Development of Nanomedicines for Tuberculosis Treatment

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1" Project Summary: 2" Sub-Saharan Africa, in particular South Africa is disproportionately challenged by a burden of deadly 3" infectious diseases including tuberculosis (TB). South Africa has the highest burden of TB in the world 4" (22.5% of the global burden). Furthermore, TB that is resistant to existing drugs is on the rise. However, 5" there are very few new drugs for TB in the drug discovery pipeline. Further, it is not encouraging to note 6" that in the current era of increasing antimicrobial resistance, new drugs are faced with a real threat of 7" pathogen resistance emerging soon after clinical use; as was recently observed with bedaquiline, 8" whereby resistance was detected 2 years after clinical use. The combination of increasing multidrug 9" resistance, global population density and international travel urgently calls for the development of 10" novel therapeutics for TB. Under this 5-year mentored K43 award, I intend to investigate a new 11" treatment modality that employs nanoparticles to activate the innate immune system for treatment of TB 12" (immuno-therapy). As a Postdoctoral fellow in nanomedicine at the University at Buffalo, we synthesized 13" nanoparticles functionalized with an immune modulating ligand (β-glucan), and demonstrated that these 14" nanoparticles could stimulate the TB host cells, i.e. macrophages, to produce cytokines and oxidative 15" species known to be critical to the eradication of the TB causative organism Mycobacterium tuberculosis 16" (M.tb). Under this award, I will determine whether this cellular response leads to death of M.tb in 17" macrophages and mice. This study will generate proof of concept data towards the development of this 18" new treatment modality. My prior training in nanomedicine was focused on the synthesis of nanoparticles 19" and how to characterize them. However, my career objective is to be a leader in the development of 20" nanomedicines for the treatment of infectious diseases. Therefore, I intend to undergo extensive training 21" in the biology and immunology of infectious diseases and pharmacokinetics, and to also improve my 22" research leadership skills. I will gain these skills through completing didactic and hands-on training 23" courses and group learning. I believe these additional skills will complement my current skills (in 24" nanoparticle synthesis), to equip me to rationally design nanomedicines and effectively collaborate with 25" infectious disease medical experts throughout my career. My mentorship team comprises established 26" researchers in TB biology and immunology and nanotechnology (South Africa mentors) and drug 27" development (US mentor). I will leverage the scarce resources such as biosafety level 3 facilities as well 28" as the excellent teaching and research environment at institutions in South Africa and the US, to 29" successfully complete my training and research goals. 30" 31"