Lunn, AM, Unnikrishnan, M and Perrier, S (2021) Dual pH-Responsive Macrophage-Targeted Isoniazid Glycoparticles for Intracellular Tuberculosis Therapy. Biomacromolecules, 22 (9). pp. 3756-3768. ISSN 1525-7797

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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.

Item Type:	Article
Additional Information:	This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biomacromolecules, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.biomac.1c00554
Uncontrolled Keywords:	03 Chemical Sciences; 06 Biological Sciences; 09 Engineering; Polymers
Subjects:	Q Science > QD Chemistry Q Science > QH Natural history > QH301 Biology R Medicine > R Medicine (General) R Medicine > RS Pharmacy and materia medica
Divisions:	Pharmacy & Biomolecular Sciences
Publisher:	American Chemical Society (ACS)
SWORD Depositor:	A Symplectic
Date Deposited:	13 Mar 2023 12:50
Last Modified:	13 Mar 2023 12:50
DOI or ID number:	10.1021/acs.biomac.1c00554
URI:	https://researchonline.ljmu.ac.uk/id/eprint/19081

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