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Inhaled SHetA2 dry power aerosols as novel treatment for tuberculosis

Lucila Garcia-Contreras Ph.D.

Principal Investigator

Agency: Presbyterian Health Foundation Seed Grant

Abstract

World-wide, tuberculosis (TB) is the leading cause of death from a single microorganism, and the largest cause of death among AIDS patients. The current TB treatment is a lengthy process requiring daily oral administration of 3-4 antibiotics for at least six months. Patients are likely to terminate treatment earlier due to unwanted toxic effects of the antibiotics, increasing the number of multidrug resistant TB cases. Therefore, new drugs and more effective treatments are desperately needed.

Recently we discovered that SHetA2, a novel anticancer drug (developed by Dr. Benbrook), has significant activity against Mycobacterium tuberculosis (MTB).However, due to its poor solubility, SHetA2 has an oral bioavailability of less than 1%. A dozen publications have reported an enhanced effect of anti-TB drugs when they are administered by inhalation, thus offering the possibility to reduce treatment times and limit drug toxicity. The goal of the future R01 application will be to develop a SHetA2 powder for inhalation to be used as an effective treatment against TB. We hypothesize that optimized SHetA2 dry poweder auerosols delivered directly to the lungs of infected guinea pigs will significantly reduce their baterial burden.

Inhalation of SHetA2 powder aerosol will have the advantage of achieving higher drug concentraation in the lungs, the main site of TB infection. Moreover, since the lung epithelial fluid contains phospholipids and surfactant, an optimized SHetA2 powder formulation will overcome its solubility limitation, increasing its bioavailability.

The seed grant funds will be used to (1) Optimize the SHetA2 dry powder formulation as inhalable microparticles; (2) Assess their efficacy in killing MTB in a murine cell line; and (3) Elucidate the probably molecular mechanisms by which SHetA2 kills MTB. We will build on this preliminary data so that in the R01 application we can propose in vivo studies to determine the pharmacokinetic disposition of SHetA2 and perform efficacy studies with this novel drug.