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Characterization of the Effect of Hyperthermia on Nanoparticle Extravasation from Tumor Vasculature¹

Departments of Biomedical Engineering [G. K.] and Radiation Oncology [R. D. B., M. W. D.], Duke University Medical Center, Durham, North Carolina 27710

The efficacy of novel cancer therapeutics can be hampered by inefficient delivery of agents to the tumor at effective concentrations. Liposomes have been used as a method to overcome some delivery issues and, in combination with hyperthermia, have been shown to increase drug delivery to tumors. This study investigates the effects of a range of temperatures (34–42°C) and hyperthermia treatment scheduling (time between hyperthermia and drug administration as well as between consecutive hyperthermia treatments) on the extravasation of nanoparticles (100-nm liposomes) from tumor microvasculature in a human tumor (SKOV-3 ovarian carcinoma) xenograft grown in athymic nude mouse window chambers. Under normothermic conditions (34°C) and at 39°C, nanoparticles were unable to extravasate into the tumor interstitium. From 40 to 42°C, nanoparticle extravasation increased with temperature, reaching maximal extravasation at 42°C. Temperatures higher than 42°C led to hemorrhage and stasis in tumor vessels. Enhanced nanoparticle extravasation was observed several hours after heating, decaying back to baseline at 6 h postheating. Reheating (42°C for 1 h) 8 h after an initial heating (42°C for 1 h) did not result in any increased nanoparticle extravasation, indicating development of vascular thermotolerance. The results of this study have implications for the application and scheduling of hyperthermia combined with other therapeutics (e.g., liposomes, antibodies, and viral vectors) for the treatment of cancer.

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