Periodic Reporting for period 3 - LIGHT4LUNGS (Inhalable Aerosol Light Source for Controlling Drug-Resistant Bacterial Lung Infections)
Período documentado: 2022-12-01 hasta 2024-05-31
The FET Open project "Inhalable Aerosol Light Source for Controlling Drug-Resistant Bacterial Lung Infections" (with acronym Light4Lungs and Grant agreement ID: 863102) proposes a novel approach to address the problem of antimicrobial resistance in the treatment of chronic lung infections, which are the leading cause of morbidity and mortality in patients with diseases such as cystic fibrosis and hospital-acquired lung infections.
The goal is to develop a novel therapeutic scheme for the treatment of the infections, replacing antibiotics by inhalable light sources that will excite bacterial endogenous photosensitizers (e.g. iron-free porphyrins), eliminating the pathogenic bacteria by the photodynamic effect (local production of cytotoxic reactive oxygen species by the combined action of light, a photosensitiser and oxygen) irrespective of its multidrug resistance profile. The aim is to have a safe treatment for the host tissue thanks to its lack of self-photosensitising ability.
Three main objectives are being pursued: (i) The design of the treatment components, based on biological models, aerosol-based light emitting particles, and the action spectrum of the photodynamic effect; (ii) the realisation of the treatment components, from the particles to the aerosol and to the mechanism of particle activation prior to inhalation; and (iii) the assessment of the treatment efficacy and safety using in vitro and in vivo models.
At the end of the project, proof of concept has been achieved: an inhalable light source has been developed that is devoid of any measurable toxicity against the lungs host tissue but inactivates bacteria through the emission of light. An stable aerosol formulation of the light-emitting particles has been developed for delivery to the lungs. The therapy components have been tested in a variety of in vitro, ex vivo and in vivo lung infections models and the mechanistic insight that has been gained has been used to boost the efficiency of the bacterial photoinactivation process. The main barriers for clinical translation of the light therapy have been identified.
The goal is to develop a novel therapeutic scheme for the treatment of the infections, replacing antibiotics by inhalable light sources that will excite bacterial endogenous photosensitizers (e.g. iron-free porphyrins), eliminating the pathogenic bacteria by the photodynamic effect (local production of cytotoxic reactive oxygen species by the combined action of light, a photosensitiser and oxygen) irrespective of its multidrug resistance profile. The aim is to have a safe treatment for the host tissue thanks to its lack of self-photosensitising ability.
Three main objectives are being pursued: (i) The design of the treatment components, based on biological models, aerosol-based light emitting particles, and the action spectrum of the photodynamic effect; (ii) the realisation of the treatment components, from the particles to the aerosol and to the mechanism of particle activation prior to inhalation; and (iii) the assessment of the treatment efficacy and safety using in vitro and in vivo models.
At the end of the project, proof of concept has been achieved: an inhalable light source has been developed that is devoid of any measurable toxicity against the lungs host tissue but inactivates bacteria through the emission of light. An stable aerosol formulation of the light-emitting particles has been developed for delivery to the lungs. The therapy components have been tested in a variety of in vitro, ex vivo and in vivo lung infections models and the mechanistic insight that has been gained has been used to boost the efficiency of the bacterial photoinactivation process. The main barriers for clinical translation of the light therapy have been identified.
The Project has achieved its objectives and milestones for the period with relatively minor deviations.
Un up-scale synthesis of the light-emitting naoparticles was developed for distribution to the other Consortium partners. A bach of fluorescent particles was prepared for mechanistic studies by attaching a fluorescent dye to the surface of the particles. The photon-storage capacity of the particles was determined ans the mechanism of persistent luminescence was unraveled. Production of singlet oxygen and inactivation of bacteria by the light-emitting barticles was successfully demonstrated. The formulation of an aerosol form of the particles was developed and the aerosol generation conditions were optimised. The aerosol emission and luminescence quantum yield were characterized. Mechanistic insight on photoinactivation of bacteria was gained: Endogenous photosensitisers in the bacteria were characterized and their ability to produce triplet excited states and singlet oxygen was established. The role of singlet oxygen and other reactive species in the bacterial photoinactivation was characterized as well and enhancers of photoinactivation were identified and tested against bacteria in planktonic and biofilm states. The aerosol biocompatibility with the human cells of the respiratory tract was studied at several levels up to analysis of gene expression profiles in human cells exposed to the particles. The results indicate that the light-emitting particles are well tolerated by the selected cell models mimicking the different districts of the respiratory tract, thus denoting excellent biocompatibility. The particles were then tested in advanced in vitro- as well as in in vivo and ex vivo models of respiratory infection. The results indicate an excellent activity of the particles and a potentiation effect of an adjuvant antibiotic therapy.
Un up-scale synthesis of the light-emitting naoparticles was developed for distribution to the other Consortium partners. A bach of fluorescent particles was prepared for mechanistic studies by attaching a fluorescent dye to the surface of the particles. The photon-storage capacity of the particles was determined ans the mechanism of persistent luminescence was unraveled. Production of singlet oxygen and inactivation of bacteria by the light-emitting barticles was successfully demonstrated. The formulation of an aerosol form of the particles was developed and the aerosol generation conditions were optimised. The aerosol emission and luminescence quantum yield were characterized. Mechanistic insight on photoinactivation of bacteria was gained: Endogenous photosensitisers in the bacteria were characterized and their ability to produce triplet excited states and singlet oxygen was established. The role of singlet oxygen and other reactive species in the bacterial photoinactivation was characterized as well and enhancers of photoinactivation were identified and tested against bacteria in planktonic and biofilm states. The aerosol biocompatibility with the human cells of the respiratory tract was studied at several levels up to analysis of gene expression profiles in human cells exposed to the particles. The results indicate that the light-emitting particles are well tolerated by the selected cell models mimicking the different districts of the respiratory tract, thus denoting excellent biocompatibility. The particles were then tested in advanced in vitro- as well as in in vivo and ex vivo models of respiratory infection. The results indicate an excellent activity of the particles and a potentiation effect of an adjuvant antibiotic therapy.
Light4lungs addresses the problem of antimicrobial resistance in the treatment of chronic lung infections in a highly innovative way, whereby antibiotics will be replaced by breathable light sources that will eliminate the pathogenic bacteria through a photodynamic effect. Adoption of the Ligh4Lungs treatment scheme will therefore contribute to stop the spread of antibiotic resistance. The key novelty of the Light4Lungs concept is the use of breathable therapeutic light sources. The results of the project will be useful for patients with chronic multidrug resistant pulmonary bacterial infections, such as cystic fibrosis, and have a strong potential for extension to other pulmonary diseases, such as fungal infections and lung cancer, and eventually to other internal organs, having a profound impact on the fields of materials, photonics and healthcare.