Modulation of tumor hypoxia by topical formulations with vasodilators for enhancing therapy

Abstract

Tumor hypoxia is a well known therapeutic problem which contributes to radioresistance and aggressive tumor characteristics. Lack of techniques for repeated measurements of tumor oxygenation (pO2, partial pressure of oxygen) has restricted the optimization of hypoxia modifying methods and their efficacious application with radiotherapy. We have investigated a non-invasive method to enhance tissue pO2 of peripheral tumors using topical application of formulationswith BN (Benzyl Nicotinate), a vasodilator, and have used EPR (Electron Paramagnetic Resonance) oximetry to follow its effect on tumor oxygenation. We incorporated 2.5% BN in both hydrogel and microemulsions and investigated the effects on pO2 of subcutaneous RIF-1 (Radiation Induced Fibrosarcoma) tumors in C3H mice. The experiments were repeated for five consecutive days. The topical application of BN in hydrogel led to a significant increase from a pre-treatment pO2 of 9.3 mmHg to 11 - 16 mmHg at 30 - 50 min on day 1. However, the magnitude and the time of significant increase in pO2 decreased with repeated topical applications. The BN in a microemulsion resulted in a significant increase from a baseline pO 2 of 8.8 mmHg to 13 - 18 mmHg at 10 - 50 min on day 1. Experiments repeated on subsequent days showed a decline in the magnitude of pO2 increase on repeated applications. No significant change in tumor pO2 was observed in experiments with formulations without BN (vehicle only). EPR oximetry was successfully used to follow the temporal changes in tumor pO 2 during repeated applications for five consecutive days. This approach can be potentially used to enhance radiotherapeutic outcome by scheduling radiation doses when an increase in tumor pO2 is observed after topical applications of BN formulations. © 2011 Springer Science+Business Media, LLC.