title: Systems biology approach for in vivo photodynamic therapy optimization of ruthenium-porphyrin compounds.
abstract: Two arene ruthenium porphyrin compounds showing interesting photodynamic activity in vitro, [Ru(η(6)-p-Pr(i)C(6)H(4)Me)(PMP)Cl(2)] (PMP=5-(3-pyridyl)-10,15,20-triphenylporphyrin) and [Ru(4)(η(6)-p-Pr(i)C(6)H(4)Me)(4)(PTP)Cl8] (PTP=5,10,15,20-tetra(3-pyridyl)porphyrin) coined Rut1 and Rut4 respectively, have been evaluated in vivo. Porphyrins alone and the arene ruthenium porphyrin derivatives (Rut1 and Rut4) showed comparable spectroscopic and photophysical properties. The in vivo study consisted in selecting the optimal arene ruthenium porphyrin photosensitizer by using an original experimental design approach on mice bearing an ectopic human oral carcinoma xenograft. The model of experimental design demonstrated to be well suited to the empirical model-building of photodynamic therapy (PDT) response. Arene ruthenium porphyrins concentration and fluence level demonstrated no statistically significant influence on the tumor growth. On the contrary, the presence of ruthenium groups improved the in vivo photodynamic efficiency. By optical fiber fluorimetry, we demonstrated that both compounds exhibited enhanced accumulation in KB tumors from 24h to 96 h post-intravenous injection. These experiments were completed by inductively coupled plasma mass spectrometry quantification of ruthenium in different organs including tumor tissue. Despite a statistically significant in vivo photodynamic efficiency for Rut4, cellular localization in human oral carcinoma KB cells using fluorescence microscopy demonstrated that both conjugates Rut1 and Rut4 accumulated only in cytoplasm of KB cells but not in the nucleus.
authors.affiliation: Université de Lorraine, CRAN, UMR 7039, Campus Sciences, BP 70239, Vandœuvre-lès-Nancy Cedex 54506, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Pernot
authors.forename: Thierry
authors.initials: T
authors.lastname: Bastogne
authors.forename: Nicolas P E
authors.initials: NP
authors.lastname: Barry
authors.forename: Bruno
authors.initials: B
authors.lastname: Therrien
authors.forename: Gunda
authors.initials: G
authors.lastname: Koellensperger
authors.forename: Stephan
authors.initials: S
authors.lastname: Hann
authors.forename: Vadzim
authors.initials: V
authors.lastname: Reshetov
authors.forename: Muriel
authors.initials: M
authors.lastname: Barberi-Heyob
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001692:Biological Transport; D045744:Cell Line, Tumor; D055808:Drug Discovery / Q000379:methods*; D005260:Female; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008665:Metalloporphyrins / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D012428:Ruthenium / Q000737:chemistry*; D013057:Spectrum Analysis; D049490:Systems Biology
chemical_list: D000970:Antineoplastic Agents; D008665:Metalloporphyrins; D017319:Photosensitizing Agents; D012428:Ruthenium