The project objective is to investigate a novel class of fullerenes called trimetallic nitride templated endohedral metallofullerenes (TNT EMFs) as dual imaging and multimodal therapeutic agents for laser cancer therapy. We will investigate the therapeutic effectiveness of TNT EMFs of the form Gd3N@C80 independently and in a peapod arrangement (Gd3N@C80 molecules within single- walled carbon nanotubes) denoted as Gd3N@C80-peapods in cancer laser induced hyperthermia therapy. These particles have been previously demonstrated as exceptional magnetic resonance imaging contrast agents due to their superior relaxivity and lower diffusion and elimination rates as compared to gadolinium. Therefore, lower concentrations of contrast agent are required thereby reducing potential toxicity. Although Gd3N@C80 have been shown to be superior imaging agents, they also have tremendous therapeutic potential which merits exploration. Gd3N@C80 possesses an absorption peak within the infrared spectrum at approximately 1050 nm at which wavelength other TNT EMFs and carbon nanotubes have been found to absorb light and generate heat. Fullerenes and metallofullerenes also generate singlet oxygen when exposed to infrared radiation permitting targeted cell cytotoxicity (5). This proposal will evaluate the therapeutic potential of Gd3N@C80 in laser therapy by measuring the thermal enhancing (ability to generate heat) and photo-toxicity (generation of reactive oxygen species) of these particles following laser excitation. Both mechanisms if directed properly can lead to cytotoxicity. The thermal sensitizing effect of Gd3N@C80 will be determined by 1) measuring heat delivery, cell death, and HSP expression following laser irradiation of cells with inclusion of Gd3N@C80-peapods and 2) characterizing the change in optical and thermal properties, temperature, cellular injury, and HSP expression distribution dependence on Gd3N@C80-peapod properties, concentration, and distribution in tissue representative phantoms. The photo-toxicity of Gd3N@C80-peapods by measuring generation of reactive oxygen species (ROS), singlet oxygen (1O2), superoxide (O2-.), and hydroxyl radical (.OH) following laser excitation of cells. Completion of this research will permit determination of the therapeutic utility of Gd3N@C80-peapods in cancer therapy and permit optimization of their properties and laser parameters to permit maximum tumor destruction. Development of dual diagnostic and therapeutic agents for cancer with heightened sensitivity, selectivity, and lower toxicity could greatly enhance the prognosis of patients suffering from this disease. The goal of this project is to explore the feasibility of employing a novel class of fullerenes called trimetallic nitride templated endohedral metallofullerenes (TNT EMFs) as dual imaging and multimodal therapeutic agents in cancer laser therapy. By integrating TNT EMFs with laser heating, lower thermal doses can be employed and more selective heating achieved, thereby permitting more precise control of the thermal energy delivery ultimately permitting effective tumor eradication while minimizing healthy tissue destruction.
