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Researchers Submit Patent Application, "Oral Administration of Melanin for Protection against Radiation", for Approval

February 27, 2014



By a News Reporter-Staff News Editor at Politics & Government Week -- From Washington, D.C., VerticalNews journalists report that a patent application by the inventors Dadachova, Ekaterina (Mahopac, NY); Casadevall, Arturo (Pelham, NY), filed on March 15, 2012, was made available online on February 13, 2014.

The patent's assignee is Albert Einstein College of Medicine of Yeshiva University.

News editors obtained the following quote from the background information supplied by the inventors: "Throughout this application various publications are referred to in parenthesis. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference in their entireties into the subject application to more fully describe the art to which the subject application pertains.

"Melanin is a high molecular weight pigment that is ubiquitous in nature and has a variety of biological functions (5). Melanins are found in all biological kingdoms. These pigments are among the most stable, insoluble, and resistant of biological materials (6). Melanins can have different structures depending on the biosynthetic pathway and precursor molecules. Some definitions of melanin have focused on chemical and physical properties of melanins instead of defined structures (7). Melanins can be synthesized in the laboratory by chemical means or by many living organisms. Melanins formed by the oxidative polymerization of phenolic compounds are usually dark brown or black (6). However, melanins may have other colors as illustrated by the finding that dopamine-derived melanin is reddish-brown. Fungi can make melanins from at least two major biosynthetic pathways, employing the precursor 1,8-dihydroxynapthalene (DHN melanin) or the oxidation of suitable tyrosine derivatives like dihydroxyphenylalanine (DOPA-melanin) (6). The fungus C. neoformans can make melanins from a wide variety of phenolic compounds which are oxidized by a laccase enzyme (8-10). Many fungi constitutively synthesize melanin (11).

"Every year 1.4 million people are diagnosed with cancer in the U.S. and half of them will undergo some form of radiation therapy in the course of their disease. The availability of radioprotective compounds would alleviate the morbidity associated with the radiation exposure. The doses received by millions of patients during diagnostic radiological procedures are also very high (the dose of a multi-slice cardiac CT scan is equal to the dose from 300 chest X-rays) and are of great concern as well; thus such patients would also benefit from the affordable and effective radioprotectors. There is also importance for public safety to have radioprotective agents readily available in the event of a nuclear accident or terrorist attack.

"Radioprotective agents that could be given prior to, or even during, radiation exposure would be of significant value in alleviating the side effects associated with exposure to ionizing radiation. Currently there are no FDA-approved radioprotectors. It would be extremely beneficial for hundreds of millions of people to have access to food supplements that could fill the niche in the absence of radioprotective drugs.

"Fungal melanins can function as energy transducing molecules capable of capturing high energy electromagnetic radiation and converting it into an energy form that is useful to fungal cells (1). Furthermore, fungal melanins can be effective shields against radiation; the efficacy of radioprotection by melanins is dependent on their chemical composition and spatial arrangement (2). In addition to free reactive radical scavenging, radioprotection by melanins involves prevention of free radical generation by Compton recoil electrons through gradual recoil electron energy dissipation by the n-electron-rich melanin until the kinetic energy of recoil electrons becomes low enough to be trapped by stable free radicals present in the pigment (3). It has also been shown that melanin-based nanoparticles protect bone marrow in mice subjected to external whole body radiation or radioimmunotherapy (4).

"The present invention addresses the need for radioprotectants in humans at risk for radiation exposure using melanin-based products."

As a supplement to the background information on this patent application, VerticalNews correspondents also obtained the inventors' summary information for this patent application: "The invention provides methods for alleviating and/or preventing one or more side effects associated with exposure to radiation in a subject exposed to radiation or at risk for exposure to radiation comprising oral administration to the subject of an amount of an edible source of melanin effective to alleviate a side effect associated with radiation.

"The invention also provides a method for increasing the survival rate of a plurality of subjects exposed to an amount of radiation likely to kill the plurality of subjects, comprising oral administration to each of the plurality of subjects of an amount of an edible source of melanin effective to increase the survival rate of the plurality of subjects exposed to the amount of radiation likely to kill the plurality of subjects.

"The invention also provides edible sources of melanin packaged for oral administration to a subject for alleviating and/or preventing one or more side effects associated with exposure of the subject to radiation, wherein the edible source provides melanin in an amount equivalent to at least 8 mg of purified melanin per kg of body weight of the subject.

"The invention also provides a drinkable suspension of melanin packaged for oral administration to a subject for alleviating and/or preventing one or more side effects associated with exposure of the subject to radiation, wherein the drinkable suspension comprises at least 500 mg melanin in a volume of 500 mL or less.

BRIEF DESCRIPTION OF THE FIGURES

"FIG. 1. Survival of CD1 mice receiving synthetic pheomelanin before 9 Gy whole body radiation dose. Three hours before receiving the whole body dose of 9 Gy, the mice were given by oral gavage either 100 mg/kg body weight synthetic pheomelanin followed by 5 days of antibiotic support, or PBS followed by 5 days of antibiotic support, or PBS alone. AB--antibiotic support. 10 mice per group were used. P values were 0.001 and 0.002 when the survival in pheomelanin group was compared with PBS and PBS plus antibiotics groups, respectively.

"FIG. 2. Survival of CD1 mice after 9 Gy whole body radiation dose. Three hours before receiving the whole body dose of 9 Gy the mice were given by oral gavage either 1 g/kg body weight of Auricolaria judae mushroom suspended in PBS, or 1 g/kg body weight of Auricolaria judae mushroom followed by antibiotics support for 5 days, or PBS followed by antibiotics support for 5 days, or PBS alone. There were 5 mice in PBS alone and in PBS plus antibiotic support groups, and 6 mice in mushrooms and mushrooms plus antibiotics groups. The P value was 0.015 for both mushrooms and mushrooms plus antibiotics when compared to PBS alone and to PBS plus antibiotics controls. Ab--antibiotics support, Mum--mushrooms.

"FIG. 3A-3E. Chemical composition of melanins and appearance of melanins from various sources and mushrooms used in the study: a) structure of eumelanin oligomer; b) structure of pheomelanin oligomer; c) electron micrograph of purified microbial melanin (melanin 'ghosts'); d) synthetic melanin--eumelanin (black) on the left and pheomelanin (brown) on the right; e) edible mushrooms used in the study--Boletus edulis (white mushrooms) on the left and Auricularia auricula-judae (black mushrooms) on the right.

"FIG. 4A-4G. Physico-chemical characterization of black and white mushrooms: a, b) EPR of dried mushrooms: a) black mushrooms; b) white mushrooms; c-e) oxidative HPLC of melanin purified from black mushrooms: c) background solution; d) PDCA standard eluting at 8 min.; e) melanin from black mushrooms showing PDCA peak; f, g) results of DPPH assay for antioxidant presence: f) butylated hydroxyanisole (BHA) positive control; g) methanol extracts from black and white mushrooms.

"FIG. 5A-5H. Survival of irradiated CD-1 mice fed with black edible mushrooms, blood counts in the surviving mice and histology of the GI tract and bone marrow. Mice were divided into groups of 5-6 and fed 1 g/kg body weight black mushroom suspension in PBS, or PBS alone, or 1 g/kg white mushroom suspension, or 1 g/kg white mushroom suspension supplemented with 100 mg/kg synthetic melanin via gavage needle. One hour after mushroom administration mice were irradiated with 9 Gy dose of Cs-137 radiation at a dose rate of 2.5 Gy/min. a) Kaplan-Meyer survival curves. The experiment was performed twice and was terminated at day 45; b) white blood cells counts; c) platelet counts; d-h) H&E stained slides with tissues from control and irradiated mice. Left, non-irradiated controls; middle, black mushroom group; right, white mushroom supplemented with melanin. d) stomach, magnification .times.400; e) LI, magnification 400; f) SI, magnification .times.200; g) bone marrow, magnification .times.400; h) spleen, magnification .times.100.

"FIG. 6A-6D. Survival and weight change in CD-1 mice ted with different doses of synthetic pheomelanin and/or antibiotics and irradiated with 9 Gy gamma radiation at 2.5 Gy/min: a) mice fed with 0-100 mg/kg body weight pheomelanin; b) mice fed with 100 mg/kg pheomelanin followed by antibiotics for 5 days, or given PBS only, or given PBS followed by antibiotics for 5 days; c) combined results from a) and b); d) weight change in irradiated groups modeled using linear regression. AB--antibiotics.

"FIG. 7A-7C. Histological evaluation of the tissue in surviving mice post-irradiation with 9 Gy gamma radiation at 2.5 Gy/min: a) stomach, small intestine, large intestine, liver and bone marrow. Mice received 100 mg/kg pheomelanin plus antibiotics (upper row); 75 mg/kg pheomelanin (middle row); 0 mg/kg plus antibiotics (lower row); b) tissues from a mouse receiving 100 mg/kg pheomelanin plus antibiotics--focal microadenoma of the small intestine (left panel) and bone marrow (right panel); c) cecum of a single survivor in 0 mg/kg plus antibiotics group. The same region of the cecum is shown with magnification .times.250 in the left panel, .times.400 in the middle panel and .times.1,000 in the right panel Each slide is a higher magnification of the same region. Magnification .times.400 in a) and b).

"FIG. 8A-8B. Toxicity evaluation of microbial and synthetic eumelanin in non-irradiated CD-1 mice: a) body weight of mice fed with 15 mg/kg microbial or synthetic eumelanin; b) histology of GI organs from CD-1 mice fed with microbial eumelanin and sacrificed 24 hr later: left, stomach; middle, small intestine; right, colon. Original magnification .times.400.

"FIG. 9A-9H. Radiation effects in CD-1 mice fed with 15 mg/kg body weight microbial or synthetic eumelanin and irradiated with 9 Gy gamma radiation at 2.5 Gy/min: (a-f) histology of GI tract tissues obtained from irradiated CD-1 mice sacrificed at 4 hr (a-c) and at 24 hr (d-f) post-irradiation: a) stomach, synthetic eumelanin group; b) stomach, microbial eumelanin group; c) stomach, PBS. Fewer apoptotic cells are seen in stomach tissue of microbial melanin fed mice than in synthetic eumelanin or PBS groups; d) colon, synthetic eumelanin group; e) colon, microbial eumelanin group; f) colon, PBS control group; g) cumulative weight loss in CD-1 mice; h) survival of the irradiated mice. Original magnification .times.400."

For additional information on this patent application, see: Dadachova, Ekaterina; Casadevall, Arturo. Oral Administration of Melanin for Protection against Radiation. Filed March 15, 2012 and posted February 13, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=3417&p=69&f=G&l=50&d=PG01&S1=20140206.PD.&OS=PD/20140206&RS=PD/20140206

Keywords for this news article include: Legal Issues, Albert Einstein College of Medicine of Yeshiva University.

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