NANO-MDR-TB

Multi-drug resistant (MDR) TB is a global public health issue. It requires treatment for over 2 years with extremely toxic drugs. These agents need smarter drug delivery systems to minimize their toxic effects and shorten treatment regimens. Incorporating drugs into nanoparticles (NP) can target host cells (macrophages) that then assemble into granulomas, where Mtb hides from the immune system. Such NP can overcome low antibiotic permeability into TB granulomas. Experience from cancer chemotherapy shows that NP targeting enhances drug efficacy and reduces toxicity towards non-target cells. This proposal combines an Oslo group developing NP for injection and an Indian group focused on TB inhalation therapy using larger microparticles (MP). A New Zealand group specializing in derivatives of the new MDR-TB drug PA-824 and two NP specialist groups in Germany and Belgium will give crucial support. We propose a hierarchical strategy to make and evaluate NP/MP containing derivatives of PA-824 that exhibit higher potency but low oral bioavailability. Three other MDR-TB drugs will also be tested. NP containing drugs will first be tested in Mtb-infected macrophages. Promising NP/MP will be evaluated in the zebrafish embryo model of granulomatous TB that allows bacteria, NP and host cells to be seen together in real time at high resolution. Little is known about dynamic cellular interaction within granulomas. The zebrafish model can address biodistribution and toxicity of drug-containing NP rapidly and inexpensively, as an optimal intermediate screen between the cellular and mammalian models. It can generate proof-of-concept of enhanced efficacy through NP targeting. NP that show safe and efficient targeting in zebrafish will be tested in the aerosol infection mouse model of TB, to generate data required for regulatory approval. Our multi-disciplinary strategy provides a rational foundation for enabling preclinical development of novel delivery systems for MDR TB.