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PubMedDate not supplied

Shiga-like toxin subunit B (SLTB)-enhanced delivery of chlorin e6 (Ce6) improves cell killing.

We used Shiga-like toxin B subunit (SLTB) to deliver the photosensitizer, chlorin e6 (Ce6), to Vero cells expressing the Gb3 receptor. Our aim was to provide an example of carrier-enhanced photodynamic cell killing with which to start a systematic consideration of photosensitizer delivery at the subcellular level. SLTB, in contrast to many other potential protein carriers, is delivered intracellularly to the Golgi apparatus and endoplasmic reticulum (ER). Ce6 was chosen both for its phototoxic properties and its potential for covalent conjugation with SLTB. Ce6-SLTB after cleanup contained < or =10% noncovalently bound Ce6. The noncovalent binding of porphyrins and chlorins to protein conjugates has been well documented, and hence the effective cleanup procedure is a significant accomplishment. We demonstrate that Ce6-SLTB enhances delivery of Ce6 to target cells as compared to free Ce6. In Vero cells, Ce6-SLTB was over an order of magnitude more photodynamically toxic than free Ce6. Moreover, we show that in the case of Ce6-SLTB, photosensitizer accumulation is in a combination of subcellular sites including mitochondria, Golgi apparatus, ER and plasma membrane. The occurrence in nature of diverse B subunit binding sites and the possibilities of varied intracellular delivery make optimized use of B subunit carriers attractive.

Animals↗
PubMed2004

Killing of periodontopathogenic bacteria by photodynamic therapy.

BACKGROUND: The aim of this study was to evaluate a new approach for killing periodontopathogenic bacteria using photodynamic therapy (PDT). METHODS: In this study, we investigated the photosensitizers chlorin e6, BLC 1010, and BLC 1014 by three different methods for their effect in PDT on the viability of periodontopathogenic bacterial species. The methods included examination of inhibition zones on agar plates, determination of colony-forming units (CFU), and the use of a bacterial viability kit. RESULTS: Using the CFU method, we were able to demonstrate that the anaerobic bacteria Porphyromonas gingivalis, Fusobacterium nucleatum, and Capnocytophaga gingivalis can be photoinactivated completely by illumination with an intensity of 5.3 J/cm2 in the presence of 10 microM chlorin e6 and 10 microM BLC 1010. With the photosensitizers chlorin e6 and BLC 1010, we were able to induce zones of inhibition on agar plates. BLC 1014 failed to produce a zone of inhibition. The results of the bacterial viability test also showed that the photosensitizer BLC 1014 provides the lowest photodynamic effect in comparison to the others. CONCLUSION: The data collected to date suggest that photodynamic therapy with chlorin e6 and BLC 1010 is advantageous for suppressing periodontopathogenic bacteria.

Aggregatibacter actinomycetemcomitans↗
PubMed2001

Chlorophyllin protects cells from the cytostatic and cytotoxic effects of quinacrine mustard but not of nitrogen mustard.

Chlorophyllin (CHL), the sodium and copper salt of chlorophyll, is capable of inhibiting the mutagenic activity of many chemical compounds. Several mechanisms have been advanced to explain the antimutagenic activity of CHL, including its antioxidant properties and its ability to form complexes with mutagens. The present study was designed to reveal whether the heterocyclic aromatic nature of a potential mutagen is essential to its sensitivity to CHL. Toward this end, the inhibitory effect of CHL on two compounds of similar chemical reactivity (mustards), that either embodied an aromatic structure (quinacrine mustard; QM) or did not (nitrogen mustard; NM), were compared. Human leukemic HL-60 and breast carcinoma MCF-7 cells were treated with QM or NM in the absence or presence of various concentrations of CHL. Both QM and NM when administered for 1-2 h at micromolar concentrations exerted similar effects; both arrested cells in G2 phase of the cell cycle, induced apoptosis and reduced the clonogenicity of MCF-7 cells. The simultaneous addition of 0.22 M CHL to cultures receiving QM virtually abolished the QM-induced inhibition of cell growth and clonogenicity. In contrast, CHL had no effect on reducing the cytostatic or cytotoxic activity of NM. CHL alone, at a concentration of 0.22 M, had minimal effect on growth of HL-60 cells slightly perturbing their progression through G2. The results are consistent with the model that explains the inhibition of the activity of mutagens or antitumor drugs with aromatic structures by CHL as mediated by its ability to sequester these molecules within heterologous mutagen:CHL complexes that are maintained by stacking interactions. Therefore, excess of chlorophyll in the diet, by sequestering aromatic mutagens (or antitumor drugs with a heterocyclic structure, if taken orally), may inhibit their accessibility to cells, thereby reducing their activity.

Antimutagenic Agents↗
PubMed1989

[The quantitative study of inhibitory effect of pentosan polysulfate and chlorophyllin on the experimental calcium oxalate stone].

The purpose of this study is to evaluate the effect of sodium pentosan polysulfate (SPP) and sodium copper chlorophyllin (SCC) on the formation, growth and aggregation of calcium oxalate crystals in vivo, and to measure the number and the volume of crystals formed in the rat kidney, quantitatively, with a Coulter counter TA-II. The deposition of calcium oxalate crystals in the rat kidney was induced by intraperitoneal injection of 2.5 g per Kg of body weight of hydroxy-L-proline and administration of 0.4% ethylene glycol as the drinking fluid ad libitum for 7 days. Daily excretions of urinary oxalate, calcium (ratio to urinary creatinine) and urinary volume were measured. Both kidneys were removed after protocol. The kidneys were homogenized with 0.2 M Tris-buffer (pH 8.0) and subsequently digested in soluene-100. After calcium oxalate crystals were collected, they were suspended in saline saturated with calcium oxalate. The crystal size distribution was measured with a Coulter counter TA-II. In addition, the renal calcium content was measured by atomic absorption spectrometry, and the kidneys were examined by optical microscopy and scanning electron microscopy. The crystals formed in the rats' kidneys were analyzed by infrared spectroscopy. The results were as follows: 1. There was no deposition of crystals in the kidney of the rats which were not treated. There was intratubular deposition of crystals in the kidneys of the rats injected with hydroxy-L-proline and administered 0.4% ethylene glycol. They consisted of calcium oxalate monohydrate. 2. Renal calcium content was significantly higher in the groups with induced crystals than the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Late-stage immature neocortical neurons reconstruct interhemispheric connections and form synaptic contacts with increased efficiency in adult mouse cortex undergoing targeted neurodegeneration.

In the neocortex, the effectiveness of potential cellular repopulation therapies for diseases involving neuronal loss may depend critically on whether newly incorporated cells can differentiate appropriately into precisely the right kind of neuron, re-establish precise long-distance connections, and reconstruct complex functional circuitry. Here, we test the hypothesis that increased efficiency of connectivity could be achieved if precursors could be more fully differentiated toward desired phenotypes. We compared embryonic neuroblasts and immature murine neurons subregionally dissected from either embryonic day 17 (E17) (Shin et al., 2000) or E19 primary somatosensory (S1) cortex and postnatal day 3 (P3) purified callosal projection neurons (CPNs) with regard to neurotransmitter and receptor phenotype and afferent synapse formation after transplantation into adult mouse S1 cortex undergoing targeted apoptotic degeneration of layer II/III and V CPNs. Two weeks after transplantation, neurons from all developmental stages were found dispersed within layers II/III and V, many with morphological features typical of large pyramidal neurons. Retrograde labeling with FluoroGold revealed that 42 +/- 2% of transplanted E19 immature S1 neurons formed connections with the contralateral S1 cortex by 12 weeks after transplantation, compared with 23 +/- 7% of E17 neurons. A greater percentage of E19-derived neurons received synapses (77 +/- 1%) compared with E17-derived neurons (67 +/- 2%). Similar percentages of both E17 and E19 donor-derived neurons expressed neurotransmitters and receptors [glutamate, aspartate, GABA, GABA receptor (GABA-R), NMDA-R, AMPA-R, and kainate-R] appropriate for endogenous adult CPNs progressively over a period of 2-12 weeks after transplantation. Although P3 fluorescence-activated cell sorting-purified neurons also expressed these mature phenotypic markers after transplantation, their survival in vivo was poor. We conclude that later-stage and region-specific immature neurons develop a mature CPN phenotype and make appropriate connections with recipient circuitry with increased efficiency. However, at postnatal stages of development, limitations in survival outweigh this increased efficiency. These results suggest that efforts to direct the differentiation of earlier precursors precisely along specific desired neuronal lineages could potentially make possible the highly efficient reconstruction of complex neocortical and other CNS circuitry.

Animals↗
PubMed1999

Photodynamic tissue adhesion with chlorin(e6) protein conjugates.

PURPOSE: To test the hypothesis that a photodynamic laser-activated tissue solder would perform better in sealing scleral incisions when the photosensitizer was covalently linked to the protein than when it was noncovalently mixed. METHODS: Conjugates and mixtures were prepared between the photosensitizer chlorin(e6) and various proteins (albumin, fibrinogen, and gelatin) in different ratios and used to weld penetrating scleral incisions made in human cadaveric eyes. A blue-green (488-514 nm) argon laser activated the adhesive, and the strength of the closure was measured by increasing the intraocular pressure until the wound showed leakage. RESULTS: Both covalent conjugates and noncovalent mixtures showed a light dose-dependent increase in leaking pressure. A preparation of albumin chlorin(e6) conjugate with additional albumin added (2.5 protein to chlorin(e6) molar ratio) showed significantly higher weld strength than other protein conjugates and mixtures. CONCLUSIONS: This is the first report of dye-protein conjugates as tissue solders. These conjugates may have applications in ophthalmology.

Chlorophyllides↗
PubMedDate not supplied

[Distribution of porphyrin sensitizers among protein and cellular blood elements].

The distribution of porphyrin pigments between plasma proteins and blood cells was studied. It was shown that the relative fraction of sensitizer bound by blood cells changed significantly depending on the physicochemical features of pigment molecules. This parameter strongly correlates with porphyrin polarity. Polar watersoluble tetraphenylporphin derivatives, chlorine e6 and hematoporphyrin are bound by plasma proteins only. The decrease in pigment polarity by substitution of polar side groups results in a drastic increase of pigment affinity to blood cells. The binding of extremely apolar pigments by cells in blood occurs for a long period of time, probably as a result of a low rate of pigment redistribution between serum proteins and cellular membrane. The data obtained show that blood cells may be involved into the control of pigment transport and distribution in organism during photodynamic therapy. The parameters of porphyrin distribution between plasma proteins and cells in blood are of certain importance when the pharmacokinetic behavior of various sensitizers is compared.

Biological Transport↗
PubMed2000

Epidermal growth factor-mediated targeting of chlorin e6 selectively potentiates its photodynamic activity.

Certain tumor cells, such as squamous carcinoma cells, express an increased number of epidermal growth factor (EGF) receptors. Therefore, we studied the targeted delivery of the photocytotoxic compound Sn-(IV)chlorin e6 monoethylenediamine [SnCe6(ED)] to tumors that overexpress the EGF receptor. EGF was conjugated to SnCe6(ED) through a carrier, such as dextran (Dex) and human serum albumin (HSA), and the photocytotoxicity on the EGF receptor-overexpressing MDA-MB-468 breast adenocarcinoma cell line was evaluated. The photobiological activities of these EGF conjugates, of the conjugates of the photosensitizer to HSA or Dex, or of the photosensitizer alone were compared. The affinity of EGF for its receptor was substantially impaired when conjugated in EGF-Dex-SnCe6(ED), in contrast to EGF-HSA-SnCe6(ED). In corresponding results, EGF-HSA-SnCe6(ED) displayed a high photocytotoxicity (IC50, 63 nM) on MDA-MB-468 cells at a light dose of 27 kJ/m2, whereas EGF-Dex-SnCe6(ED) showed very limited photocytotoxicity. EGF-HSA-SnCe6(ED) was no longer photocytotoxic in the presence of a competing EGF concentration. The high photocytotoxicity of EGF-HSA-SnCe6(ED) was shown to be the result of a high intracellular concentration in MDA-MB-468 cells, which could be lowered dramatically by incubating the conjugate with a competing EGF concentration. In contrast, EGF-Dex-SnCe6(ED) accumulated poorly in MDA-MB-468 cells, in agreement with its low EGF receptor affinity and photocytotoxicity. EGF-HSA-SnCe6(ED) produced much more intracellular reactive oxygen species on light irradiation than EGF-Dex-SnCe6(ED). It is concluded that the photodynamic activity of the EGF-HSA conjugate of SnCe6(ED) on MDA-MB-468 breast adenocarcinoma cells is EGF specific and is much more potent than EGF-Dex-SnCe6(ED) or free SnCe6.

Adenocarcinoma↗
PubMed2000

[Pigment molecules linked to polymer support: blue rayon, blue chitin, and green chitosan-synthesis and applications].

The fact that hemin can inhibit the mutagenic activity of compounds bearing polycyclic structures is ascribable to the ability of the porphyrin structure to complex with the planar surface of the mutagens. The elucidation of this mechanism has led to the discovery of copper phthalocyanine trisulfonate (cpt) as an efficient ligand to trap polycyclic compounds on polymeric supports that bear cpt through covalent bond linkages. In blue cotton, the support for cpt is cotton, in blue rayon, it is amorphous rayon, and in blue chitin it is poly-N-acetylglucosamine. Using these blue materials, we have successfully isolated mutagens of polycyclic structures, e.g., heterocyclic amines, from environmental complex mixtures such as food, urine, feces, and river water. Preparation and properties of these adsorbents are described. Chlorophyllin linked to Sepharose and chitosan is also described. The use of these green materials is discussed.

Adsorption↗
PubMedDate not supplied

Anti-promotion effect of chlorophyllin in DMBA-TPA-induced mouse skin carcinogenesis.

This study aimed to elucidate the inhibitory effects of chlorophyllin (CHL) at different promotion stages in a DMBA-TPA-induced mouse skin carcinogenesis model. TPA promotion was undertaken for 6, 18 and 24 weeks, respectively. Proliferating activity was observed immunohistochemically and the ornithine decarboxylase (ODC) mRNA level was analyzed by reverse transcriptase-polymerase chain reaction. Messenger RNAs for c-fos, c-jun and jun-B were also observed. CHL treatment clearly reduced proliferating activity and the level of ODC mRNA at the 18-week-promotion stage. When promoted for 24 weeks, CHL was not effective in reducing proliferating activity and ODC mRNA expression. These results indicate that the promotion stage of each target tissue should be considered in a chemopreventive program.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2000

Experimental photoimmunotherapy of hepatic metastases of colorectal cancer with a 17.1A chlorin(e6) immunoconjugate.

Photoimmunotherapy (using a monoclonal antibody-targeted photosensitizer and red light) may be a strategy to overcome the limitations inherent in photodynamic therapy of liver tumors. The aims of this study were (a) to test the efficacy of selective treatment of hepatic metastases of colorectal cancer in an orthotopic murine xenograft using the murine monoclonal antibody 17.1A conjugated to the photosensitizer chlorin(e6), and (b) to compare the tumor response after the same light dose was delivered at two different fluence rates. Based on previous biodistribution studies that had shown that the photoimmunoconjugate with a polyanionic charge had both a higher absolute tumor chlorin(e6) content and a greater tumor:normal liver ratio than those obtained with a photoimmunoconjugate bearing a polycationic charge, mice were treated 3 h after i.v. injection of the polyanionic 17.1A chlorin(e6) conjugate or unconjugated photosensitizer. Red light was delivered into the liver tumor by an interstitial fiber, and tumor response end points were total tumor weight in the short term and survival in the long term. There was a highly significant reduction (<20% of controls; P = 0.0035) in the weight of the tumors in the mice treated with photoimmunotherapy, and the median survival increased from 62.5 to 102 days (P = 0.015). Photodynamic therapy with free chlorin(e6) produced a smaller decrease in tumor weight and a smaller extension of survival, neither of which were statistically significant. A comparison of photoimmunotherapy with 10 J of light delivered at 30 or 300 mW showed that the higher fluence rate prolonged survival significantly more than the lower fluence rate. This may have been because the high fluence rate gave a contribution of laser-induced hyperthermia to the photodamage. Correlation studies showed that the amount of normal liver remaining at necropsy correlated best with survival. Photoimmunotherapy shows efficacy in destroying liver tumors, and future studies should maximize selectivity to minimize the destruction of normal liver.

Animals↗
PubMed2000

[Targeting of chlorine E6 by EGF increasing its photodynamic activity in selective ways].

Certain tumor cells, such as squamous carcinoma cells, express an increased number of epidermal growth factor (EGF) receptors. The goal of this study was the targeted delivery of the photocytotoxic compound Sn(IV)chlorine e6 monoethylenediamine++ (SnCe6(ED)) to tumors that overexpress the EGF receptor. Therefore EGF was conjugated to SnCe6(ED) through a carrier, such as dextran (Dex) and human serum albumin (HSA), followed by the evaluation of the photocytotoxicity on the EGF receptor overexpressing MDA-MB-468 cell line. The photobiologic activity of these conjugates was then compared to a conjugate of the photosensitizer to HSA or dextran, or to the photosensitizer alone. In contrast to EGF-HSA-SnCe6(ED), the affinity of EGF for its receptor was substantially impaired upon conjugation in EGF-Dex-SnCe6(ED). In correlation with these results, EGF-HSA-SnCe6(ED) displayed a high cytotoxicity (IC50, 63 nM) on MDA-MB-468 cells at a light dose of 27 kJ/m2, whereas EGF-Dex-SnCe6(ED) showed very limited photocytotoxicity. In the presence of a competing EGF concentration (10 microM), EGF-HSA-SnCe6(ED) was not cytotoxic anymore. The high photocytoxicity of EGF-HSA-SnCe6(ED) was shown to be a result of a high intracellular concentration in MDA-MB-468 cells, which could be lowered dramatically by incubating the conjugate with a competing EGF concentration. In contrast, EGF-Dex-SnCe6(ED) displayed very poor accumulation in MDA-MB-468 cells, in agreement with its low EGF receptor affinity and photocytoxicity. Besides, it could be demonstrated that EGF-HSA-SnCe6(ED) produced intracellularly ROS (reactive oxygen species) upon light irradiation, more than EGF-Dex-SnCe6(ED) did. It was concluded that, in contrast to EGF-Dex-SnCe6(ED) the photodynamic activity of the EGF-HSA conjugate of SnCe6(ED) on MDA-MB-468 breast adenocarcinoma cells is EGF-specific and more potent than free SnCe6(ED).

Adenocarcinoma↗
PubMed2000

Transplanted neuroblasts differentiate appropriately into projection neurons with correct neurotransmitter and receptor phenotype in neocortex undergoing targeted projection neuron degeneration.

Reconstruction of complex neocortical and other CNS circuitry may be possible via transplantation of appropriate neural precursors, guided by cellular and molecular controls. Although cellular repopulation and complex circuitry repair may make possible new avenues of treatment for degenerative, developmental, or acquired CNS diseases, functional integration may depend critically on specificity of neuronal synaptic integration and appropriate neurotransmitter/receptor phenotype. The current study investigated neurotransmitter and receptor phenotypes of newly incorporated neurons after transplantation in regions of targeted neuronal degeneration of cortical callosal projection neurons (CPNs). Donor neuroblasts were compared to the population of normal endogenous CPNs in their expression of appropriate neurotransmitters (glutamate, aspartate, and GABA) and receptors (kainate-R, AMPA-R, NMDA-R. and GABA-R), and the time course over which this phenotype developed after transplantation. Transplanted immature neuroblasts from embryonic day 17 (E17) primary somatosensory (S1) cortex migrated to cortical layers undergoing degeneration, differentiated to a mature CPN phenotype, and received synaptic input from other neurons. In addition, 23.1 +/- 13.6% of the donor-derived neurons extended appropriate long-distance callosal projections to the contralateral S1 cortex. The percentage of donor-derived neurons expressing appropriate neurotransmitters and receptors showed a steady increase with time, reaching numbers equivalent to adult endogenous CPNs by 4-16 weeks after transplantation. These results suggest that previously demonstrated changes in gene expression induced by synchronous apoptotic degeneration of adult CPNs create a cellular and molecular environment that is both permissive and instructive for the specific and appropriate maturation of transplanted neuroblasts. These experiments demonstrate, for the first time, that newly repopulating neurons can undergo directed differentiation with high fidelity of their neurotransmitter and receptor phenotype, toward reconstruction of complex CNS circuitry.

Animals↗
PubMed2001

Epidermal growth factor receptor-targeted immunophotodiagnosis and photoimmunotherapy of oral precancer in vivo.

Immunophotodiagnosis uses a fluorescence-labeled monoclonal antibody (MAb) that recognizes a tumor-associated antigen to image the fluorescence emitted from the fluorophore-bound MAb that has localized in the tissue. It may be used to diagnose malignant or precancerous lesions, to delineate the margins for tumor resection, or as a feedback mechanism to assess response to treatment. In oral precancer, the epidermal growth factor receptor (EGFR) is overexpressed and could be used as a marker for early detection or as a target for therapy. The goal of this study was to test an anti-EGFR MAb (C225) coupled to either the near-infrared fluorescent dye N,N'-di-carboxypentyl-indodicarbocyanine-5,5'-disulfonic acid for detection or a photochemically active dye (chlorin(e6)) for therapy of early premalignancy in the hamster cheek pouch carcinogenesis model. Fluorescence levels in the carcinogen-treated tissue correlated with the histological stage of the lesions when the C225-N,N'-di-carboxypentyl-indodicarbocyanine-5,5'-disulfonic acid conjugate was used but did not do so with the irrelevant conjugates. Discrete areas of clinically normal mucosa with high fluorescence (hot spots) were subsequently shown by histology to contain dysplastic areas. The best contrast between normal and carcinogen-treated cheek pouches was found at 4-8 days after injection. To test the potential of immunophotodiagnosis as a feedback modality for therapeutic intervention, experiments were conducted with the same MAb conjugated to chlorin(e6) followed by illumination to reduce expression of the EGFR by a photodynamic effect. Subsequent immunophotodiagnosis showed that this treatment led to a significant reduction in fluorescence in the carcinogen-treated cheek pouch compared with nonilluminated areas. This difference between illuminated and dark areas was not seen in the normal cheek pouch. Taken together, the results demonstrate the potential for development of immunophotodiagnosis as a diagnostic tool and as a method of monitoring response to therapy and that the EGFR may be an appropriate target in head and neck cancer.

Animals↗