Infectious diseases have formed human history and still there are many disease-causing infection agents circulating among us. These infections are caused by diverse pathogens of which most are intracellular, such as viruses, several bacteria, fungi, and protozoan parasites. Particularly, Mycobacterium tuberculosis (Mtb), causative agent of tuberculosis (TB), has afflicted humanity for thousands of years, it is currently one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent. The treatment of TB is long, costly and the currently used anti-TB drugs have several side effects. Moreover, the emergence of multidrug-resistant and extensively drug-resistant TB with limited chances of a successful treatment is very alarming and it could lead to a major public health crisis. Therefore, there is an urgent need to find new strategies to overcome this disease.
TB is an airborne disease, it typically affects the lungs, but it can cause disease in any organ. Mtb is an intracellular bacterium and it is considered as the most successful pathogen. It has developed several strategies to avoid being eliminated by the host immune response and it is adapted to survive and persist within its host cells (mainly macrophages) for many years. Therefore, focusing on host cell directed drug-delivery could promote the efficient elimination of the intracellular bacteria. The orally or intravenously administered drugs in the free forms tend to be distributed all over the body through the systemic blood circulation and the majority of the molecules do not reach their targets. Applying nanoparticles as formulating antitubercular drugs can be a powerful tool to increase their bioavailability and selectivity while reducing their undesirable side effects. Nanotechnology-based drug carriers allow slow, sustained and controlled drug release, they have tunable physiochemical properties, enhanced carrying capacity, enhanced stability and feasibility of different routes of administration (e.g. oral or pulmonary administration). Nanocarriers have the potential of minimizing the dosing frequency, improving the treatment success rate, and reducing the development of drug resistance.
The objective of the TBNANO project is to design and develop drug-loaded nanocapsules decorated with targeting molecules to enhance their cellular uptake by host cell macrophages in order to reach the intracellular bacteria as site of action (Figure 1). For this purpose, chitosan- and alginate-based nanocapsules have been developed. Macrophage receptor specific peptides and carbohydrates have been used as targeting ligands. As anti-TB agents, bedaquiline, a recently approved antitubercular and antimicrobial peptides (AMPs) have been used. Besides the careful chemical characterization of the nanocapsules, their efficiency to inhibit both extracellular and intracellular bacteria is being assayed in vitro, as well as their cytotoxicity and cellular uptake.
Another goal of this MSCA Individual Fellowship is to promote the development of the individual researcher by a positive impact on her career, and to enhance her professional maturity and independence.
Overall conclusions:
The synthesis and characterization of fluorophore or antitubercular agent-loaded and functionalized nanocapsules has been optimized. With the optimized methods a high nanocapsule stability was achieved, which is a key aspect in the nanotechnology-based drug delivery.
The nanocapsules showed favorable behavior in the in vitro biological studies, such as moderate cytotoxicity, high cellular internalization, and outstanding antimycobacterial activity.
