Comparative Study of Photodynamic Properties of 13, 15‐N‐cycloimide Derivatives of chlorin p6^¶

Abstract

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.

Synthesis and Investigation of Photophysical and Biological Properties of Novel S-Containing Bacteriopurpurinimides

“…In addition, they were similar to the spectra recorded from these compounds in solution with 1% CrEL (Figure , III). Previous studies showed that CrEL emulsion was well suited to model cellular lipid-like environment of hydrophobic chlorine and bacteriochlorine PSs. ,, Thus, intracellular spectral characteristics of compounds 4 and 6 are consistent with their localization in lipid structures, e.g., lipid droplets and membrane-bound organelles.…”

“…Lipid droplets are lipid storage and metabolic organelles . Intracellular accumulation in lipid droplets is a property of chlorine and bacteriochlorine PSs with increased hydrophobicity. , As was shown previously, cancers cells were highly sensitive (both in vitro , and in vivo) to photodynamic action initiated by PSs localized in lipid droplets.…”

Confocal fluorescence spectral imaging technique and its applications to drug development

“…The CSI technique was successfully used in the studies of sulfonated phthalocyanines [9][10][11], cycloimide derivatives of chlorin p 6 (CIC) [12][13][14][15][16][17][18] and bacteriochlorin p (CIBC) [19]. It helped to clarify the fact that chelating with a metal atom was not essential for the efficiency of phthalocyanines in anticancer PDT [9].…”

“…These photosensitizers absorb in the 705-745 nm range, where human tissues are relatively transparent for the exciting light. Varying different substituents the CIC derivatives were found, which accumulated intensely (distribution ratio of 5-11) in cytoplasm of cancer cells in a lipid-bound monomeric photoactive form [12][13][14][15][16]. Hydrophobic substituents provided predominant accumulation of CICD in lipid droplets.…”