Mycobacterium tuberculosis (MTb), the underlying cause of tuberculosis (TB), infects approximately one-third of the world human population (2 billion of people), representing a huge reservoir of potential dissemination [1]. In most cases, bacterium and host establish equilibrium, and thus infected individuals can remain asymptomatic for several decades and even for the entire life. However, about 10% of the infected individuals develop the disease [2]. TB causes about 1.4 million fatalities per year, being the main cause of death among infectious diseases [1]. TB infection is usually initiated by the entry of MTb in the respiratory system through aerosol droplets. In the lungs, the facultative intracellular parasite MTb is phagocytized by the alveolar macrophages (AMs), within which is able to survive and multiply [3-4].
Notwithstanding, the significant progress that has been made to reduce the global impact of TB, the emergence of drug resistant TB threatens these advancements [1]. In this context, the main goal of this project is to develop biocompatible lung endogenous mimetic nanoparticles for pulmonary delivery of the first-line anti-tuberculosis drugs specifically to the AMs, improving the therapeutic index of the carried drugs and also the lung compliance. The innovation in this proposal is the accomplishment of this objective using lipid nanoparticles made of endogenous compounds with no pulmonary toxicity, while being a potential strategy to improve the lung compliance by the replacement of the lung surfactant, which is compromised in the TB pathology. The nanoparticles will also include in their composition tuftsin, a physiological basic tetrapeptide that have shown, in previous studies, to increase the internalization of the nanoparticles in the AMs, having also capacity to stimulate the phagocytic activity [5]. Essentially, nanoparticles will be engineered to specifically release the encapsulated anti-TB drugs within the infected cells, thereby preventing the drugs? systemic absorption and the normal lung parenchyma from non-specific cytotoxic effects of drugs.
The present project represents a major breakthrough in the fight against TB by allowing the decrease of treatment duration, and consequently improve compliance to  therapy, optimizing the drug regimes to fight TB and reducing occurrence of drug resistant TB.
For a successful management of the project to be accomplished in the period of 3 years, it will be divided into 4 phases. Firstly, a systematic design, development and characterization of the nanoparticles unloaded and loaded with the anti-TB drugs will be performed (Tasks 1 to 3). In the second phase, the in vitro studies will be performed at the membrane and cell levels (Task 4-5). Then, an appropriate inhaler device will be developed to the pulmonary administration of the formulations (Task 6). Finally, the safety and the therapeutic potential of the selected formulations will be tested in animal models (Task 7).