Ana Grenha has received her PhD in Pharmacy-Pharmaceutical Technology from the University of Santiago de Compostela – Spain in 2007. She is Assistant Professor in Pharmaceutical Technology at the University of Algarve in Portugal since 2007 and is a Senior Researcher at both the Centre of Marine Sciences and the Centre for Biomedical Research, at the same University. She is the PI of the Drug Delivery Laboratory, which is dedicated to the design and development of particulate carriers for drug delivery, with a particular focus on inhalation.
She has been the PI of several funded projects, and has authored 33 original papers in international peer-reviewed journals, 5 book chapters and 1 patent in the field of drugs and drug delivery systems.
Tuberculosis remains a leading cause of death, although effective therapy is available for many years. Therapeutic failure is mainly due to non-compliance with prolonged treatments, often associated with severe side-effects. New therapeutic strategies are therefore demanded. As tuberculosis is an air-borne pathology and the lung is the primary site of infection, with alveolar macrophages hosting mycobacteria, direct lung delivery of antibiotics appears as a potentially effective approach. In this context, therapeutic success depends on suitable carriers that reach the alveolar zone and on their ability to undergo macrophage capture, providing the intracellular accumulation of drugs.
This work proposes alternative inhalable tuberculosis therapy based on spray-dried polysaccharide-based microparticles. Several polysaccharides have been tested, including locust bean gum, chondroitin sulfate, fucoidan, chitosan, xanthan gum, among others. Isoniazid and rifabutin, two first-line antitubercular drugs, were simultaneously associated to microparticles in order to establish a combined therapy, as recommended by WHO. The proposed polysaccharides bear structural units (mannose, fucose and galactose units, sulfate groups, etc.) that may provide privileged targeting of macrophage surface receptors. The aerodynamic properties of microparticles were characterised, as well as their ability to provide specific macrophage targeting. The cytotoxic effect of microparticles in cells relevant for the objective of the work (A549 alveolar epithelial cells, macrophage-derived THP-1 cells) was determined. Considering that most of the proposed polysaccharides have not been explored for pulmonary delivery, an in vivo study was established to determine evidence of allergic reactions and/or apoptotic and autophagic markers in blood or organs. Additionally, an in vivo proof-of-concept on the therapeutic efficacy of selected formulations was performed in a mouse model of tuberculosis. The results demonstrated the ability of spray-drying to produce aerodynamically adequate microparticles for the purpose of the work, based on the selected polysaccharides. The materials were shown to not induce allergic reactions after lung administration and the in vivo proof of concept demonstrated the potential of the inhalable therapy in reducing the infection.