Abstract 4644: A novel strategy for targeted drug delivery to the tumor vasculature by radiation-induced receptor expression on endothelial cells
Authors: Meenakshi Upreti, Azemat Jamshidi-Parsian, Elden Swindell, Scott Apana, Marc C. Berridge, Nathan A. Koonce, Jessica S. Webber, Thomas V. O'Halloran, Robert J. Griffin
Journal: Cancer Research (2012)

Abstract One of the primary goals of a successful cancer treatment regimen is to deliver an effective combination of radiation and/or drugs to tumors while minimizing damage to normal tissues. Many anti-angiogenic agents, while not able to control tumor growth, possess the ability to selectively target the location and process of tumor blood vessel formation. Conversely many chemotherapy agents are highly cytotoxic and lack selective targeting ability thus decreasing the therapeutic ratio. We are investigating a new drug delivery strategy exploiting the tumor endothelium “stimulated” by ionizing radiation to preferentially target and deliver a nanoparticulate formulation of arsenic trioxide (ATO) encapsulated in liposomal vesicles or “nanobins” to the irradiated tumor tissue. The targeting is via the 33 amino acid anti-angiogenic peptide, anginex. The identification of galectin-1 as the receptor for anginex expressed on activated endothelial cells involved in tumor angiogenesis has revealed a solid basis for this therapeutic rationale. Unlike the antiangiogenic agent Avastin, which is an antibody that targets the vascular endothelial growth factor (VEGF) released by the tumor cells into the microenvironment, this peptide binds to galectin-1, a tumor endothelial cell specific antigen that is expressed in solid tumors. We have made the novel discovery that galectin-1 expression is further upregulated in the tumor after radiation exposure, particularly on the endothelial cell surface. Exposure of murine SCK breast tumors to a clinical radiation dose of 2Gy induced a substantial average increase of 141 +/− 49% in anginex uptake as assessed by [18]-F-labeled anginex biodistribution. These results suggest that anginex may be an effective targeting molecule for image and radiation-guided therapy of solid tumors. To assist in delineating the exact mechanisms for our radiation-guided drug delivery strategy, we have developed a system to grow 3D tumor cell-endothelial cell spheroids and have observed increased galectin-1 expression upon radiation exposure. We are using these spheroidal cultures to implant tumors in dorsal skin fold window chambers for intravital wavelength imaging of drug delivery to tumor tissue before and after radiation exposure. Understanding how anginex uptake selectively increases in endothelial cells after irradiation and its nexus to radiation-sensitivity and drug delivery is our current focus. Further studies are underway to characterize the in vivo targeting of arsenic trioxide chemotherapy via anginex-conjugated ‘nanobins’ in combination with radiation exposure and assess the therapeutic potential in our solid tumor model. Supported by NCI grant CA107160 and the Central Arkansas Radiation Therapy Institute. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4644. doi:1538-7445.AM2012-4644