Projeto Portugal 2030

Sumário

This project aims to undertaken the PRECLINICAL EVALUATION OF LUZ51 with the goal of establishing PDT AND/OR PDP USING LUZ51 AS A NEW AND INNOVATIVE MEDICAL APPROACH FOR THE TREATMENT OF PDAC. To achieve this major goal, this project includes three main objectives. THE FIRST OBJECTIVE is to evaluate the biodistribution/ pharmacokinetics (Task1), safety/ toxicity (Task2), and therapeutic potential (Task 3) of PDT using LUZ51 in different mouse models of PDAC with the ultimately goal of achieving a PDT protocol enabling the complete eradication of the primary tumor. In case of success, this optimization will open the door for a thorough exploration of the therapeutic benefits of PDT using LUZ51 for PDAC. THE SECOND MAJOR OBJECTIVE will be the development of PDT protocols that might be used to combat the desmoplasia associated with PDAC, ultimately allowing for the improvement of the delivery of anti-cancer therapeutic agents (Task 4). Although PD priming (PDP) has been shown mostly with subtherapeutic PDT protocols (6, 14, 15, 16), enhanced tumor permeability is also being reported with certain PSs at therapeutic doses (5, 17, 18, 19). Thereof, this project will investigate the potential of PDT at high (significant increase of overall survival), moderate (moderate increase of overall survival) and low doses (no increase of overall survival) to enhance the delivery of various classes of anti-cancer therapeutics. These therapeutics will include small drugs (e.g. LUZ51 itself and redaporfin), antibodies (e.g. cetuximab-IR700 and PD-L1-IRDye800), and nanocarriers (e.g. albumin-bound paclitaxel labelled with IRDye800). Tumor delivery will be followed at different time points using in vivo non-invasive fluorescence imaging and/or photoacoustic tomography. This will enable the identification of variables influencing PDP and to establish correlations between the PDP protocol and the agent that is intended for delivery THE THIRD MAIN OBJECTIVE of this project is to provide a better understanding of the priming effects of PDT/PDP on the TME (Task 5). To achieve this, we will evaluate the impact of high, moderate, and low PDT doses on various aspects of the TME. We will assess the effects of PDT on the tumor blood flow and on the tumor vasculature structure and permeability. Additionally, we will evaluate the impact of PDT on acellular components of the ECM such as, different types of collagen (I, II, III, IV), elastin, fibronectin, and on the cancer-associated fibroblasts, which are the main source of collagen. Furthermore, immune cells (from the innate and adaptive arms of the immune system) will be evaluated both at the tumor bed and systemically, while an array of serum cytokines will be also quantified. The knowledge acquired will contribute to advance our understanding of the priming effects of PDT at different doses and its potential implications for the control of desmoplasia associated to PDAC. Finally, the confirmation that the photoactivation of LUZ51 primes the TME, namely by enhancing tumor permeability and/or inducing an active immune state, will be succeeded by a more-in-depth exploration of this strategy to improve the action of both i) LUZ51 itself at therapeutic doses (PDP + PDT, using LUZ51) or ii) other anti-cancer drugs. Special focus will be given to ICBs, considering that this class of therapeutics is revolutionizing cancer treatment. However, as with other macromolecules, their efficacy is hindered by poor delivery.