Experimental grounds for using chlorin ρ6 in the photodynamic therapy of malignant tumors

Kostenich, Genady; Zhuravkin, Ivan N.; Zhavrid, Edvard

doi:10.1016/1011-1344(93)06974-8

Cited by 91 publications

(47 citation statements)

References 18 publications

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“…When free ce6 is used as a PS for cancer treatment, illumination is usually carried out relatively soon after injection into the bloodstream. 35 The present study has not shed any light on the mechanism of plaque localization by free ce6, but plausible hypotheses include accumulation in lipid-rich areas of plaques, penetration through leaky endothelial barriers, and even uptake by the macrophages present in the lesions.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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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 bloodfilled 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. Macrophagetargeted photosensitizer conjugates may have applications in both detecting and treating inflamed vulnerable plaque.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…Their cytotoxicity is mediated through the production of reactive intermediates that damage cellular components, leading to cell death (Dolmans, Fukumura, & Jain, 2003). Chlo-rin e6 is a naturally occurring chlorin derivative that has shown promise as a cancer therapeutic (Kostenich, Zhuravkin, & Zhavrid, 1994). The chlorin e6 molecule has been adapted to improve its clinical efficacy, and the conjugation of a trisodium salt of chlorin e6 to polyvinylpyrrolidone (PVP), a water-soluble polymer, has been reported (Parkhots et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Photolon™, a chlorin e6 derivative, triggers ROS production and light-dependent cell death via necrosis

Copley

Watt

Wirtz

et al. 2008

The International Journal of Biochemistry & Cell Biology

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PhotolonTM is a photosensitiser with demonstrated potential as an anti-tumour agent. In this study, an in vitro investigation was performed to determine the mechanism of Photolon TM -induced cell death. Cell killing was observed in a light-dependent manner and light-activated Photolon TM resulted in a significant production of reactive oxygen species (ROS), which could be blocked by type I ROS scavengers. Inhibition of ROS production using Trolox prevented Photolon TM -induced cell death. Lightactivated Photolon TM caused no increase in caspase-3/7 activity, but a rapid increase in lactate dehydrogenase (LDH) release suggesting a loss of membrane integrity and subsequent cell death by necrosis. We conclude that the mechanism of Photolon TMinduced cell death involves the induction of ROS via a type I mechanism, which is ultimately responsible for cell killing by necrosis.

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“…Since the chlorophyllides have been known to have antiviral activity for more than 40 years and have been shown to have activity against HIV-1 (6, 24) and more recently to be safe in animals (8,(18)(19) and, for chlorophyllin, even to be safe in people at 300 mg/day for 4 months (9,18), it is an open question as to why they have not been developed further. Perhaps the chlorophyllides have not been used against their most sensitive targets, or perhaps it is the undesirable color residues associated with the charged, copper-containing parent compounds and/or formulation reasons.…”

Section: Discussionmentioning

confidence: 99%

Alkylated Porphyrins Have Broad Antiviral Activity against Hepadnaviruses, Flaviviruses, Filoviruses, and Arenaviruses

Guo

Pan

Mao

et al. 2011

Antimicrob Agents Chemother

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We screened ϳ2,200 compounds known to be safe in people for the ability to reduce the amount of virion-associated hepatitis B virus (HBV) DNA in the culture medium of producer cells. These efforts led to the discovery of an alkylated porphyrin, chlorophyllide, as the compound that achieved the greatest reduction in signal. Here we report that chlorophyllide directly and quantitatively disrupted HBV virions at micromolar concentrations, resulting in the loss of all detectable virion DNA, without detectably affecting cell viability or intracellular viral gene products. Chemophores of chlorophyllide were also tested. Chlorin e6, a metal-free chlorophyllide-like molecule, showed the strongest antiviral activity against HBV as well as profound antiviral effects on other enveloped viruses, such as hepatitis C virus (HCV), human immunodeficiency virus (HIV), dengue virus (DENV), Marburg virus (MARV), Tacaribe virus (TCRV), and Junin viruses (JUNV). Remarkably, chlorin e6 inactivated DENV at subnanomolar-level concentrations. However, the compound had no antiviral effect against encephalomyocarditis virus and adenovirus, suggesting that chlorin e6 may be less active or inactive against nonenveloped viruses. Although other porphyrin derivatives have been previously reported to possess antiviral activity, this is the first analysis of the biochemical impact of chlorophyllide and chlorin e6 against HBV and of the dramatic anti-infectivity impact upon DENV. The possible application of this family of compounds as antiviral agents, as microbicides and systemic virus neutralizing agents, is discussed.There are currently 7 U.S. FDA-approved medications for the management of chronic hepatitis B (2). These fall into two categories: the interferons (IFNs) and the nucleos(t)ide polymerase inhibitors. Both have medical value, but both have limitations. The IFNs require parenteral injections and are associated with adverse affects that limit their use (15). The polymerase inhibitors are compromised by drug-resistant viruses, and prolonged treatment may be necessary (23). Drugs in both categories are expensive, further limiting use, and are beneficial only in subsets of chronic hepatitis B patients (16). Clearly, alternatives and complements are necessary. However, the pathway to discovery and approval of a new drug entity usually involves years of development and large financial investments.Drug safety, formulation, and pharmacokinetics are usually the limiting steps in drug development, often being responsible for most of the preclinical cost and failure (1). Therefore, we have been searching for compounds with antiviral activity from libraries of drugs that are already known to be safe in animals or people. Our priority has been hepatitis B virus (HBV). However, since we have been using libraries of compounds that mostly target host functions and these functions could be commonly used by many virus families, we remained open to the possibility of finding broadly active agents.We have tested approximately 2,200 compounds for the abi...

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Experimental grounds for using chlorin ρ6 in the photodynamic therapy of malignant tumors

Cited by 91 publications

References 18 publications

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

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

Photolon™, a chlorin e6 derivative, triggers ROS production and light-dependent cell death via necrosis

Alkylated Porphyrins Have Broad Antiviral Activity against Hepadnaviruses, Flaviviruses, Filoviruses, and Arenaviruses

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