mTHPC-loaded extracellular vesicles outperform liposomal and free mTHPC formulations by an increased stability, drug delivery efficiency and cytotoxic effect in tridimensional model of tumors

Efficient photodynamic therapy with meta-tetra(hydroxyphenyl)chlorine requires the application of specific nanoformulations. mTHPC liposomal formulation (Foslip(®)) demonstrated favorable pharmacokinetics properties. However, rapid liposomes destruction in circulation and rapid mTHPC release impedes Foslip(®) applications. Alternatively, mTHPC nanovectorization using extracellular vesicles (EVs) could be an attractive option. EVs are naturally secreted by the organism to play a role in intercellular communication due to the capacity to transport proteins and nucleic acids. EVs also possess a natural ability to deliver therapeutic molecules into cancer cells. The aim of the present study was to evaluate photophysical and photobiological properties of mTHPC loaded in endothelial EVs as nanocarriers. We also studied efficiency of nanovectorisation on mTHPC distribution and PDT activity in multicellular tumor spheroids (MCTSs). MCTS is a nonvascularized in vitro 3D model of cells that mimics a similar microenvironment to in vivo situation. mTHPC-EVs were characterized by means of spectroscopic techniques, flow cytometry and nanoparticle tracking analysis. Compared with Foslip(®), mTHPC-EVs are stable in murine plasma. Better mTHPC accumulation and penetration (up to 100 µm) in MCTS was observed for mTHPC-EVs compared with liposomal mTHPC. These factors could explain enhanced photodynamic activity of mTHPC-EVs compared with free and liposomal mTHPC. The light dose inducing 50% of cell death with mTHPC-EVs was 4 and 2.5-times lower than that of free and liposomal mTHPC. The obtained results demonstrate that EVs should be considered as perspective nanocarriers for mTHPC-mediated PDT.