Strategies for overcoming the lung surfactant barrier and achieving success in antimicrobial photodynamic therapy

The impressive increase in antimicrobial resistance has required the development of alternative treatments that act on multiple non-specific molecular targets and are effective against a broad range of microorganisms. Antimicrobial Photodynamic Therapy (aPDT) is based on microbial inactivation from oxidative stress and represents an important tool for inactivating microorganisms with low risk of resistance selection. Therefore, our research group has been devoted to demonstrating its effectiveness against pathogens that cause pneumonia, one of the most lethal infections worldwide. Previous studies reported the efficiency and safety of an in vitro photoinactivation protocol for Streptococcus pneumoniae and the delivery of infrared light (external illumination) and photosensitizer (PS) in an animal model. However, the in vivo inactivation of microorganisms still poses challenges due to the presence of lung surfactant (LS), which traps PSs, preventing them from reaching the microbial target. This study investigated different approaches such as use of emulsifiers, perfluorocarbon, oxygen nanobubbles, and copolymer towards overcoming LS and optimizing aPDT response. The most promising strategy consisted in combining indocyanine green (ICG) with Gantrez^TM AN-139 - a Polyvinyl Methyl Ether/Maleic Anhydride copolymer (PVM/MA) – showing high microbial inactivation and safety for human lung epithelial (A549) and fibroblast (MRC-9) cell lines. The in vitro experiments provided an alternative to overcome the limited PS distribution through LS and will serve as the basis for in vivo studies.