..................................................................................................................................... 3 Introduction ............................................................................................................................... 3 The tumor microenvironment .................................................................................................... 4 Disarrayed vasculature ....................................................................................................................... 5 Tumor hypoxia effects ........................................................................................................................ 6 Effect of radiotherapy on the tumor microenvironment............................................................ 8 Tumor cell death ................................................................................................................................. 8 Effects of hypoxia pathway post-treatment ......................................................................................... 9 Nanoparticle based radio-chemotherapy ................................................................................... 9 Nanotherapeutic specific for HIF-1a inhibition ................................................................................ 9 Specific targeting and the synergist effects of radio-chemotherapy .................................................. 10 Conclusion ................................................................................................................................ 12 Limitations........................................................................................................................................ 12 Future Research ............................................................................................................................... 12 Acknowledgments .................................................................................................................... 13 Citations ................................................................................................................................... 14 Appendix A ............................................................................................................................... 17 Appendix B ............................................................................................................................... 18 INCREASING THE EFFICACY OF RADIOTHERAPEUTICS 3 Increasing the Clinical Efficacy of Radiotherapeutics for Solid Tumors by Inhibition of Hypoxia Inducible Factor-1a Abstract: Radiotherapy is commonly used in a variety of tumor types and is effective in control of long term progression and may be curative under certain circumstances. Radiotherapeutics have been shown to be the single most effective therapeutic for cancer and only account for 5% of the total cost. However, treatment of cells with radiation causes the tumor microenvironment to undergo changes and leads to cycles of hypoxia inside the tumor which allows for the cell to undergo angiogenesis, metastasize and may lead to repopulation of the tumor. Current systemic chemotherapeutics typically have an additive toxicity due to the unintended targeting of non-cancerous cells. A nanoparticle conjugated with the iRGD peptide is proposed to allow for selective uptake by the CendR pathway in the tumor tissues. A systemic selective chemotherapeutic agent that will inhibit hypoxia inducible factor1, preventing angiogenesis, that is co-administered with radiotherapy may increase the clinical efficacy of the radiotherapeutics and may have the greatest impact on currently available cancer treatment. Radiotherapy is commonly used in a variety of tumor types and is effective in control of long term progression and may be curative under certain circumstances. Radiotherapeutics have been shown to be the single most effective therapeutic for cancer and only account for 5% of the total cost. However, treatment of cells with radiation causes the tumor microenvironment to undergo changes and leads to cycles of hypoxia inside the tumor which allows for the cell to undergo angiogenesis, metastasize and may lead to repopulation of the tumor. Current systemic chemotherapeutics typically have an additive toxicity due to the unintended targeting of non-cancerous cells. A nanoparticle conjugated with the iRGD peptide is proposed to allow for selective uptake by the CendR pathway in the tumor tissues. A systemic selective chemotherapeutic agent that will inhibit hypoxia inducible factor1, preventing angiogenesis, that is co-administered with radiotherapy may increase the clinical efficacy of the radiotherapeutics and may have the greatest impact on currently available cancer treatment.