ATPS-89LOCAL DELIVERY OF A SMALL-MOLECULE INHIBITOR OF HYPOXIA INDUCIBLE FACTOR-1: A NEW CANDIDATE DRUG FOR BRAIN TUMOR THERAPY

This work investigated the efficacy of intracranial delivery of acriflavine (ACF), a small-molecule hypoxia-inducible factor 1α (HIF-1α) therapeutic inhibitor, for the treatment of primary brain malignancies. ACF, a mixture of two closely related acridine molecules, has only recently been recognized as a potent hypoxia-inducible factor 1α (HIF-1α) inhibitor, but has already demonstrated highly effective anti-tumor activity against a wide spectrum of cancers. Thus far, no study has reported its efficacy in either glioma cell lines or brain tumor models. In our in vitro study on rodent and human glioma cell lines, we showed that ACF suppressed cell viability and increased cell death in a dose-dependent manner. Our in vivo study examined the safety and efficacy of locally delivered ACF in monotherapy. To overcome ACF's poor systemic bioavailability and limited BBB penetration, we delivered ACF directly to the site of the tumor via biodegradable polymer wafers. Throughout three separate experiments, enrolling a total of 60 F334 Fisher rats, we showed that animals receiving local implantation of ACF wafers achieved an extraordinary 100% survival rate of up to 300 days (p <0.0001 vs. controls and 0.0002 vs. a Temozolomide-treated positive control), whereas the systemic administration of ACF provided no survival benefit compared to the control. Neuropathological examination at 120 days, as well as neuroimaging follow-up using MRI, confirmed tumor growth arrest in animals treated with ACF wafers, as opposed to progressive tumor growth in both untreated animals and animals treated with empty wafers. This is the first study to describe the extraordinary potential of ACF for the treatment of brain tumors as well as the effectiveness of interstitial local therapy via biodegradable polymer wafers for the use of ACF for brain tumor therapy.