medicine. Current radiopharmaceuticals employ small quantities (nanograms to milligrams) of drugs containing specially chelated radioisotopes of metals for imaging or therapeutic applications. The chelating ligands prevent direct binding of the toxic metal ions with serum components and tissue by providing a thermodynamically stable molecular environment. A major concern with these drugs, however, is their in vivo kinetic instability, which can allow the release of small amounts of toxic radiometals (16). It is envisioned, therefore, that metallofullerenes could provide a unique alternative to chelating compounds because of their resistance to metabolism and their high kinetic stability. Additionally, the large carbon-based surface area of fullerenes and metallofullerenes (Ϸ200 Å 2 ) facilitates the development of tissue-targeting compounds by using established metallofullerene derivative chemistry (10-15). Thus, the metallofullerenes may be useful as a new, more stable alternative for transporting radiometals in vivo.Empty fullerenes have low cytotoxicity both in vitro (17-22) and in vivo (17,(23)(24)(25)(26), despite one report of a photosensitizing C 60 derivative (24). In addition, empty fullerenes and their derivatives have been tested for their biodistribution, and some C 60 derivatives have shown promise as anti-HIV (27-34) and anticancer (35-37) agents and as an agent to reduce reactive oxygen species (20,21). Dugan et al. (17,38) have also demonstrated the usefulness of fullerene derivatives as biological freeradical scavengers in vivo. Research involving the biodistribution of fullerenes in vivo is limited to studies on C 60 and La@C 82 suspensions (23, 25), and to three water-soluble C 60 derivatives (26,30,39). All of these studies indicate rapid localization and long-term residency in the liver (Ͻ1% clearance), and one of the studies demonstrated that fullerenes are not metabolized rapidly in vivo (39). To help opti...

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Pulmonary endothelium plays an important role in the maintenance of normal pulmonary physiology and its dysfunction is involved in a number of pulmonary diseases. Correction of endothelial dysfunction via antisense oligodeoxynucleotides (ODN) is dependent on the development of a delivery vehicle that can efficiently deliver the ODN to pulmonary endothelium with minimal toxicity. To this end, we have developed a novel lipidic vector that is highly efficient in targeted delivery of ODN to pulmonary endothelium. This is based on a method that utilizes an ionizable aminolipid (1,2-dioleoyl-3-dimethylammonium propane) and an ethanol-containing buffer system for encapsulating large quantities of polyanionic ODN in lipid vesicles. An endothelium-specific antibody (273-34A) is incorporated into the lipid vesicles via a distearoylphosphatidylethanolamine-poly(ethylene glycol) spacer. The 273-34A antibody efficiently mediated delivery of ODN to mouse lung endothelial cells in vitro and in vivo. Furthermore, systemic administration of this formulation is associated with minimal hematological toxicities and induces little acute change in systemic and pulmonary hemodynamics. These results provide a basis for lipid-mediated delivery of ODN for the treatment of pulmonary diseases. They also suggest the utility of this approach as a research tool to characterize the function of genes in the pulmonary endothelium.

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