Photodynamic therapy with conventional and PEGylated liposomal formulations of mTHPC (temoporfin): comparison of treatment efficacy and distribution characteristics in vivo

Abstract

Vadzim Reshetov,1–3 Henri-Pierre Lassalle,1,2 Aurélie François,1,2,4 Dominique Dumas,5 Sebastien Hupont,5 Susanna Gräfe,6 Vasco Filipe,7 Wim Jiskoot,7 François Guillemin,1,2,4 Vladimir Zorin,3 Lina Bezdetnaya1,2,41Université de Lorraine, Centre de Recherche en Automatique de Nancy, Campus Sciences, Vandœuvre-lès-Nancy, France; 2Centre National de la Recherche Scientifique, Centre de Recherche en Automatique de Nancy, France; 3Laboratory of Biophysics and Biotechnology, Physics Faculty, Belarusian State University, Minsk, Belarus; 4Lorraine Cancer Institute, Vandoeuvre-lès-Nancy, France; 5Université de Lorraine, Plate forme d'Imagerie et de Biophysique Cellulaire Plate Forme IBiSA d'Imagerie et de Biophysique Cellulaire de Nancy, Centre National de la Recherche Scientifique, Vandœuvre-lès-Nancy, France; 6Biolitec Research GmbH, Research and Development, Jena, Germany; 7Division of Drug Delivery Technology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, the NetherlandsAbstract: A major challenge in the application of a nanoparticle-based drug delivery system for anticancer agents is the knowledge of the critical properties that influence their in vivo behavior and the therapeutic performance of the drug. The effect of a liposomal formulation, as an example of a widely-used delivery system, on all aspects of the drug delivery process, including the drug's behavior in blood and in the tumor, has to be considered when optimizing treatment with liposomal drugs, but that is rarely done. This article presents a comparison of conventional (Foslip®) and polyethylene glycosylated (Fospeg®) liposomal formulations of temoporfin (meta-tetra[hydroxyphenyl]chlorin) in tumor-grafted mice, with a set of comparison parameters not reported before in one model. Foslip® and Fospeg® pharmacokinetics, drug release, liposome stability, tumor uptake, and intratumoral distribution are evaluated, and their influence on the efficacy of the photodynamic treatment at different light–drug intervals is discussed. The use of whole-tumor multiphoton fluorescence macroscopy imaging is reported for visualization of the in vivo intratumoral distribution of the photosensitizer. The combination of enhanced permeability and retention-based tumor accumulation, stability in the circulation, and release properties leads to a higher efficacy of the treatment with Fospeg® compared to Foslip®. A significant advantage of Fospeg® lies in a major decrease in the light–drug interval, while preserving treatment efficacy.Keywords: mTHPC, liposomes, drug release, liposomal pharmacokinetics, biodistribution, photodynamic therapy