Nanoparticle delivery of anti-tuberculosis drugs Formulation and testing of clofazimine containing nanoparticles using a zebrafish embryo tuberculosis model
Year: 2016
Type: dissertation
Abstract: Tuberculosis is an infectious disease that, despite the introduction of antibiotics over 50 years ago still causes more than 1.3 million deaths per year.The last decades have seen the emergence of multi-drug resistant tuberculosis (MDR-TB) bacteria that require treatments lasting up to 2 years and the use of more toxic and less effective drugs than in the treatment of drug-susceptible tuberculosis.Improving the treatment against MDR-TB is therefore of uttermost importance.Clofazimine (CFZ) is an antileprosy drug that is currently used as a last resort in treatment of MDR-TB.Despite conflicting reports on its effect, recent studies have associated CFZ with highly effective treatment of MDR-TB.CFZ treatment leads to massive skin and tissue drug accumulation and formation of intracellular inactive drug deposits.This is likely to hamper the treatment effect, and also causes visible skin discoloration in treated patients.Improved delivery of CFZ at the infection site could therefore potentially both enhance the therapeutic effect and reduce the side effects of the drug.Animal studies using different drug-loaded polymeric nanoparticles (NP) have shown that they localise at tuberculosis infection sites and lead to an enhanced therapeutic outcome.In this work, we wished to develop a NP treatment approach with CFZ.Firstly, we tested several ways to formulate polymeric CFZ-NP.Using nanoprecipitation, we managed to find conditions for encapsulation of CFZ into the biocompatible polymer poly (lactic-co-glycolic) acid (PLGA).By refining the encapsulation technique, we found a way to reproducibly formulate PLGA-CFZ NP in a narrow size-range well suited for studies in biological systems.In macrophages, the encapsulated CFZ behaved strikingly different from CFZ in its free form.Thus, the PLGA-CFZ NP were present in the macrophages as large aggregations with a prolonged retention in the cells.Importantly, the PLGA-CFZ NP demonstrated drastically reduced macrophage toxicity as compared to the free drug.The therapeutic effect of the PLGA-CFZ NP was tested against Mycobacterium marinum infections in a zebrafish embryo tuberculosis model.Although a tendency towards a therapeutic effect was seen in some experiments, the overall therapeutic outcome was unclear.The most promising result was obtained by combining treatment with PLGA-CFZ NP with the tuberculosis first-line drug rifampicin, and such combination regimens is a promising approach that should be explored in further studies.
Author: Håkon Høgset
Language: English
Subfield: Biomaterials
Field: Materials Science
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W2412005958