This original concept shown here dated 2011, has now been brought up-to date by my collaborators, being a novel method to kill M.tuberculosis in vivo, and when used in TB therapy, will increase the efficacy of most antibiotics.

Idea and novelty- Precision hyperthermia (the selective killing of individual cells by generating intracellular heat through nanoparticle exicitation) is a new, low cost, portable technology that has not been considered for use in combating infectious diseases. It may be implemented to great effect in tuberculosis (TB) therapy by acting synergistically with antibiotic treatment (i.e. DOTS) in early-stage therapy of progressive TB to significantly decrease TB treatment duration, kill multi-drug resistant Mycobacterium tuberculosis strains and improve clinical outcomes.

Scientific Basis- To hide from the host immune system, TB bacilli infect lung macrophage cells and inactivate them. This allows the bacteria to thrive and multiply within the cells, protected from the body’s defence systems and antibiotic treatment. Over time, infected macrophages form granulomas, which can rupture/cavitate in the future to cause recurrent TB. A 2005 study by Leemans et al. showed that non-selective pharmacological deletion of alveolar macrophages (after TB infection) improved clinical outcomes in a murine model such as bacterial burden, spread of the disease and survival rate. In short, depriving the bacteria of their hiding place, for durations long enough to make them more accessible to antibiotics treatment, will significantly enhance the effectiveness of TB treatment strategies and shorten the duration of therapy. Precision hyperthermia, currently used in cancer treatment, exploits the ability of metal nanoparticles (examples gold and iron oxide) to generate highly localised, intracellular areas of high temperature in response to external application of short frequency radio waves. In cancer patients, it has been shown to selectively destroy cancer cells without showing toxicity to adjacent healthy cells and significantly enhances the effects of radiation therapy. This project will explore translating the promise of precision hyperthermia to the field of TB to selectively destroy macrophages which have been recruited to the sites of cavitating lesions in progressive TB. The treatment will ideally 1. physically destroy all bacteria hidden within macrophage cells (regardless of their strain) 2. remove for a significant duration (5-7 days) the ability for TB bacilli to hide within macrophages, thus increasing their susceptibility to concurrent antibiotic treatment, 3. reduce the formation of granulomas which may cause recurrent TB and 4. show no detrimental side effects to the patient.

Precision hyperthermia treatment is portable and can be implemented in a simple, cost-efficient manner in poor or remote areas of the world, where TB incidence is a massive public health burden. In the first week of DOTS treatment, the patient would inhale an inexpensive dry powder composed of inert, non-toxic, biodegradable mannose-coated iron oxide nanoparticles (~50-80 nm).  The nanoparticles will be incorporated into aerosolisable phospholipid microspheres (made from e.g. dipalmityl phosphytidylcholine, a natural component of the lung surfactant) for delivery to the deeper lung where the alveolar macrophages are primarily resident. Disposable, low cost inhaler devices are available for administration of the powder. The microspheres will deposit in the lung and dissolve, releasing the nanoparticles into the lung lining fluid. Due to their mannose-coating, the nanoparticles will be preferentially taken up by alveolar macrophages, even infected cells. After waiting a short period of time (to be determined) for the nanoparticles to accumulate sufficiently in the macrophage cells, the patient will be exposed for approximately 1 hour to short frequency radio waves applied externally by a portable, inexpensive radio frequency wave generator. The radio waves will excite the nanoparticles causing vibrations that generate intracellular loci of sustained heat in the range of 90–130°C within macrophage cells, leading to protein denaturation and induction of apotosis.  The intracellular heat will also hopefully be sufficient to destroy internalised bacilli in the same process. Non-internalised iron-oxide nanoparticles will not be able to generate localised hyperthermia and will therefore be non-toxic to surrounding tissue. These particles will be safely cleared and or degrade naturally in the lung. Precision hyperthermia treatment is expected to be necessary only once or possibly twice at the beginning of the therapy scheme to decrease the numbers of macrophages enough to achieve enhanced efficacy of the antibiotics given. 

With regard to the safety of the strategy, studies of pharmacological depletion of alveolar macrophages using liposome-encapsulated clodronate shows replenishment of the macrophage population within 5-7 days. In animal models, transient macrophage depletion does not induce serious side effects and is fully reversible. It should be noted that precision hyperthermia will be safer and more effective than clondronate treatment because clondronate exhibits non-specific toxicity towards other mammalian cells and lacks antimicrobial properties.

copyright © Gino Francesco 2011