Comparative Study of Photodynamic Properties of 13,15-N-cycloimide Derivatives of Chlorin p6

• Published in: Photochemistry and photobiology Vol. 79; no. 2; pp. 172 - 188
• Main Authors: Feofanov, Alexei, Sharonov, George, Grichine, Alexei, Karmakova, Tatyana, Pljutinskaya, Anna, Lebedeva, Victoria, Ruziyev, Ramzes, Yakubovskaya, Raisa, Mironov, Andrei, Refregier, Matthieu, Maurizot, Jean-Claude, Vigny, Paul
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-02-2004; Wiley
• Subjects: Biological Transport; Cell Death; Cell Line, Tumor - drug effects; Cell Line, Tumor - metabolism; Dose-Response Relationship, Drug; Humans; Photochemotherapy; Photosensitizing Agents - pharmacology; Photosensitizing Agents - toxicity; Porphyrins - analysis; Porphyrins - pharmacology; Porphyrins - toxicity; Reactive Oxygen Species - metabolism; Research s; Solubility; Spectrometry, Fluorescence; Staining and Labeling; Structure-Activity Relationship; Subcellular Fractions - drug effects; Subcellular Fractions - metabolism; Subcellular Fractions - pathology; Temperature
• ISSN: 0031-8655; 1751-1097; 0031-8655
• DOI: 10.1562/0031-8655(2004)079<0172:CSOPPO>2.0.CO;2

Comparative study of 13,15-[N-(2-hydroxyethyl)]cycloimide chlorin p6 (2), 13,15-(N-acetoxy)cycloimide chlorin p6 (3), 13,15-(N-hydroxy)cycloimide chlorin p6 methyl ester (4) and 13,15-(N-methoxy)cycloimide chlorin p6 methyl ester (5) together with the previously investigated 13,15-[N-(3-hydroxypropyl)]cycloimide chlorin p6 (1) was performed. The dependence of the key photodynamic properties of 1–5 on the introduced substituents was analyzed. The photoinduced cell-killing activity of 4 is 100- and 280-fold higher than that of chlorin p6 and Photogem, respectively, as estimated on A549 human lung adenocarcinoma cells. The activity is reduced eight times in the order 4 > 5 > 1 > 2 > 3. The intracellular accumulation of 1–5 occurs in cytoplasm in a monomeric form bound to the lipids of cellular membranes. This form of 1, 2, 3, 4 and 5 is characterized by the high quantum yield of singlet oxygen generation, which depends on the introduced substituents, 0.66, 0.59, 0.35, 0.51 and 0.73, respectively. The photostability is two-fold less for 1 and four-fold less for 2, 3 and 5 than for 4. The rates of cellular uptake and efflux of 1–5 vary widely, thus providing the way to optimize the pharmacological properties of the photosensitizer (PS) using the respective substituents. Modifying the substituents, 1–5 were targeted to different cellular organelles. The enhanced accumulation in the Golgi apparatus and mitochondria complemented with diffuse staining of intracellular membranous structures is a property of 1–4. Compound 5 accumulates selectively in the lipid droplets and stains weakly perinuclear structures. Temperature-sensitive mechanisms of transport are responsible for the 1–4 uptake. Diffusion can play a role in the internalization of 5 but not of 1–4. Endocytosis via caveolae, clathrin-dependent and adenosine triphosphate–dependent pathways are not noticeably involved in the 1–5 internalization. Independently from their intracellular localization 1, 4 and 5 are highly efficient near-IR PS, which induce predominantly an apoptotic type of cell death under conditions providing ca 50% level of phototoxicity and necrosis at the 100% level of phototoxicity.