Inhalable nanomedicines for treatment of tuberculosis

Lead Research Organisation: Imperial College London
Department Name: Civil & Environmental Engineering

Abstract

The rapid spread of multi drug-resistant tuberculosis (TB) is a major threat to global public health. According to WHO ~1.8 million people die every year of TB, with an estimated 9.8 million new infections per year, which is exacerbated due to the number of patients infected with HIV/AIDs. Treatment of TB is lengthy (6-months for the short course), with the development of drug resistant organisms (Mycobacterium tuberculosis (M.tb)) due to incomplete or inappropriate treatment. We propose that many of the shortfalls of treatment of multidrug-resistant TB could be overcome by reducing the high toxicity and poor efficacy of injectable small molecule antibiotics drugs.
The aim of the PhD is to develop an aerosolised, inhalable nanomedicine that delivers first line anti-tuberculous drugs embedded within antibacterial silver (Ag) and zinc oxide (ZnO) nanoparticles (NPs) locally to the M.tb inside the host macrophages which will exhibit all the properties required to reach the peripheral respiratory zone.
The engineered drug system will consist of a poly(lactic-co-glycolic acid) (PLGA) microparticle-encapsulation platform into which a combination of ZnO+AgNPs and first-line antibiotics (alone and in combination) will be loaded. The early focus will be given to first-line antibiotics, however the platform will be tailored for later inclusion second-line drugs and emerging, new drugs. The antibacterial Ag and ZnO NPs can permeabilise the M.tb cell envelope barrier to increase drug efficacy - with clinical potential to reduce the drug doses needed for treatment, avoid systemic side effects and increase patient compliance and reduce development of multidrug resistance. The student will develop a new inhalable nanomedicine, fully characterise its properties before and after after aerosolisation and test the nanodrug aerosols in unique in vitro human co-culture of models of the human alveolar unit infected with M.tb, to assess its efficacy and safety and how it interacts with the host's immune system to facilitate successful microbial killing. The student will develop aerosol exposure systems to deliver the MMP-drug formulations in vitro; medical drug delivery devices - either nebulisers or dry-powder inhalers - will be tested as potential delivery systems for use in the clinic to achieve therapeutically inhaled drug doses. We will characterise whether the MMP-drug formulation, including the uniformity of particle shape, structure and surface chemistry, are maintained during aerosolization and modify as necessary. Ultimately, we aim for the student to Reproducibly synthesise MMPs loaded with the drugs with pH responsive degradability and uniform properties during aerosolisation and develop standard protocols for optimised particle processing.
Relevant EPSRC research areas: Analytical science, Particle technology, Sensors and instrumentation, Clinical technologies (excluding imaging)

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/S023593/1 01/04/2019 30/09/2027
2275016 Studentship EP/S023593/1 01/10/2019 30/09/2023 Khaled Alzahabi