Abstract 2666: Radiation increases permeability and retention of PEG-conjugates in solid tumors.

Abstract

Abstract Poly-ethylene glycol (PEG), a hydrophobic polymer used to improve the circulation and biocompatibility of biomolecules, accumulates in solid tumors in a size-dependent manner that has been attributed to the enhanced permeability and retention (EPR) effect. Irradiation of cancer disrupts cancer microvasculature, resulting in enhanced EPR effect. In the present study, we found that radiation increases the retention of PEG in solid tumors. The accumulation of PEG in solid tumors was observed with in vivo imaging. Nude mice were prepared with heterotopic unilateral murine and human glioma (GL261, U87) and lung carcinoma (LLC, A549) tumors. A near-infrared (NIR) dye conjugated to PEG was then administered by IV to the mice which were imaged by NIR for seven days. There was increased retention of PEG-dye in tumors that had been irradiated. To further elucidate the mechanism of this increased retention, a similar in vivo imaging experiment was conducted in bilateral heterotopic tumor models (GL261, U87, LLC, A549) for seven days. The irradiated tumors demonstrated increased accumulation of PEG-dye, suggesting that the response to irradiation influenced the accumulation of PEG-dye. To observe the distribution of PEG-dye in the solid tumors, after the in vivo imaging was complete, the tumors were harvested and then sectioned for microscopy and histological staining. PEG-dye was observed in both the necrotic and non-necrotic regions of the tumor. The cancer microvasculature environment differs depending on where the tumor is located; to determine if the increased uptake was limited to only the hind limb, in vivo imaging was conducted in nude mice bearing orthotopic brain (GL261) and lung (LLC) tumors. PEG-dye was also observed to accumulate in these irradiated tumor models. Radiation induced EPR led to cancer specific delivery of PEG conjugates. Collectively, our data suggest that irradiation increases the retention of PEG-dye in solid tumors. This effect appears in more than one tumor type suggesting that the mechanism may arise from an increase in EPR following irradiation of cancer. If so, the concurrent administration of radiation therapy with polymer-conjugated therapeutic complexes may improve targeted drug delivery to cancer. Citation Format: Jerry Fong, Daniel J. Ferraro, Jeremy Hunn, Stefan Roberts, Mikhail Y. Berezin, Buck E. Rogers, Dennis E. Hallahan. Radiation increases permeability and retention of PEG-conjugates in solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2666. doi:10.1158/1538-7445.AM2013-2666