Dual pH-Responsive Macrophage-Targeted Isoniazid Glycoparticles for Intracellular Tuberculosis Therapy

Abstract

Tuberculosis (TB) is a global epidemic that kills over a million people every year, particularly in low-resource communities. Mycobacterium tuberculosis, the most common bacterium that causes TB, is difficult to treat, particularly in its latent phase, in part due to its ability to survive and replicate within the host macrophage. New therapeutic approaches resulting in better tolerated and shorter antibiotic courses that target intracellular bacteria are critical to effective treatment. The development of a novel, pH-responsive, mannosylated nanoparticle, covalently linked with isoniazid, a first-line TB antibiotic, is presented. This nanoparticle drug delivery agent has increased macrophage uptake and, upon exposure to the acidic phagolysosome, releases isoniazid through hydrolysis of a hydrazone bond, and disintegrates into a linear polymer. Full antibiotic activity is shown to be retained, with mannosylated isoniazid particles being the only treatment exhibiting complete bacterial eradication of intracellular bacteria, compared to an equivalent PEGylated system and free isoniazid. Such a system, able to effectively kill intracellular mycobacteria, holds promise for improved outcomes in TB infection.