Despite tuberculosis (TB) mortality has fallen 47% since 1990, TB remains one of the world's deadliest diseases, resulting in 1.5 million deaths each year. Tuberculous meningitis (TBM) is the most severe manifestation of TB, associated with a high frequency of neurologic sequelae and mortality in more than 30% of adult patients. TBM treatment consists of the same first-line TB drugs as for pulmonary TB: a combination of isoniazid, rifampicin, pyrazinamide and ethambutol for the first 2 months, followed by an additional 4 months of rifampicin and isoniazid, drugs for which several resistant strains are arising. Moreover, to reach the mycobacteria in the brain/meninges, anti-TB drugs have to cross the central nervous system barriers, the blood brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSF) and high concentrations of the antibacterial must be retained within the brain throughout treatment duration for effective management of meningitis. Drugs must pass these barriers passively based on their lipophilicity and molecular size. Therefore, the combination of new chemical entities, acting by novel mode of action, with the nose-to-brain pathway, which can be considered a valid route for the transport of medicinal agents avoiding the BBB, can be considered a valid strategy to be developed for fighting TBM. The project proposed here aims at combining new chemical entities, acting by novel mode of action, with nanovectors for the nose-to-brain (N2B) delivery for TBM treatment.
The project proposed here it's an interdisciplinary project which is expected to make a difference in the field of TB treatment, with the goal of developing new antimicrobial drugs endowed with novel mechanism of action encapsulated in nanocarriers for the N2B delivery for the treatment of TBM. Because of its interdisciplinary structure, will gain both fundamental scientific knowledge and immediate important applicative effects. The results obtained by the application of the techniques developed in the framework of this project to biological matrices have great importance from the biological, medical and technological point of view, for the improvement of the health, of the welfare and in general of the quality of life. Administration of new and more potent anti-TB compounds in nanoparticle-based formulations can improve patient adherence by shortening drug regimen duration and ultimately improving the treatment of TBM. The use of the drug loaded nanocarriers for brain targeting via intranasal route has been showing high potential for the treatment of different CNS disorders. Chitosan has the capability of opening tight junctions in the nasal epithelium and thus enhances drug permeability. The mucoadhesive properties of chitosan also increase the retention time of drugs in the nasal mucosa, leading to an increase in drug permeation [1,2]. Moreover, it has also been shown in recent studies that chitosan glutamate (CG) and other chitosan salts have better mucoadhesiveness than chitosan [3]. It is evident that the novel types of delivery systems and administration route described in this project have to manage to achieve a good balance between efficiency and safety/toxicity.
References
1) L Casettari, et al. J Control Release. 190 (2014) 189.
2) G Rassu, et al. J Control Release. 201 (2015) 68
3) L Illum, J Control Release. 161 (2012) 254.