Ablação Fotodinâmica na Fibrilação Auricular

The overarching objective of this project is to develop a better therapy for atrial fibrillation (AF) and improve the quality of life of millions of patients. This will be done meeting a series of subsidiary scientific objectives: 1) Devise a new synthetic route to stable bacteriochorins with variable water solubilities, that allows for their isolation with high purities; 2) Make cardiomyocyte-targeted bacteriochlorins that are 10x more internalized by cardiomyocytes than by fibroblasts; 3) Understand the mechanism of cell uptake of targeted bacteriochlorins, the possible role of endocytosis and its consequences for the integrity of the photosensitizer, and its subcellular localization; 4) Characterize the photochemistry of BChl-CTP photosensitizers in the perspective of their use as PDT photosensitizers. 5) Establish structure-activity relations based on cardiomyocyte phototoxicity with one hour of incubation, and predict the molecular structures of the BChl-CTP that may best perform in PAAF; 6) Develop a biocompatible formulation for intravenous administration; 7) Determine the pharmacokinetics, biodistribution and toxicity of selected BChl-CTP photosensitizers; 8) Select a drug candidate for isolated heart experiments. The realization of subsidiary objectives 2 and 3 will offer a fundamental scientific understanding of photosensitizers targeted with cell-penetrating peptides. This may have profound consequences for the development of photosensitizers targeting other tissues and cells. The last clinical approval of a photosensitizer for cancer was cetuximab saratolacan (Akalux®), which is a dye (IR700) bound to an antibody targeting the epidermal growth factor receptor (cetuximab) (15). Opening the way for alternative bioconjugates where a peptide replaces an antibody will impact cancer therapies. In addition to these scientific objectives, there are also objectives in the training of highly-qualified human resources and in the transfer of knowledge. In particular: 9) This project includes 5 undergraduate/graduate students, which will have the opportunity to learn all the steps of a Medicinal Chemistry campaign with a team that patented and developed a drug that completed Phase II clinical trials. Participating in this project, the graduated students will acquire skills to work at the highest research level in pharma/biotech companies. 10) Drug development requires huge investments and is only profitable if the drug has robust patent protection. We consulted specialized patent lawyers (Olbrich Patentanwälte, Frankfurt am Main) to understand the patent landscape around PAAF. The compounds are novel and patentable. CTP was patented in 2010 but only in the US, and is licensed to Vivasc Therapeutics. Freedom to operate is not expected in the US before 2030, but elsewhere that should not be a problem. If this project is successfully completed by 2027 and clinical trials last until 2030, commercialization in 2031 would not be limited anywhere. These objectives are aligned with Regional Strategy of Intelligent Specialization (ENEI/RIS3) of the Center of Portugal, which elected Health and Wellbeing as a differentiating area with the vision of fostering new research and transferring it to tech companies and society. Finally, we have a strong track-record in communicating science to the general public and in pitching to venture capitalists. Outreach to society and to investors is an integral part of our objectives in this project.