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PubMed1993

The use of internalizable derivatives of chlorin E6 for increasing its photosensitizing activity.

Experiments with human hepatoma PLC/PRF/5 cells and human embryo skin fibroblasts involving the use of three different tests (colony formation, Trypan blue exclusion, labeled thymidine incorporation) have demonstrated a significantly higher photosensitizing activity of chlorin e6 conjugates with internalizable ligands as compared to that of chlorin e6 itself. Receptor-mediated internalization of chlorin e6 conjugates ensures a greater photosensitization of cells than binding of those conjugates to cell surface receptors. The suitability of such conjugates that permit the delivery of a photosensitizer to sensitive intracellular targets is discussed.

Cells, Cultured↗
PubMed1993

Metabolically convertible lipophilic derivatives of pH-sensitive amphipathic photosensitizers.

We propose the use of acetoxymethyl esters of pH-sensitive amphipathic photosensitizers (PS) for photodynamic therapy (PDT). These compounds may be applicable for PDT involving endocytosis of lipophilic carriers leading to lysosomal uptake of the esterified PS by target cells. Partial and/or total enzymatic de-esterification may result in the extralysosomal distribution of the photoactive agents, possibly culminating in a multisite photochemical response. We report here the synthesis and properties of chlorin e6 triacetoxymethyl ester (CAME) and pheophorbide a acetoxymethyl ester (PAME). Chlorin e6 and pheophorbide a are photocytotoxic chlorins that possess free carboxylate groups and exhibit optimum wavelengths of excitation substantially red shifted relative to hematoporphyrin derivative. Acetoxymethyl esterification of chlorin e6 and pheophorbide a was accomplished with bromomethyl acetate. High-performance liquid chromatography allowed for the purification of PAME, in 87% purity, and CAME, in 63% yield and 94% purity, as well as the detection of the presumed mono- and diesters of chlorin e6 as transient intermediates in the synthesis of CAME. The ultraviolet-visible absorption, fluorescence excitation and emission, NMR and mass spectra of the chlorin e6 triester are consistent with those expected for CAME. The pH-sensitive amphipathicity of pheophorbide a and chlorin e6 but not CAME was demonstrated using a water/1-octanol partition assay. The production of pheophorbide a from PAME and the sequential formation of the di- and monoesters and free chlorin e6 from CAME, by the action of lysosomal esterases obtained from cancer cells, demonstrate the potential of cellular enzymes to convert the lipophilic esters to pH-sensitive amphipathic PS.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma↗
PubMed1997

The effect of charge on cellular uptake and phototoxicity of polylysine chlorin(e6) conjugates.

The effect of charge on the cellular uptake, localization and phototoxicity of conjugates between chlorin(e6) (ce6) and poly-L-lysine was studied in vitro. These conjugates (average MW 35-55 kDa) were synthesized to have polycationic, polyanionic or neutral charges. Two human cell lines (A431 epidermoid carcinoma cells and EA.hy926 hybrid endothelial cells) were studied and the cellular uptake of ce6 delivered by the conjugates of varying charge and free ce6 was measured at conjugate ce6 equivalent concentrations up to 0.4 microM. Uptake was time and concentration dependent and temperature dependent in the case of neutral and anionic conjugates. Relative uptake at 6 h for A431 cells was 73:15:4:1 and for EA.hy926 cells was 63:11:3:1 for cationic, anionic, neutral and free ce67 respectively, but EA.hy926 cells took up 1.5-2 times as much ce6 from all the conjugates as A431 cells. Localization as studied by fluorescence microscopy indicated that the cationic conjugate was in aggregates bound to the plasma membrane, while the other forms were internalized in organelles and membranes. Phototoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT) assay after irradiation with 5-20 J cm2 of 666 nm light. In contrast to the uptake, the order of phototoxicity for both cell types per mole of ce6 uptake per cell was neutral >> anionic > cationic > free ce6. Polymeric ce6 conjugates bearing positive, negative and neutral charges may have different tissue-localizing properties and could play a role in photodynamic therapy.

Cell Line↗
PubMedDate not supplied

Photosensitizer delivery to vulnerable atherosclerotic plaque: comparison of macrophage-targeted conjugate versus free chlorin(e6).

We have previously shown that a conjugate (MA-ce6) between maleylated serum albumin and the photosensitizer chlorin(e6) (ce6) is targeted in vitro to macrophages via class A scavenger receptors. We now report on the ability of this conjugate to localize in macrophage-rich atherosclerotic plaques in vivo. Both the conjugate and the free photosensitizer ce6 are studied after injection into New Zealand White rabbits that are rendered atherosclerotic by a combination of aortic endothelial injury and cholesterol feeding into normal rabbits. Rabbits are sacrificed at 6 and 24 h after injection and intravascular fluorescence spectroscopy is carried out by fiber-based fluorimetry in intact blood-filled arteries. Surface spectrofluorimetry of numbered excised aortic segments together with injured and normal iliac arteries is carried out, and quantified ce6 content by subsequent extraction and quantitative fluorescence determination of the arterial segments and also of nontarget organs. There is good agreement between the various techniques for quantifying ce6 localization, and high contrast between arteries from atherosclerotic and normal rabbits is obtained. Fluorescence correlates with the highest burden of plaque in the aorta and the injured iliac artery. The highest accumulation in plaques is obtained using MA-ce6 at 24 h. Free ce6 gives better accumulation at 6 h compared to 24 h. The liver, spleen, lung, and gall bladder have the highest uptake in nontarget organs. Macrophage-targeted photosensitizer conjugates may have applications in both detecting and treating inflamed vulnerable plaque.

Animals↗
PubMed1998

Targeted antimicrobial photochemotherapy.

This study explores a new approach for antimicrobial therapy with light activation of targeted poly-L-lysine (pL)-chlorin e6 (ce6) conjugates. The goal was to test the hypothesis that these conjugates between pL and ce6 would efficiently target photodestruction towards gram-positive (Actinomyces viscosus) and gram-negative (Porphyromonas gingivalis) oral species while sparing an oral epithelial cell line (HCPC-1). Conjugates of ce6 with pL (average molecular weight, 2,000) having a positive, neutral, or negative charge were prepared. Illumination with red light (lambdamax = 671 nm) from a diode array produced a dose-dependent loss of CFU from the bacteria, under conditions that did not affect the viability of the epithelial cells. For P. gingivalis, the cationic conjugate produced 99% killing, while the neutral conjugate killed 91% and the anionic conjugate killed 76% after 1 min of incubation and exposure to red light for 10 min. For A. viscosus, the cationic conjugate produced >99.99% killing while HCPC-1 cells remained intact. The importance of the positive charge was shown by the effectiveness of ce6-monoethylenediamine monoamide (a monocationic derivative of ce6) in killing both bacteria. The clinically employed benzoporphyrin derivative under the same conditions killed epithelial cells while leaving P. gingivalis relatively unharmed. A mixture of ce6 with pL did not show phototoxicity comparable with that of the cationic conjugate. These results were explained by the selective uptake of the conjugates by bacteria (20- to 100-fold) compared to that by mammalian cells, while free ce6 showed much less selectivity for bacteria (5- to 20-fold). The data suggest that the cationic pL-ce6 conjugate may have an application for the photodynamic therapy of periodontal disease.

Animals↗
PubMed2005

Effect of cell-photosensitizer binding and cell density on microbial photoinactivation.

Photodynamic therapy involves the use of nontoxic dyes called photosensitizers and visible light to produce reactive oxygen species and cell killing. It is being studied as an alternative method of killing pathogens in localized infections due to the increasing problem of multiantibiotic resistance. Although much has been learned about the mechanisms of microbial killing, there is still uncertainty about whether dyes must bind to and penetrate various classes of microbe in order to produce effective killing after illumination. In this report, we compare the interactions of three antimicrobial photosensitizers: rose bengal (RB), toluidine blue O (TBO), and a poly-L-lysine chlorin(e6) conjugate (pL-ce6) with representative members of three classes of pathogens; Escherichia coli (gram-negative bacteria), Staphylococcus aureus (gram-positive bacteria), Candida albicans (yeast). We compared fluence-dependent cell survival after illumination with the appropriate wavelengths of light before and after extracellular dye had been washed out and used three 10-fold dilutions of cell concentration. pL-ce6 was overall the most powerful photosensitizer, was equally effective with and without washing, and showed a strong dependence on cell concentration. TBO was less effective in all cases after washing, and the dependence on cell concentration was less pronounced. RB was ineffective after washing (except for S. aureus) but still showed a dependence on cell concentration. The overall order of susceptibility was S. aureus>E. coli>C. albicans, but C. albicans cells were 10 to 50 times bigger than the bacteria. We conclude that the number and mass of the cells compete both for available dye binding and for extracellularly generated reactive oxygen species.

Candida albicans↗
PubMed2006

Protease-stable polycationic photosensitizer conjugates between polyethyleneimine and chlorin(e6) for broad-spectrum antimicrobial photoinactivation.

We previously showed that covalent conjugates between poly-L-lysine and chlorin(e6) were efficient photosensitizers (PS) of both gram-positive and gram-negative bacteria. The polycationic molecular constructs increased binding and penetration of the PS into impermeable gram-negative cells. We have now prepared a novel set of second-generation polycationic conjugates between chlorin(e6) and three molecular forms of polyethyleneimine (PEI): a small linear, a small cross-linked, and a large cross-linked molecule. The conjugates were characterized by high-pressure liquid chromatography and tested for their ability to kill a panel of pathogenic microorganisms, the gram-positive Staphylococcus aureus and Streptococcus pyogenes, the gram-negative Escherichia coli and Pseudomonas aeruginosa, and the yeast Candida albicans, after exposure to low levels of red light. The large cross-linked molecule efficiently killed all organisms, while the linear conjugate killed gram-positive bacteria and C. albicans. The small cross-linked conjugate was the least efficient antimicrobial PS and its remarkably low activity could not be explained by reduced photochemical quantum yield or reduced cellular uptake. In contrast to polylysine conjugates, the PEI conjugates were resistant to degradation by proteases such as trypsin that hydrolyze lysine-lysine peptide bonds, The advantage of protease stability combined with the ready availability of PEI suggests these molecules may be superior to polylysine-PS conjugates for photodynamic therapy of localized infections.

Candida albicans↗
PubMed2006

Selective antitumor effect of novel protease-mediated photodynamic agent.

A new approach to selective photodynamic therapy (PDT) was developed by designing chlorin e6 (Ce6)-containing macromolecules, which are sensitive to tumor-associated proteases. The agents are nontoxic in their native state but become fluorescent and produce singlet oxygen on protease conversion. Coupled with optimized delivery systems, we show that (a) the agents efficiently accumulate in tumors due to the enhanced permeability and retention effect, (b) the agents are locally activated by proteases, (c) local drug concentrations can be measured by quantitative fluorescence tomography, and (d) light-treated tumors show reduced growth. A single low dose of PDT (0.125 mg Ce6 equivalent/kg) was sufficient to suppress tumor growth by >50%. Activatable singlet oxygen generation agents provide increased efficacy with reduced toxicity, and it could become a powerful PDT.

Animals↗
PubMed2006

Induction of apoptosis in HaCaT cells by photodynamic therapy with chlorin e6 or pheophorbide a.

The two photosensitizers, chlorin e6 and pheophorbide a, were tested in an in vitro model of topical photodynamic therapy (PDT). Both dyes accumulate in HaCaT keratinocytes as verified by fluorescence measurement but pheophorbide a is enriched fivefold more strongly than chlorin e6 after 24 h. HaCaT cells are susceptible to PDT with both dyes. The phototoxicity measured by ATP bioluminescence is caused by necrosis and apoptosis depending on the photosensitizer used and the treatment modality. Chlorin e6 shows higher toxic potential because it elicits nearly 90% cell mortality 24 h after PDT comparable to pheophorbide a but with a fivefold lower rate of accumulation. These results implicate caution with topical PDT of oncologic diseases due to the risk of serious side effects on healthy skin in the course of topical photodynamic treatment. But the lack of dark toxicity and the time-dependent enrichment of both dyes in HaCaT cells are arguments for the application of these sensitizers in topical PDT of non-malign skin disorders. Further studies are necessary to discover appropriate lower doses and mechanisms of action of topical PDT with both compounds.

Apoptosis↗
PubMed1983

Effect of chlorophyllin on urinary odor in incontinent geriatric patients.

This randomized, double-blind, crossover, placebo-controlled study involved 20 incontinent geriatric patients; all had indwelling Foley catheters. Each patient received chlorophyllin 100 mg/d for two weeks and placebo daily for two weeks, separated by a washout period of one week. For each subject, the intensity of urinary odor was measured ten times during both the treatment and placebo regimen and three times during the washout period, using a visual analog scale. A decrease in urinary odor was associated with chlorophyllin in 12 patients and with placebo in 6 patients at the end of two weeks on each regimen. Chlorophyllin treatment was associated with about a 21-percent decrease in mean urinary odor intensity, whereas placebo increased the odor by about 9 percent. The mean intensity of urinary odor was lowest during the second week of chlorophyllin treatment. Despite the decrease in urinary odor in many patients receiving chlorophyllin, its effect was not significantly greater than that of placebo. Our data suggest that chlorophyllin 100 mg/d for two weeks may not be effective in incontinent geriatric patients with mild to moderate urinary odor.

Aged↗
PubMed2003

Effect of dietary constituents with chemopreventive potential on adduct formation of a low dose of the heterocyclic amines PhIP and IQ and phase II hepatic enzymes.

We conducted a study to evaluate dietary chemopreventive strategies to reduce genotoxic effects of the carcinogens 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). PhIP and IQ are heterocyclic amines (HCAs) that are found in cooked meat and may be risk factors for cancer. Typical chemoprevention studies have used carcinogen doses many thousand-fold higher than usual human daily intake. Therefore, we administered a low dose of [14C]PhIP and [3H]IQ and utilized accelerator mass spectrometry to quantify PhIP adducts in the liver, colon, prostate, and blood plasma and IQ adducts in the liver and blood plasma with high sensitivity. Diets supplemented with phenethylisothiocyanate (PEITC), genistein, chlorophyllin, or lycopene were evaluated for their ability to decrease adduct formation of [14C]PhIP and [3H]IQ in rats. We also examined the effect of treatments on the activity of the phase II detoxification enzymes glutathione S-transferase (GST), UDP-glucuronyltransferase (UGT), phenol sulfotransferase (SULT) and quinone reductase (QR). PEITC and chlorophyllin significantly decreased PhIP-DNA adduct levels in all tissues examined, which was reflected by similar changes in PhIP binding to albumin in the blood. In contrast, genistein and lycopene tended to increase PhIP adduct levels. The treatments did not significantly alter the level of IQ-DNA or -protein adducts in the liver. With the exception of lycopene, the treatments had some effect on the activity of one or more hepatic phase II detoxification enzymes. We conclude that PEITC and chlorophyllin are protective of PhIP-induced genotoxicity after a low exposure dose of carcinogen, possibly through modification of HCA metabolism.

Animals↗
PubMed2002

Preventive effects of chlorophyllin fixed on chitosan towards DNA adduct formation of 3-amino-1-methyl-5H-pyrido [4,3-b]indole in CDF1 mice.

Chlorophyllin, a water-soluble derivative of chlorophyll, is known to suppress the mutagenic and carcinogenic action of compounds having polycyclic structures, e.g., heterocyclic amines and aflatoxin B1. Recently, we reported that chlorophyllin fixed on chitosan (chl-chitosan), which is insoluble in water, can efficiently and tightly trap these heterocyclic amines. We have studied whether this adsorption to chl-chitosan can result in an interference with DNA-adduct formation caused by 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), a heterocyclic amine, in CDF1 mice, in which Trp-P-2 had been shown to induce hepatocellular carcinomas. Mice were fed a diet containing Trp-P-2 with or without chl-chitosan. After 3 d of feeding, DNA-adduct formation in liver and lung was examined by 32P-postlabeling analysis. Adducts formed from Trp-P-2 were significantly decreased by the chl-chitosan addition (p<0.05, t-test). These results suggest that the uptake of Trp-P-2 into the mouse was lowered by its adsorption to chl-chitosan, either within the digestive tract or within the food itself. This trapping agent, chl-chitosan, is thus worthy of study for cancer chemoprevention.

Animals↗
PubMed2004

No effects of chlorophyllin on IQ (2-amino-3-methylimidazo[4,5-f]-quinoline)-genotoxicity and -DNA adduct formation in Drosophila.

Previously we demonstrated that chlorophyllin suppressed the genotoxicities of many carcinogens. However, the genotoxicity of IQ (2-amino-3-methylimidazo[4,5-f]quinoline), a carcinogenic heterocyclic amine, was not suppressed in Drosophila. On the contrary, it has been reported that chrolophyllin suppressed the genotoxicity of IQ in rodents, rainbow trout and Salmonella. We demonstrated that the chlorophyllin-induced suppression of MeIQx (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline)-genotoxicity was associated with a decrease in MeIQx-DNA adduct formation in Drosophila larval DNA. MeIQx represents another type of heterocyclic amine and is similar to IQ in structure. In this study we utilized (32)P-postlabeling to examine whether chlorophyllin reduced IQ-DNA adduct formation in Drosophila DNA in the same way as MeIQx. The results revealed that the formation of IQ-DNA adducts was unaffected by treatment with chlorophyllin. This was consistent with the absence of any inhibitory effect on genotoxicity as observed in the Drosophila repair test. These results suggest that IQ-behavior in Drosophila is not affected by chlorophyllin, indicating that the process of IQ-DNA adduct formation followed by expression of genotoxicity in Drosophila may be different from that in other organisms.

Animals↗