Lipophilicity of Bacteriochlorin-Based Photosensitizers as a Determinant for PDT Optimization through the Modulation of the Inflammatory Mediators

Abstract

Photodynamic therapy (PDT) augments the host antitumor immune response, but the role of the PDT effect on the tumor microenvironment in dependence on the type of photosensitizer and/or therapeutic protocols has not been clearly elucidated. We employed three bacteriochlorins (F 2 BOH, F 2 BMet and Cl 2 BHep) of different polarity that absorb near-infrared light (NIR) and generated a large amount of reactive oxygen species (ROS) to compare the PDT efficacy after various drug-to-light intervals: 15 min. (V-PDT), 3h (E-PDT) and 72h (C-PDT). We also performed the analysis of the molecular mechanisms of PDT crucial for the generation of the long-lasting antitumor immune response. PDT-induced damage affected the integrity of the host tissue and developed acute (protocol-dependent) local inflammation, which in turn led to the infiltration of neutrophils and macrophages. In order to further confirm this hypothesis, a number of proteins in the plasma of PDT-treated mice were identified. Among a wide range of cytokines (IL-6, IL-10, IL-13, IL-15, TNF-α, GM-CSF), chemokines (KC, MCP-1, MIP1α, MIP1β, MIP2) and growth factors (VEGF) released after PDT, an important role was assigned to IL-6. PDT protocols optimized for studied bacteriochlorins led to a significant increase in the survival rate of BALB/c mice bearing CT26 tumors, but each photosensitizer (PS) was more or less potent, depending on the applied DLI (15 min, 3 h or 72 h). Hydrophilic (F 2 BOH) and amphiphilic (F 2 BMet) PSs were equally effective in V-PDT (>80 cure rate). F 2 BMet was the most efficient in E-PDT (DLI = 3h), leading to a cure of 65 % of the animals. Finally, the most powerful PS in the C-PDT (DLI = 72 h) regimen turned out to be the most hydrophobic compound (Cl 2 BHep), allowing 100 % of treated animals to be cured at a light dose of only 45 J/cm 2 .In practice, three fundamental PDT approaches are investigated: vascular-targeted PDT (V-PDT), tumor cellular-targeted PDT (C-PDT) and endothelial cells-targeted PDT (E-PDT). V-PDT is characterized by short drug-to-light intervals (DLI = 5-15 min). The main target of this protocol is the tumor vascularization. C-PDT targets tumour cells directly through specific molecules on cancer cells' surfaces. In this case, longer drug-to-light intervals (DLI > 12h) are used [8][9][10][11]. At intermediate DLIs (e.g., 3 h) the PS is found mainly in the blood and endothelial cells, with partial accumulation in tumor cells [6,12], and protocols using such intermediate DLIs are designated here as E-PDT.The first step in PDT is the selection of a PS with physicochemical and pharmacological properties adequate for the intended PDT regime [13]. The hydrophilicity/lipophilicity of the PS is one of the most important factors influencing its biological behavior, including uptake by cancer cells, intracellular localization, biodistribution and pharmacokinetics [14,15]. The high expression of low-density lipoprotein (LDL) receptors in tumors makes LDL-bounded lipophilic PSs more likely to achieve LDL-receptor-mediated endocyt...

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