Novel Polymer-Based Photodynamic Therapy Following Aerosol Lung Delivery

The ANR/BMBF funded TARGET-THERAPY project is a multilateral collaboration, gathering French and German research teams bringing their expertise in chemistry, biology, and medicine.

The specific objective of this project is to significantly improve the treatment of recalcitrant infections with the WHO priority-1 pathogen Pseudomonas aeruginosa, which is one of the most dangerous key multi-drug resistant (MDR) bacteria, inside biofilms in the lungs. The therapeutic approach designed is based on photodynamic therapy (PDT), which holds great promise to overcome the loss of efficiency of current antibiotics. The TARGET-THERAPY approach makes use of photosensitizers that upon light exposure induce oxidative damages killing pathogens in the surrounding environment.

An integrated protocol is developed that comprises (i) the use of specifically designed PDT systems, (ii) administration to the pulmonary airways by means of a viable clinically applicable method, and (iii) in situ PDT activation by application of a localized light treatment. This new combined approach aims to overcome the key drawback of novel potent photosensitizers, i.e. limited solubility, by safeguarding a high local concentration through chemical design. In addition, the difficulties to administer neat active substances to the site of action across the pulmonary mucus and biofilms in patients with chronic pulmonary disease are circumvented by exploiting the properties of specifically tailored polymer systems.

A key advantage of this advanced approach is the spatially targeted and dose-controlled irradiation via a bronchoscope fiber, which permits localized generation of highly reactive oxygen species to kill pathogens selectively within the irradiated tissue area. The protocol is designed to ensure both efficiency and safety, as well as to circumvent pre-existing bacterial resistance, while limiting the emergence of new ones.

The approach relies on published proof-of-concept data of all partners and is developed and validated using bacteria and cell culture models (including mucus and/or biofilms), as well as animal models of MDR pneumonia. Particular attention is paid to the biodistribution following in vivo nebulization, to evaluate both the elimination pathway(s) and the potential release of photosensitizers into the environment. 

The novel TARGET-THERAPY approach will afford a highly effective in vivo treatment with spatio-temporal control to the benefit of patients suffering from a wide range of medical conditions associated to chronic pulmonary diseases.