ANGI-01: NANONIZATION OF HET0016 IMPROVED THE CONTROL OF GMB IN RAT MODEL

N-hydroxy-N'-(4-butyl-2 methylphenyl) formamidine (HET0016) has been reported to be a highly selective inhibitor of 20-hydroxy arachidonic acid (20-HETE) synthesis that involves enzymes of the cytochrome P450, family 4, subfamily A (CYP4A) and CYP4F families. HET0016 was found to inhibit angiogenic responses to several growth factors as well as angiogenesis in the cornea induced by implanted human U251 glioma cells and angiogenesis in 9L gliosarcoma. Recently our group has published the effectiveness of HET0016 in controlling different malignant tumors in animal models. However, to achieve optimal blood level of the administered HET0016 to control tumor growth, HET0016 is administered intraperitoneally (IP) two times a day for 7 days a week. HET0016 is highly insoluble in water and needs an organic solvent such as DMSO or ethanol for making formulation for IP administration. We have nanonized HET0016 for IV formulation using FDA approved nanoparticle and administered in rats bearing orthotopic human glioma. Animals were treated at different stages of tumor growth and the effect of the IV formulation was investigated by magnetic resonance imaging (MRI). All animals were euthanized on day 22 of tumor implantation for molecular and immunohistochemical analysis. All the findings were compared with that of corresponding animals treated with vehicle and HET0016 (intraperitoneal administration).IV administration of nanonized HET0016 significantly decreased the growth of the tumor at all treatment schedules. Effect was pronounced when treatments started in developed tumors (8 or 15 days old tumor). IP administration did not significantly decrease the tumor growth. Vascular parameters were also significantly altered when HET0016 was administered IV in 8 days old tumor. Whereas IP administered tumor did not show any significant changes compared to that of corresponding control. Released of different growth factors and tumor cell migration were significantly decreased in IV administered animals.