This project proposes to utilize the multimodal characteristics of metallofullerene nanoparticles to produce novel combination therapy nanoplatforms for brain cancer treatment and test their efficacy with in vivo models. The two therapeutic modalities to be delivered by the nanoplatform are the cytokine melanoma differentiation-associated gene-7/interleukin-24 (MDA- 7) and a ?-emitter, 177Lu, as the radiotherapeutic agent for brachytherapy. MDA-7 has widespread cancer-specific toxicity and radiosensitization effects, two aspects that provide a therapeutic advantage while causing less damage to normal tissue. Thus this proposal will couple the radiosensitizing and killing power of MDA-7 with brachytherapy delivered by a metallofullerene based nanoplatform. The functionalized gadolinium metallofullerene (f- Gd3N@C80) nanoparticles will be surface modified to carry both a highly stable 177Lu macrocyclic chelate and human recombinant MDA-7 protein. Stability testing will be conducted under biological conditions to determine the overall stability of the nanoplatform against release of components. Biodistribution of the nanoplatform will also be assessed. This project will test the multi-modal nanoplatform synthesized in survival studies using a murine orthotopic xenograft brain tumor model of glioblastoma multiforme. Experiments will be designed to compare the results versus the independent MDA-7 and brachytherapy treatments delivered via f-Gd3N@C80 nanoparticles. This project also aims to define a novel mechanism of enhanced therapeutic efficacy through Mcl-1 RNA splicing. The expression of Mcl-1 has been linked to a better prognosis for GBM patients as well as the sensitivity of GBM cells to radiation and chemotherapy. Validation of this mechanistic route would allow for direct manipulation of Mcl-1 splicing to be developed as a therapeutic approach. Along with the proposed research, mentoring and training activities will be undertaken to prepare the applicant as an independent investigator in the biomedical research. The skills and knowledge obtained through the proposed mentoring will be invaluable to the success of the applicant and lead to unique and innovative projects in future endeavors.
In 2010, new cases of cancers of the nervous system are estimated at 22,020 linked to an estimated 13,140 deaths in the United States of America. Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor in adults, corresponding to over 70% of primary brain tumors. The incidence rate of GBM starts to increase significantly around age 30 and peaks between ages 60-84. Veterans are significantly affected by GBM, particularly due to being an older overall patient population;thus, VA health care systems are also likely to see a higher fraction of GBM cases compared to the general US population. These tumors are extremely resistant to therapy and are key candidates for new and innovative treatments.