Evaluation of the pharmacokinetics and efficacy of 2 Methoxyestradiol polymeric nanoformulation

Abstract

Angiogenesis, the formation of new blood vessels, is one of the important pathological events in tumour development and progression, and thereby its inhibition is a potential strategy for therapeutic intervention of cancer. However, this strategy alone has not resulted in tumour volume reduction, as most of the anti-angiogenic drugs are only cytostatic and not cytotoxic. Moreover, a hypoxia-mediated resistance mechanism regulated by HIF-1and#945; in a tumour renders these drugs ineffective, resulting in a more metastatic tumour phenotype. Combination therapy with other chemotherapeutic drugs, though widely in use, is still limited by reduced blood flow to a tumour due to the long-term use of anti-angiogenesis drugs, which in turn decreases the bioavailability of the chemotherapeutic drug. To overcome some of the above limitations, we propose the use of a single drug molecule that has both cytotoxic and anti-angiogenic activities. 2-Methoxyestradiol (2-ME2), a natural metabolite of estrogen, is proven anti-cancerous, anti-angiogenic, and inhibits hypoxia-mediated signalling. 2-ME2 has specific toxicity towards actively proliferating cells. The drug destabilizes the microtubule by binding to its colchicine-binding region, thereby preventing the nuclear translocation of HIF-1and#945;. Thus, the production of VEGF and other angiogenic factors are inhibited. However, because of its hydrophobicity, rapid clearance, and low bioavailability, the utility of 2-ME2 is limited. The drug showed little efficacy in clinical trials as well. Moreover, it is known to undergo rapid conversion by liver enzymes. Even a therapeutic dose of 1g administered orally every 6 hours did not result in an effective plasma concentration in Phase II clinical trial, all these pointing to the limitations in the pharmacokinetics of the drug. The current research is an attempt to improve the bioavailability and activity of 2-Methoxyestradiol and evaluate its therapeutic efficacy in a tumour implanted animal model. (abstract attached).