Polymersomes as selective drug delivery carriers for innovative anti-TB agents

Despite the global efforts to develop innovative therapeutic approaches, tuberculosis (TB) remains one of the leading causes of mortality from a single infectious agent, surpassed in 2020 only by COVID-19. We focused our attention on two protein targets known to be essential for the survival of Mycobacterium tuberculosis (Mtb) during the infection: salicylate synthase I (MbtI), an enzyme that catalyses the first step in the biosynthesis of the iron-chelating siderophores, and Low-Molecular-Weight Phosphatase B (MptpB), which interferes with the host immune response. We have previously developed effective MbtI and MptpB inhibitors [1,2]. Now, we have encapsulated these potential drugs in poly(2-(methacryloyloxy)ethyl phosphorylcholine)–poly(2- (diisopropylamino)ethyl methacrylate) (PMPC-PDPA) polymersomes (POs). These carriers allowed 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. POs combine the advantages of long-term stability with the potential to encapsulate a broad range of compounds. The POs were fully characterised by Dynamic Light Scattering (DLS), High-Pressure Liquid Chromatography (HPLC), and Transmission electron microscopy (TEM); their cytotoxicity was assessed against a 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 [3].