Document Type

Dissertation - Open Access

Award Date

2021

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

First Advisor

Joshua Reineke

Abstract

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (M.tb), with an estimated 1.5 million deaths and 10 million infections each year. Although TB can be effectively treated with antibiotics, because of the complications and length of treatment, many people fail to complete the treatment which exacerbates the emergence of drug-resistant M. tb strains. The goal of this work is to develop biomimetic particles as host-directed therapy to target the infected macrophages. Two types of metal-organic frameworks (MOFs), MIL-100(Fe) and MIL-88A(Fe) were developed for bacteriamimicking particles. As a proof-of-concept, Mannose was selected as a ligand to target macrophages because many pathogens express mannose on the surface. MOFs were successfully modified with mannose via EDC/NHS coupling method. No difference was observed in cell uptake between MIL-100(Fe) and mannose-MIL-100(Fe). Mannose- MIL-88A(Fe) showed a significant increase in macrophage uptake compared to its unmodified counterpart. MIL-88A(Fe) is rod-shaped and has a size similar to M. tb making it a natural platform for mycobacteria mimicking. MIL-88A(Fe) was coated with two-layer hybrid lipids and mycolic acid (MA), the most abundant lipid in mycobacteria cell wall, was also incorporated. The coating was confirmed by transmission electron microscopy with energy dispersive x-ray analysis (TEM-EDX). Lipids coated MIL- 88A(Fe) with MA directly extracted from Mycobacterium. Avium exhibited the highest cell uptake compared to lipids coated MIL-88A(Fe) with commercial MA or without MA. As MIL-100(Fe) is readily taken by macrophages, unlike MIL-88A(Fe) for bacteria mimicking, MIL-100 (Fe) nanoparticles were designed to have immunomodulatory property by functionalized with the immunomodulatory ligand curdlan. Curdlan coated MIL-100(Fe) was prepared by nanoprecipitation method. The difference in surface charge, intracellular stability, and thermal property confirms the coat of curdlan on MIL- 100(Fe). Overall, MOFs are promising candidates for the development of biomimetic particles as HDT to target infected cells. M.tb-mimetic MIL-88A(Fe) particles and immunomodulator MIL-100(Fe) may potentially enhance host cell response to an M.tb infection by encapsulated HDT drugs or the carriers themselves.

Number of Pages

185

Publisher

South Dakota State University

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Rights Statement

In Copyright