Phagocyte-targeting polymersomes as intracellular delivery carriers for enzymatic inhibitors with antitubercular activity

Despite global efforts to develop innovative therapeutic approaches, tuberculosis (TB) remains one of the leading causes of mortality from a single infectious agent. We focused our attention on two protein targets known to be essential for the survival of Mycobacterium tuberculosis (Mtb) during infection: salicylate synthase I (MbtI), an enzyme that catalyses the first step in the biosynthesis of the iron-chelating siderophore mycobactin T, and Low-Molecular-Weight Phosphatase B (MptpB), which interferes with the host immune response. We have previously developed potent MbtI and MptpB inhibitors, which showed antimycobacterial activity at MIC concentrations as low as 30 µM. Now, we have encapsulated these drugs in PMPC-PDPA polymersomes (POs). Such a carrier allows us to (i) solubilise the hydrophobic drugs, (ii) target infected phagocytes via phenotypic association to scavenger receptors class B, (iii) efficiently deliver the cargo within the cell cytosol where most bacilli harbour, and (iv) effectively kill intracellular pathogens selectively. These POs combine the advantages of long-term stability with the potential to encapsulate a broad range of compounds. The POs were fully characterised by DLS, HPLC, TEM; their cytotoxicity was assessed against macrophage cell line (THP-1) and Primary Human Lung Fibroblasts (HLF). Future work includes evaluating the antimycobacterial activity of the drug-containing POs in Mtb-infected primary cells.