Methods of using beta glucan as a radioprotective agent

a radioprotective agent and beta glucan technology, applied in the direction of antibacterial agents, immunological disorders, extracellular fluid disorders, etc., can solve the problems of poor patient compliance, no consensus achieved, and not provided a convenient formulation of beta glucan, so as to enhance the regeneration of promote stem cell attachment to the injury site, and enhance the regeneration of glucan-mediated hematopoietic progenitor stem cells

Inactive Publication Date: 2005-11-03
BIOTHERA INC (US) +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012] Also described herein are methods of enhancing glucan-mediated hematopoietic progenitor stem cell recovery after exposure to radiation via the complement system, comprising administering to an individual a therapeutically effective orally bioavailable amount of whole glucan particles, wherein the glucan enhances regeneration of hematopoietic progenitor stem cells. The β(1,3 / 1,6) glucan functions with complement activation after injury to promote stem cell attachment to the injury site via stem cell CR3 binding to iC3b stem cells that are attached via iC3b by providing the “second signal” for CR3 activation. This ligation of glucan to the lectin domain of CR3 is more efficient than the natural lectin site signal mediated by damaged tissue heparin sulphate. In certain embodiments of the methods of the invention, the orally administered glucan is transported to the bone marrow and degraded. At the bone marrow, the the degraded oral glucan activates stem cells via the complement system by binding to iC3b deposited on injured stem cell and activating CR3. That is, the method of the invention pertains to a method of enhancing glucan-mediated hematopoietic progenitor stem cell recovery after exposure to radiation via the complement system, comprising administering to an individual a therapeutically effective orally bioavailable amount of whole glucan particles, wherein the glucan via the complement system enhances regeneration of hematopoietic progenitor stem cells. The orally administered glucan is taken up by macrophages, transported to the bone marrow, degraded and the released fragments primes the CR3 of stem cell thereby activating the stems cell to differentiate and proliferate. The β(1,3 / 1,6) glucan in via the complement system promotes stem cell proliferation and differentiation by binding to iC3b deposited on injured stem cells and activating CR3.

Problems solved by technology

However, despite extensive investigation, no consensus has been achieved on the source, size, and form of β(1,3) glucan ideal for use as an immunostimulant.
However, these laboratory studies have not provided a convenient formulation of β-glucan.
The majority of these applications utilize soluble material that requires administration by injection, a costly and painful route that can result in poor patient compliance.
However, many drugs are not amenable to oral formulation due to properties that limit oral bioavailability.

Method used

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  • Methods of using beta glucan as a radioprotective agent
  • Methods of using beta glucan as a radioprotective agent

Examples

Experimental program
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Effect test

example 1

[0077] This example concerns the intravenous administration of WGP obtained using the described procedure from S. cerevisiae to mice to observe radioprotectant activity. WGP was suspended in sterile saline by placing it in a sonicating water bath at room temperature for 30 minutes to produce a fine suspension. Alternately, The WGP can be passed through a syringe needle of decreasing diameter until the material is capable of passing through the needle used for tail vein injection. A 4.0 mg / ml solution prepared in this fashion was administered to a group of 20 wild type C57Bl / 6 mice 1 day before irradiation with 6.5 Gy 60Co radiation by injecting 0.1 ml of the suspension into the tail vein. Survival rates of the treated mice changed dramatically over days 10 to 15 post-irradiation. Thirty days post-irradiation, 51% of the glucan treated mice were alive, while in control experiments, none of the mice survived beyond 21 days post-irradiation.

example 2

[0078] This example concerns the oral administration of WGP obtained using the described procedure from S. cerevisiae to mice to observe radioprotectant activity. WGP, was suspended in sterile saline by passing it through a gavage needle to ensure the elimination of lumps of material. A 0.8 mg / ml suspension prepared in this fashion was administered to a group of 20 wild type C57Bl / 6 mice 1 day before irradiation with 6.5 Gy 60Co radiation by gavaging the suspension. Dosing was continued ever day up to 10 days after irradiation. Survival rates of the treated mice were the same as that observed with intravenous administration. Thirty days post-irradiation, 51% of the glucan treated mice were alive, while in control experiments, none of the mice survived beyond 21 days post-irradiation.

example 3

[0079] This example concerns the intravenous administration of WGP obtained using the described procedure from S. cerevisiae to mice to observe the stimulation of post-radiation myelosuppressive recovery. WGP was suspended in sterile saline by placing it in a sonicating water bath at room temperature for 30 minutes to produce a fine suspension. Alternately, The WGP can be passed through a syringe needle of decreasing diameter until the material is capable of passing through the needle used for tail vein injection. A 4.0 mg / ml solution prepared in this fashion was administered to a group of 5 wild type C57Bl / 6 mice 1 day before irradiation with a nonfatal 650-rad dose of total-body gamma radiation by injecting 0.1 ml of the suspension into the tail vein. Myelosuppression recovery, as indicated by white blood cell (WBC) count, had diverged 7 days post-irradiation, as shown on the chart below, with mice treated with WGP showing significantly higher white blood cell counts than mice tre...

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Abstract

The invention relates to methods for treating and preventing radiation and / or chemotherapy related injury and / or afflictions, such as myelosuppression and decreased macrophage activity, by administering a prophylactically or therapeutically effective amount of particulate, bioavailable β(1,3; 1,6) glucan. The invention also relates to methods in which β(1,3; 1,6) glucan is provided in the form of whole glucan particles, microparticulate β-glucan particles or a combination thereof.

Description

RELATED APPLICATIONS [0001] This application is a continuation of International Application No. PCT / US03 / 25237, which designated the United States and was filed on Aug. 13, 2003, published in English, which claims the benefit of U.S. Provisional Application No. 60 / 403,424, filed on Aug. 13, 2002. The entire teachings of the above applications are incorporated herein by reference.GOVERNMENT SUPPORT [0002] The invention was supported, in whole or in part, by grant CA84612 from the National Institutes of Health and by grant DAMD17-02-1-0445 from the U.S. Army. The Government has certain rights in the invention.BACKGROUND OF THE INVENTION [0003] Beta(β)-glucan is a complex carbohydrate, generally derived from several sources, including yeast, bacteria, fungi and cereal grains. Each type of β-glucan has a unique structure in which glucose is linked together in different ways, resulting in different physical and chemical properties. For example, β(1,3) glucan derived from bacterial and al...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/715A61K31/716
CPCA61K31/716A61K31/715A61P7/00A61P27/04A61P31/04A61P31/10A61P31/12A61P33/00A61P35/00A61P37/04A61P39/00A61P43/00
Inventor OSTROFF, GARY R.ROSS, GORDON D.ROSS, TRUNETTA JO DOCKTER
Owner BIOTHERA INC (US)
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