Glycan-functionalized liposomes as a cell-selective drug delivery approach for the treatment of Tuberculosis

Tuberculosis (TB) is one of the top 10 causes of death worldwide. The current treatment standard regimen requires a 6 to 9 months course combination therapy of antimicrobial drugs that are provided daily, which leads to low... [ view full abstract ]

Tuberculosis (TB) is one of the top 10 causes of death worldwide. The current treatment standard regimen requires a 6 to 9 months course combination therapy of antimicrobial drugs that are provided daily, which leads to low compliance and failure in the treatment resulting in emergence of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) cases. For this reason, improved treatment of TB is a major medical need. Nanocarriers such as liposomes offer a promising approach for drug delivery due to their size and hydrophobic/hydrophilic character which makes them highly biocompatible and because their surfaces can be modified in order to functionalize them for cell-selective drug delivery. In the present study we use a glycan-decorated liposomal formulation to target antigen-presenting cells (APC) by binding of C-type lectin receptors (CLR) exposed on the surface of these cells. CLR play a crucial role in pathogen uptake by sensing carbohydrate structures that are prominent constituents of various pathogens such as HIV-1, dengue virus, C. albicans and M. tuberculosis and therefore can be exploited by various glycan-functionalized particles. 

The CLR expression profile as well as the uptake of glycan-decorated liposomes was studied in human immune cell subsets derived from blood, secondary lymphoid organs such as tonsils and lymph nodes, as well as in cells derived from human lung tissue. Furthermore, the potency of such liposomes to deliver antibiotics was assessed with an in vitro BCG-infection model in human monocyte derived macrophages. Our results demonstrate that dendritic cells and macrophages have a superior uptake of liposomes in comparison to other non-APC like T and B cells. Glycan-decorated liposomes showed a preferential subcellular localization in endosomal compartments, presumably due to receptor-mediated endocytosis through CLR, whereas non-decorated liposomes appear to be ingested by receptor-independent mechanisms and are mainly trafficked into the cytoplasm. Most importantly, liposomes that are both glycan-decorated and loaded with antibiotics effectively inhibited bacterial growth in BCG-infected macrophages. Thus, functionalized liposomal formulations might be suitable to treat tuberculosis, while minimizing adverse effects even upon effective dosage escalation by directing active compounds directly into infected target cells.