Heavy-Atom-Free Photosensitizer-Loaded Lipid Nanocapsules for Photodynamic Therapy

Photodynamic therapy (PDT) is a clinically approved noninvasive treatment for cancer that employs a photosensitizer (PS) to generate cytotoxic reactive singlet oxygen (ROS) species that precisely destroy cancer cells at the targeted tumor sites. There is growing interest in the development of innovative photosensitizing agents and advanced delivery methods, offering superior phototherapeutic performance. The delivery of PS is a challenging task in PDT in regard to the high hydrophobicity of the PS molecule. To address this challenge, the incorporation of heavy-atom-free PS (HAF-PS) in effective drug delivery carriers is promising for PDT improvement. Herein, we propose a strategy to encapsulate the HAF-PS from the perylenediimide (PDI) family in the oily core of lipid nanocapsules (LNCs). The resulting HAF-PS-loaded LNCs formulations have the advantage to efficiently generate singlet oxygen (¹O₂) in a biorelevant environment. The LNCs formulations loaded with <b>O-PDI</b> (<b>O-PDI@LNC</b>) and <b>1S-PDI</b> (<b>1S-PDI@LNC</b>) were obtained by a solvent-free phase-inversion temperature (PIT) method. Our study demonstrates that optimized LNCs formulation loaded with <b>1S-PDI</b> acting as PS is a highly efficient approach to deliver phototherapeutic agents for PDT. Overall, it has been shown that illumination of <b>1S-PDI</b> leads to dramatic ¹O₂ production with an impressive quantum yield (<i>φSOQY</i> = 0.94) which was tested with 1,3-diphenylisobenzofuran (<b>DPBF</b>) as a specific trap. Moreover, the ¹O₂ generation was calculated in a phosphate buffer solution (<i>φSOQY</i> = 0.52) for loaded nanocarrier <b>1S-PDI@LNC</b>. <i>In vitro</i> cytotoxicity studies demonstrated a low dark toxicity of <b>1S-PDI@LNC</b> while illumination significantly enhanced its photocytotoxicity in cells. Furthermore, the cellular internalization of LNCs was demonstrated in U-87 MG cells using <b>O-PDI@LNC</b> as a model, exploiting the excellent fluorescence properties of <b>O-PDI</b>. This study has significant potential for advancing the development of HAF-PS-loaded LNCs for minimally invasive PDT.