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PubMed2001

Evaluation of different photosensitizers for use in photochemical gene transfection.

Many potentially therapeutic macromolecules, e.g. transgenes used in gene therapy, are taken into the cells by endocytosis, and have to be liberated from endocytic vesicles in order to express a therapeutic function. To achieve this we have developed a new technology, named photochemical internalization (PCI), based on photochemical reactions inducing rupture of endocytic vesicles. The aim of this study was to clarify which properties of photosensitizers are important for obtaining the PCI effect improving gene transfection. The photochemical effect on transfection of human melanoma THX cells has been studied employing photosensitizers with different physicochemical properties and using two gene delivery vectors: the cationic polypeptide polylysine and the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP). Photochemical treatment by photosensitizers that do not localize in endocytic vesicles (tetra[3-hydroxyphenyl]porphyrin and 5-aminolevulinic acid-induced protoporphyrin IX) do not stimulate transfection, irrespective of the gene delivery vector. In contrast, photosensitizers localized in endocytic vesicles stimulate polylysine-mediated transfection, and amphiphilic photosensitizers (disulfonated aluminium phthalocyanine [AlPcS2a] and meso-tetraphenylporphynes) show the strongest positive effect, inducing approximately 10-fold increase in transfection efficiency. In contrast, DOTAP-mediated transfection is inhibited by all photochemical treatments irrespective of the photosensitizer used. Neither AlPcS2a nor Photofrin affects the uptake of the transfecting DNA over the plasma membrane, therefore photochemical permeabilization of endocytic vesicles seems to be the most likely mechanism responsible for the positive PCI effect on gene transfection.

Aminolevulinic Acid↗
PubMed2002

Porphyrins in photodynamic therapy - a search for ideal photosensitizers.

The utility of light as a therapeutic agent can be traced back over thousands of years when it was used in Ancient Egypt, India and China to treat a variety of skin diseases like psoriasis, vitiligo, rickets, cancer and psychosis. The isolation of porphyrins and their inherent tumor localizing properties coupled with its ability to generate reactive singlet oxygen when activated by light of particular wavelength which in turn results in cytotoxicity led to the emergence of a new modality namely, photodynamic therapy (PDT) as a therapeutic tool. The higher degree of selectivity offered by this modality and fewer side effects when compared to chemotherapy and radiotherapy has prompted the researchers around the globe to generate new photosensitizers. Porphyrins and expanded porphyrins are one class of molecules under intense investigation due to their photosensitizing ability for PDT application. Expanded porphyrins result from the expansion of the phi electron conjugation by increasing the number of heterocyclic rings or bridging carbons of the existing porphyrin framework. These chromophores show strong absorptions in the red region (650-800 nm) compared to that of normal 18phi porphyrins. The strong absorption of light by a water soluble nontoxic photosensitizing molecule in the therapeutic window resulting in maximum penetration of light into the tissues coupled with high singlet oxygen production will conceptualize an ideal photosensitizer. This review highlights various porphyrinoid sensitizers reported till date and their photosensitizing ability both in vitro and in vivo studies. Furthermore, the urgent need for developing ideal photosensitizer for PDT will also be highlighted.

Animals↗
PubMed1999

Role of nuclear factor-kappa B in colon cancer cell apoptosis mediated by aminopyropheophorbide photosensitization.

Aminopyropheophorbide (APP) is a second generation of photosensitizer for photodynamic therapy (PDT). We demonstrated that APP strongly absorbed red light and, after being taken up by colon cancer cells (HCT-116 cells), was localized in cytoplasmic and internal membranes but not in mitochondria. The APP-mediated photosensitization was cytotoxic for HCT-116 cells through an induction of apoptosis. Indeed, DNA fragmentation (DNA laddering and terminal deoxyuridine nick-end labeling) and chromatin condensation (4',6-diamidine-2'-phenylindole staining) could be visualized soon after photosensitization. Because nuclear factor (NF)-kappa B is involved in the response to many photosensitizers, we also demonstrated its nuclear translocation in two waves: a rapid and transient one, followed by a slow and sustained phase. The NF-kappa B turned out to be involved in an antiapoptotic response to APP-mediated photosensitization because the HCT-116 cell line expressing the dominant negative mutant of inhibitor-kappa B alpha was more sensitive to apoptosis as measured by DNA fragmentation and caspase activation. These data unambiguously show that a membrane-located photosensitizer can lead to effective apoptosis, reinforcing the idea that PDT can be an effective means to eradicate colon cancer cells.

Apoptosis↗
PubMed2003

Study of solar photosensitization processes on dermatophytic fungi.

The antifungal activity of solar simulator was evaluated in presence of haematoporphyrin derivative (HPD), methylene blue (MB) and toluidine blue O (TBO) as photosensitizers. Seven dermatophytes were used as test fungi. The solar simulator at fluence rate 400 W/m2 for 30 minutes induced marked inhibition for spore germination of the photosensitized fungi. The rate of inhibition varied according to the fungal species and concentration of the photosensitizer. There was an increase in percentage inhibition of spore germination as the concentration of HPD or MB increased. Complete inhibition for spore germination of Trichophyton. verrucosum, T. mentagrophytes, and Miccrosporum canis was induced when these species were pretreated with 10(-3) M of HPD or MB before irradiation. Epidermophyton floccosum, T. rubrum, M. gypseum and T. violaceum were less sensitive to irradiation when pretreated with HPD or MB. On contrary, the maximum reduction in percentage spore germination was induced at the lowest concentration (10(-7) M) of TBO. The tested dermatophytes were mostly capable of producing different enzymes (keratinase, phosphatases, amylase, lipase). The separate application of radiation or photosensitizer was ineffective or exerted slight inhibition on enzyme production. However, the activity of the enzymes was drastically inhibited when the fungi were irradiated after their treatment with photosensitizer. T. verrucosum and T. mentagrophytes were the most sensitive. In a trail to apply a control measure against dermatomycosis using solar simulator radiation, the results revealed that the radiation was successful in curing the MB-photosensitized guinea pigs, artificially infected with T. verrucosum, T. mentagrophytes or M. canis. The percentage of recovery reached 100% in some treatments.

Amylases↗
PubMed2005

ABCG2-mediated transport of photosensitizers: potential impact on photodynamic therapy.

In photodynamic therapy (PDT), a tumor-selective photosensitizer is administered followed by activation of the photosensitizer by exposure to a light source of a given wavelength. This, in turn, generates reactive oxygen species that induce cellular apoptosis and necrosis in tumor tissue. Based on our earlier finding that the photosensitizer pheophorbide a is an ABCG2 substrate, we explored the ability of ABCG2 to transport photosensitizers with a structure similar to that of pheophorbide a. ABCG2-overexpressing NCI-H1650 MX50 bronchoalveolar carcinoma cells were found to have reduced intracellular accumulation of pyropheophorbide a methyl ester and chlorin e6 compared to parental cells as measured by flow cytometry. The ABCG2 inhibitor fumitremorgin C was found to abrogate ABCG2-mediated transport. Intracellular fluorescence of hematoporphyrin IX, meso-tetra(3-hydroxyphenyl)porphyrin, and meso-tetra(3-hydroxyphenyl)chlorin was not substantially affected by ABCG2. ABCG2-overexpressing cells also displayed decreased intracellular fluorescence of protoporphyrin IX generated by exogenous application of 5-aminolevulinic acid. Mutations at amino acid 482 in the ABCG2 protein known to affect substrate specificity were not found to impact transport of the photosensitizers. In cytotoxicity assays, ABCG2-transfected HEK-293 cells were 11-fold, 30-fold, 4-fold, and >7-fold resistant to PDT with pheophorbide a, pyropheophorbide a methyl ester, chlorin e6, and 5-aminolevulinic acid, respectively. ABCG2-transfected cells were not resistant to PDT with meso-tetra(3-hydroxyphenyl) chlorin. Neither multidrug resistance-associated protein 1 expression nor P-glycoprotein expression appreciably decreased the intracellular fluorescence of any of the photosensitizers examined as determined by flow cytometry. The results presented here implicate ABCG2 as a possible cause for cellular resistance to photodynamic therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Scientific problems of photosensitivity.

Photosensitive skin reactions occur when human skin reacts to ultraviolet radiation or visible light abnormally. The forms of photosensitivity are phototoxicity and photoallergy. Phototoxic disorders have a high incidence, whereas photoallergic reactions are much less frequent in human population. Several hundred substances, chemicals, or drugs may invoke phototoxic and photoallergic reactions. In order to avoid photosensitive reactions it is essential to determine the photosensitizing properties of such substances before drugs are introduced in therapy or products made available on the market. The article reviews the mechanisms of photosensitization, explains the most important differences between phototoxic and photoallergic reactions, summarizes the most common photosensitizers, and presents the clinical features and diagnostic procedures of phototoxic and photoallergic reactions.

Adult↗
PubMed1988

Experimentally induced photosensitization in cattle with Cooperia pedunculata.

Photosensitization was induced in 2 Charolais heifers following administration of a mixture of air-dried, ground, green (75%) and dead (25%) leaves of the south Texas forb, Cooperia pedunculata, and subsequent exposure to sunlight. Plant material used in this study was collected from a pasture where natural cases of primary bovine photosensitization were occurring. Signs of photosensitization were observed in one heifer after 2 doses of plant material--10 g/kg on day 1 and 5 g/kg on day 2. Continued administration of plant material at 5 g/kg/d on days 3, 4, 7, 8, and 9 resulted in severe signs and lesions of photosensitization and death on day 23. A second heifer developed signs of mild photosensitization following administration of plant material at 1.7 g/kg/d for 4 days. This heifer recovered by day 18. Clinical and pathologic findings of this trial were consistent with the primary form of photosensitization observed in natural cases seen in cattle of south Texas exposed to this plant.

Animals↗
PubMed1994

Photosensitizers in photodynamic therapy.

Photodynamic therapy (PDT) is based on the use of light-sensitive molecules called photosensitizers. Photoactivation causes the formation of singlet oxygen, which produces peroxidative reactions that can cause cell damage and death. Porfimer sodium (Photofrin, manufactured by Lederle Parenterals, Carolina, Puerto Rico, under license from Quadra Logic Technologies, Inc, Vancouver, BC, Canada) is the photosensitizer that has been studied most extensively. Patients generally have to be hospitalized for 2 days prior to light treatment after administration of porfimer sodium; it takes approximately 48 hours after injection to reach optimal concentration in tumor tissue. The tumoricidal capacity of PDT with porfimer sodium is determined in part by the maximum depth of penetration of light having a wavelength of 630 nm. Porfimer sodium causes cutaneous photosensitivity that may last for up to 6 weeks. Benzoporphyrin derivative (BPD verteporfin; BPD-Quadra Logic Technologies, Inc, Vancouver, BC, Canada), another photosensitizer, accumulates more rapidly in tumor tissue, permitting optimal PDT 30 to 150 minutes following intravenous administration. It is rapidly cleared from the body, and skin photosensitivity does not extend beyond a few days. The primary mechanism of action of PDT is related to the selective accumulation of photosensitizers in cancer tissue. Photodynamic therapy also shows promise in the treatment of a number of nonneoplastic conditions, including psoriasis, macular degeneration of the retina, atherosclerotic plaque and restenosis, bone marrow purging for treatment of leukemias with autologous bone marrow transplantation, inactivation of viruses in blood or blood products, and several autoimmune conditions, including rheumatoid arthritis. Physiologic characteristics shared by this disparate group of diseases, and the mechanisms by which they may mediate photoactivation, are discussed.

Antiviral Agents↗
PubMed1998

Variation in photodynamic efficacy during the cellular uptake of two phthalocyanine photosensitizers.

A decrease in the efficacy of photodynamic therapy (PDT) with phthalocyanine photosensitizers was observed for lymphoblastic murine and human cell lines as the time between the addition of the photosensitizer, aluminum phthalocyanine (AIPc), to the culture medium and exposure to light was increased from 4 h to 18 h. The total intracellular concentration of photosensitizer did not decrease significantly during this 18 h interval. For the murine cell lines, the maximum cytotoxic and mutagenic effects were observed when the time between addition of the photosensitizer and irradiation was between 1 and 4 h. The time course of the variations in efficacy did not vary greatly from one murine cell line to another, even though the cell lines differ markedly in the extent of their cytotoxic and mutagenic response. The time course of the variation was similar for cytotoxicity and mutagenicity, as well as for the induction of DNA fragmentation. The human lymphoblastic cell line, WTK1, showed less variation in survival and mutability with time than did the murine cell lines. With Pc 4 (HOSiPcOSi[CH3]2[CH2]3N[CH3]2) as the photosensitizer, the photocytotoxicity for murine L5178Y (LY)-S1 cells did not change significantly as the time between addition of Pc 4 and irradiation was increased from 2 to 18 h. However, the mutagenicity decreased by a factor of three during this interval. The mutagenicity of PDT with Pc 4 was much less in LY-S1 cells than that with AlPc. The results suggest that the variation in the efficacy observed for AlPc-induced photocytotoxicity is caused by changes in the intracellular distribution and/or the aggregation of the photosensitizer with time after its addition.

Aluminum↗
PubMed1998

[Photosensitivity as presenting sign of HIV infection. Control with triple antiretroviral therapy].

BACKGROUND: We report a case of photosensitivity which occurred as the presenting sign of HIV infection. Photosensitivity regressed completely after introducing antiretroviral tritherapy. CASE REPORT: A 44-year-old woman developed a photo-distributed eczematous eruption which did not respond to topical steroids or hydroxychloroquine. Histologic examination showed eczematous dermatitis. T-cell marker analysis showed a majority of CD8 cells in the infiltrate. The patient was found to be HIV-positive and CD4 counts were markedly reduced to 190/mm3 while CD8 counts were increased to 1260/mm3. Antiretroviral tritherapy cured the photosensitivity. Cure was apparently related to increased CD4 lymphocyte and normalized CD8 lymphocyte counts. DISCUSSION: Photosensitivity was the presenting disorder of HIV infection in this case. Cure of the photosensitivity with antiretroviral tritherapy has not been reported previously. CD8 T-cell infiltration and very low CD4/CD8 ratio would appear to play a key role in the pathogenesis of photosensitivity in these patients.

Adult↗
PubMed1989

Neutral red-labeled influenza virus loses photosensitivity during absorption to host cells but not to erythrocytes.

Neutral red (NR)-labeled influenza virus is extremely photosensitive. Unlike NR-labeled picornaviruses which lose their photosensitivity only after penetrating the host cell, NR-labeled influenza virus loses most of its photosensitivity during adsorption at 4 degrees C. We demonstrate that the underlying reaction occurs within seconds of adsorption and that it is irreversible, i.e., NR virus eluted from chick embryo cells after adsorption is hardly photosensitive anymore. In contrast to this, NR virus adsorbed to and eluted from erythrocytes retains its original photosensitivity. We suggest that the loss of photosensitivity during adsorption of NR virus to host cells reflects a conformational change in the virion which is not elicited by adsorption to red blood cells.

Adsorption↗
PubMed1990

On the recovery of photosensitivity in two passerine species, American tree sparrows (Spizella arborea) and Harris' sparrows (Zonotrichia querula).

To test the hypothesis that a spontaneous increase in plasma luteinizing hormone (LH) signals recovery of photosensitivity in castrated passerine birds, LH concentrations were measured weekly in intact and in castrated photorefractory tree sparrows and Harris' sparrows transferred to short days. After 7 weeks on short days (Experiment 1) or after 1, 3, 5, 7, and 10 weeks (Experiment 2) were challenged with long days (1 week) to determine if photosensitivity had been restored. As evidenced by a significant LH response to photostimulation, tree sparrows had regained at least partial photosensitivity after 7 weeks on short days. However, during exposure to short days, plasma LH concentrations in castrated males did not differ from those in intact males, and plasma LH concentrations in intact or castrated males did not vary with time. The first indication that photosensitivity had been partially restored in Harris' sparrows came after 7 weeks on short days, when castrated males responded to photostimulation with a fourfold elevation in plasma LH concentration. However, before week 7 and through week 10, LH concentrations remained suppressed in both intact and castrated males retained on short days. These data show that recovery of photosensitivity in castrated tree sparrows and Harris' sparrows held on short days is not signaled by a spontaneous elevation in plasma LH concentration, and that plasma LH concentrations in acutely photosensitive intact male tree sparrows and Harris' sparrows held on short days are not suppressed because of gonadal negative feedback.

Animals↗
PubMed1992

Photosensitivity induced by fibric acid derivatives and its relation to photocontact dermatitis to ketoprofen.

BACKGROUND: Photosensitivity reactions to fibric acid derivatives are not well understood and have been rarely reported. OBJECTIVE: The aim of this study was to describe two cases of photosensitivity, one induced by fenofibrate and one by bezafibrate; to study the in vivo photosensitizing potential of these drugs; and to evaluate the possibility of cross-reactivity between fenofibrate and ketoprofen. METHODS: Patch and photopatch tests with fibric acid derivatives and ketoprofen were performed in the patients, in 12 normal volunteers, and in 7 patients with photopatch-proven photocontact dermatitis to ketoprofen. Phototesting studies were performed both while the patients were taking the drugs and after withdrawal of them, as well as in a group of 18 hyperlipemic volunteers without history of photosensitivity who were taking therapeutic doses of fenofibrate or bezafibrate for 2 to 3 months. RESULTS: Positive photopatch test responses to ketoprofen and to fenofibrate were obtained only in the first patient, who also had a weaker positive ordinary patch test response to the latter. Five patients photosensitized to ketoprofen also had a positive patch test to fenofibrate. Phototesting studies were abnormal in both patients but normal in all volunteers. CONCLUSION: An association between systemic photosensitivity to fenofibrate and photocontact sensitivity to ketoprofen seems to exist. The structural similarities of these chemicals favor cross-reactivity.

Aged↗
PubMed1992

Relationship between photosensitizing activities and chemical structure of hypocrellin A and B.

Hypocrellins A (HA) and B (HB) are two main pigments isolated from the parasitic fungi Hypocrella bambusae (B. et Br) Sacc. and Shiraia bambusicola P. Heen found in China. These pigments have a long history as traditional medicinal agents. Although HA and HB have the same perylene quinonoid structure, there are different side rings. The different photosensitizing activities of HA and HB due to their different side rings were studied by electron paramagnetic resonance (EPR), spin trapping and spin counteraction techniques. It is demonstrated that the ability to generate active oxygen (1O2, O2.- and .OH) is stronger during HA photosensitization than during HB photosensitization. Under anaerobic conditions, the ability to generate HA.- during HA photosensitization is stronger than the ability to generate HB.- during HB photosensitization. There is a relationship between photosensitizing ability and chemical structure.

Cyclic N-Oxides↗
PubMed1992

Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy.

The tissue photosensitizer protoporphyrin IX (PpIX) is an immediate precursor of heme in the biosynthetic pathway for heme. In certain types of cells and tissues, the rate of synthesis of PpIX is determined by the rate of synthesis of 5-aminolevulinic acid (ALA), which in turn is regulated via a feedback control mechanism governed by the concentration of free heme. The presence of exogenous ALA bypasses the feedback control, and thus may induce the intracellular accumulation of photosensitizing concentrations of PpIX. However, this occurs only in certain types of cells and tissues. The resulting tissue-specific photosensitization provides a basis for using ALA-induced PpIX for photodynamic therapy. The topical application of ALA to certain malignant and non-malignant lesions of the skin can induce a clinically useful degree of lesion-specific photosensitization. Superficial basal cell carcinomas showed a complete response rate of approximately 79% following a single exposure to light. Recent preclinical studies in experimental animals and human volunteers indicate that ALA can induce a localized tissue-specific photosensitization if administered by intradermal injection. A generalized but still quite tissue-specific photosensitization may be induced if ALA is administered by either subcutaneous or intraperitoneal injection or by mouth. This opens the possibility of using ALA-induced PpIX to treat tumors that are too thick or that lie too deep to be accessible to either topical or locally injected ALA.

Aminolevulinic Acid↗
PubMed1998

Light diffusion in photosensitive epilepsy.

Photosensitivity is usually tested by intermittent photic stimulation. Photoparoxysmal responses in the EEG are enhanced when the eyes remain closed during stimulation. We tested the hypothesis that this is due to diffusion of light by the eyelids. In 25 photosensitive patients, conditions 'eye closure', 'eyes closed', 'eyes open' and 'eyes open with diffuser' were tested for frequencies of 2-60 Hz. Additional influences of a red filter and fixation were also examined. The photosensitivity range was maximal in the condition 'eyes open with diffuser', due to an increase of the upper limit to a median 60 Hz (range 25-60), from 35 (15-50) Hz with eyes open, 37.5 (25-60) Hz with eyes closed and 40 (23-60) Hz with eye closure (P = 0.0002). This effect was attenuated in patients on valproic acid and with the use of a red or white filter. Testing with a diffuser was more sensitive than without, except for one patient who was photosensitive only in the eye closure condition. The influence of the eyelids on photosensitivity can be explained by diffusion of light, attentuated by an intensity loss. Use of a diffuser may simplify testing for photosensitivity in the EEG laboratory. The diffusion effect may explain seizure susceptibility in front of 50 and 60 Hz television screens.

Adolescent↗
PubMed2001

Synthesis of beta-galactose-conjugated chlorins derived by enyne metathesis as galectin-specific photosensitizers for photodynamic therapy.

A first report on the synthesis and biological evaluation of the beta-galactose-conjugated purpurinimides (a class of chlorins containing a six-membered fused imide ring system) as Gal-1 (galectin-1) recognized photosensitizers, prepared from purpurin-N-propargylimide via enyne metathesis, is discussed. On the basis of examination of the available crystal structure of the galectin-1 N-acetyllactose amine complex, it was considered that the chlorin-based photosensitizers could be introduced into a carbohydrate skeleton to expand the repertoire of the galectin-1-specific ligands. Preliminary molecular modeling analysis utilizing the modeled photosensitizers and the available crystal structures of galectin-carbohydrate complexes indicated that addition of the photosensitizer to the carbohydrate moiety at an appropriate position does not interfere with the galectin-carbohydrate recognition. Under similar drug and light doses, compared to the free purpurinimide analogue, the purpurinimides conjugated either with galactose or with lactose (Gal(beta1-4)-Glc) produced a considerable increase in photosensitizing efficacy in vitro. This indicates the possibility for development of a new class of specific photosensitizers for photodynamic therapy (PDT) based on recognition of a cellular receptor.

Carbohydrates↗
PubMed2001

Analysis of photosensitivity in Japanese cancer-bearing patients receiving photodynamic therapy with porfimer sodium (Photofrin).

A major disadvantage of a new cancer treatment, porfimer sodium (Photofrin)-mediated photodynamic therapy (PF-PDT), is photosensitivity for several weeks after cessation of the treatment. To characterize persistent sensitivity to visible light following PF-PDT, phototestings were performed in 59 Japanese cancer-bearing patients with a slide projector lamp 3 weeks or more after the treatment. The duration of photosensitivity was analyzed in relation to the patients' sex, skin phototype (SPT), site of tumor and liver function. There was no correlation of the photosensitivity persistency with the site of cancers and the function of liver. However, female subjects needed significantly longer recovery periods than male subjects from potential photosensitivity after PF-PDT. Patients with SPT2 were significantly more sensitive than patients with SPT3 and 4. These results suggest that the prolonged photosensitivity occurs after PF-PDT especially in female patients and in cases with a lighter SPT. Such patients should be carefully followed up for post-PDT photosensitivity.

Adult↗