Inhalable Nanomedicine for Treatment of Pulmonary Tuberculosis
Theme: Aerosols and Health
Start date: Cohort 1: 2019
Supervisors: Prof Terry Tetley (Imperial) and Dr Alexandra Porter (Imperial)
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, with the development of drug resistant organisms 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.
Tuberculosis (TB) is a bacterial infectious disease that affects different human organs mainly lungs, liver, spleen, and spine, causing severe symptoms of fever, fatigue, continuous cough and death, if not treated properly. Every year, 10 million patients fall ill with active TB resulting in the death of approximately 1.5 million people. Current treatment guidelines recommend oral administration of first-line anti-TB drugs, such as rifampicin and isoniazid, for at least 6 months. Lengthy treatment, low bioavailability, short half-life and poor lung delivery of anti-TB drugs, and associated side effects, are the main reasons for patient non-compliance and emergence of multi drug resistant-TB (MDR-TB) which accounts for 19% of previously infected cases, illustrating that first-line anti-TB drugs cannot always cure or control TB. Addressing these issues by designing a new pulmonary drug delivery system and using additional anti-TB treatments would save people’s lives, improve TB treatment regimens, significantly decrease TB incidence, minimize MDR-TB and mortality. Pulmonary drug delivery (PDD) is an effective route for treating many respiratory diseases (e.g. asthma) and it shows superior advantages compared to oral drug delivery system, primarily in accelerating the onset of therapy, delivering pharmaceutically active ingredients directly into the lungs and avoiding side effects, so increasing the safety and efficacy. Metal nanoparticles, such as silver and zinc, show promising antibacterial effects and have been used in many applications as antibacterial agents.
We aim to enhance TB therapy and decrease the treatment period by combining the anti-TB drugs and metal nanoparticles for co-inhalation therapy. Our goal is to design and characterize novel inhalable poly (lactic-co-glycolic acid) (PLGA) micro particles loaded with silver nanoparticles and one or more anti-TB formulations to be directly aerosolized into the lungs using a tested inhalation device. The prepared micro particles will be fully characterized for their size, morphology, surface charge and therapeutic drug content using validated methods. The release behavior, efficacy and toxicity of anti-TB drugs and silver nanoparticles will be assessed in vitro against Mycobacterium tuberculosis(M-tb) organisms and against novel 2 models of M-tb infected human pulmonary alveolar target lung cells.
Finally, a suitable inhalation device will be optimized to ensure optimal drug delivery in experimental conditions, prior to pre-clinical studies. This promising proposal will have a huge impact on improving TB treatments, patient compliance and could be clinically used in the future as a new intervention to effectively treat TB and save lives.