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Communication Dans Un Congrès Année : 2016

Influence of mTHPC liposomal distribution in multicellular spheroid on the photodynamic therapy efficacy

Résumé

Meta-tetra(hydroxylphenylchlorin) (mTHPC, Foscan®) is a clinically approved photosensitizer (PS) for the photodynamic therapy (PDT) of cancer and is characterized by high absorption in the deep red and high 1O2 quantum yield(1). Various studies demonstrated that PDT efficacy is tightly related to intracellular and intratissular localization of mTHPC(2). However, Foscan® is a highly hydrophobic compound, it is partially aggregated even in the bloodstream thus resulting to unfavorable biodistribution and important side effects. Poor tumor selectivity and pharmacokinetics of Foscan® led to the development of mTHPC liposomal formulation, Foslip®(1). In vivo, Foslip® has showed a rapid biodistribution and clearance from the bloodstream(3). This formulation is interesting for PDT due to the decreased accumulation in skin compared to Foscan® and reduced pain upon intravenous administration(4). Multicellular spheroid is a non-vascularized micro-tumor tridimensional model of cells, similar to micro-metastases. Compared to monolayer cells, multicellular spheroid shows micro-environment similar to in vivo situation. Heterogeneous population of cells is the consequence of the oxygen gradient, naturally found in multicellular spheroid making it a suitable model to study PDT parameters(5). Thus, importance of irradiation fluence rate and nonuniform distribution of mTHPC has been demonstrated earlier(6, 2). The aim of this study was to determine whether mTHPC nanovectorization could induce a different spatiotemporal distribution of Foscan® and its impact on PDT efficacy. After 3, 6 and 24 h incubation, mTHPC uptake in HT29 multicellular spheroids was assessed by fluorescence measurements while the time-related diffusion of Foscan® and Foslip® was studied with fluorescence microscopy. After irradiation with various fluences administrated at the fluence rate of 30 mW.cm-2, cell survival was estimated using clonogenic assays. Already 3 h after incubation, a better accumulation in multicellular spheroids is observed with Foscan®. The maximum of mTHPC uptake is found after 24 hours. Foslip® displays less intracellular accumulation irrespective to incubation time along with a shorter diffusion distance. Unexpectedly, Foslip® demonstrated higher photocytotoxicity compared to liposome-free mTHPC. For instance, the 50% Foslip- mediated cells photoinactivation was observed at 30 J.cm-2, while much less photokilling was noted with Foscan®. This result can be partially linked to the difference of diffusion observed between Foscan® and Foslip® (see the figures here enclosed) and Foslip® monomer state. Further investigations are in progress to unravel these results. In conclusion, integration of mTHPC in liposomes improves photocytotoxicity in HT29 multicellular spheroids.
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Dates et versions

hal-02994934 , version 1 (08-11-2020)

Identifiants

  • HAL Id : hal-02994934 , version 1

Citer

Marie Millard, Ilya Yakovets, Sophie Marchal, Lina Bezdetna, Henri-Pierre Lassalle. Influence of mTHPC liposomal distribution in multicellular spheroid on the photodynamic therapy efficacy. Joint Congress of the French and Italian Photochemists and Photobiologists, Sep 2016, Bari, Italy. ⟨hal-02994934⟩
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