WO2017008768A1 - Glucane et procédé de préparation de ce dernier, et application dans la préparation de médicaments et d'aliments fonctionnels stimulants immunitaires et antitumoraux. - Google Patents

Glucane et procédé de préparation de ce dernier, et application dans la préparation de médicaments et d'aliments fonctionnels stimulants immunitaires et antitumoraux. Download PDF

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WO2017008768A1
WO2017008768A1 PCT/CN2016/095989 CN2016095989W WO2017008768A1 WO 2017008768 A1 WO2017008768 A1 WO 2017008768A1 CN 2016095989 W CN2016095989 W CN 2016095989W WO 2017008768 A1 WO2017008768 A1 WO 2017008768A1
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glucan
preparation
tumor
antitumor
functional food
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PCT/CN2016/095989
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English (en)
Chinese (zh)
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于广利
郝杰杰
丛大鹏
管华诗
赵峡
吕友晶
胡婷
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青岛海大海洋生物医药销售有限公司
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Publication of WO2017008768A1 publication Critical patent/WO2017008768A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans

Definitions

  • the invention belongs to the field of marine medicine, and relates to a method for preparing high-purity low-molecular-weight glucan by using seaweed and application thereof, in particular to a glucan and a preparation method thereof, and a medicament and a function for preparing for immune enhancement and anti-tumor. Food applications.
  • Glucan is a polysaccharide material with glucose as the sole component. It is widely found in animals, plants and microorganisms as well as brown algae. There are many kinds of glucans in nature, and there are linear or branched ⁇ / ⁇ -glucans. The connection between glucose is 1,2-linkage, 1,3-linkage, 1,4-linkage and 1, 6-linked form, in which ⁇ -1,3 and ⁇ -1,6-glucan have good biological activities, such as anti-tumor, enhance immunity, promote wound healing, anti-radiation and prevent hyperlipidemia. According to the World Health Organization, in the next 20 years, cancer cases will rise from 14 million in 2012 to 22 million. In China, 8,550 people become cancer patients every day, and one out of every seven to eight people die of cancer.
  • ⁇ -1,3-glucan has a wide range of uses in the fields of substitute plasma, prevention of oral mucosal ulcers and cosmetics, and has broad market applications.
  • ⁇ -1,3-glucan on the market mostly comes from terrestrial organisms such as barley, oats, edible fungi (chanterelle, ash tree, schizophyllum), yeast, etc., due to different sources of raw materials, the resulting ⁇ -1,
  • the molecular weight, the connection mode and the branching degree of 3-glucan are very different, and the quality is difficult to control.
  • the ⁇ -glucan for injection medicine is mainly derived from shiitake mushroom, and is a ⁇ -1,6-branched group.
  • --1,3-glucan has poor water solubility due to its molecular weight of up to 400-800 kDa. With the continuous expansion of the application field of ⁇ -glucan and the increasing market demand, the existing mushroom ⁇ -glucan can no longer meet the needs of the market.
  • a Chinese invention patent (Patent No. 201010169739.7) was found to involve the preparation method of seaweed low molecular weight glucan.
  • the raw materials are kelp, wakame and sarcophagus. It is a method of fractional precipitation of 80% ethanol and oxidation of hydrogen peroxide.
  • the obtained product has a molecular weight of only 800-1000 Daltons (Da), the structure is not clear, and no activity report inhibiting tumor growth and metastasis is reported.
  • the present invention provides a glucan which is ⁇ -1,3/1,6-glucan, which has ⁇ -1,3-glucose as the main chain and ⁇ -1,6- Glucose is branched, and the weight average molecular weight is 1.1 kDa to 50 kDa; the content of glucose in the ⁇ -1,3/1,6-glucan is 90 wt% to 98 wt%, and the crude protein content is 0.5% wt-2.5% wt. The rest is moisture.
  • the ⁇ -1,3/1,6-glucan is extracted from Antarctic brown algae, which is sea velvet, sea bamboo shoot or rosenbergea.
  • the invention provides a preparation method of the glucan, which comprises the following steps:
  • step (3) the crude polysaccharide of step (3) is dissolved in distilled water, and distilled water and sodium chloride aqueous solution are used as The mobile phase was separated and purified by anion exchange resin, detected by a phenolic acid method, and the water-eluting fraction was collected, concentrated under reduced pressure, and lyophilized to obtain the ⁇ -1,3/1,6-glucan.
  • the ratio of the volume of the organic solvent added in the step (1) to the mass ratio of the algal powder is 10 to 20:1, and degreasing by immersion or intermittent stirring for 2 to 8 hours, and the organic solvent used is ethanol, acetone or methanol. One or several.
  • the volume of the calcium chloride aqueous solution added in the step (3) is 1 to 3 times the volume of the supernatant, the concentration of the calcium chloride aqueous solution is 1-3 mol/L, and the membrane for the dialysis or ultrafiltration is retained.
  • the molecular weight is from 1,000 to 3,000 Da.
  • the concentration of the aqueous solution of sodium chloride used in the purification of the anion exchange resin in the step (4) is 0.01 to 2.0 mol/L, and elution is 2 to 8 column volumes.
  • the present invention also provides the use of the ⁇ -1,3/1,6-glucan for the preparation of a medicament for immunoenhancement and antitumor and a functional food.
  • the concentration of the ⁇ -1,3/1,6-glucan is from 1 to 100 ⁇ g/mL, the macrophage is promoted to phagocytose neutral red.
  • ⁇ -1,3/1,6-glucan has a concentration of 1 to 200 ⁇ g/mL, it has an effect of promoting proliferation of T and B lymphocytes.
  • ⁇ -1,3/1,6-glucan dose is greater than 0.5 mg/kg/day, the tumor growth and tumor metastasis of the tumor-bearing mice can be effectively inhibited.
  • the index of the immune organs of the tumor-bearing mice can be effectively increased.
  • ⁇ -1,3/1,6-glucan is compounded with paclitaxel, cisplatin or fluorouracil, and docetaxel for preparing an antitumor drug.
  • the present invention dries and pulverizes Antarctic seaweed, and is purified by degreasing, calcium chloride precipitation and anion exchange resin to obtain ⁇ -1,3-glucose as a main chain and ⁇ -1,6-glucose in high purity.
  • Branched low molecular weight -1-1,3/1,6-glucan having a glucose content of 90% by weight to 98% by weight, a protein content of 0.5% by weight to 2.5% by weight, and a weight average molecular weight of 1.1 kDa to 50 kDa.
  • the raw material is derived from edible brown algae in Antarctica and has high safety.
  • the ⁇ -1,3/1,6-glucan prepared by the method of the invention has a purity of 90 wt% to 98 wt% and a molecular weight of 1.1 kDa to 50 kDa.
  • the low molecular weight ⁇ -1,3/1,6-glucan prepared by the method of the present invention has immunopotentiation and inhibits tumor growth and metastasis at the cell and animal levels.
  • Fig. 1 is a HPLC diagram showing the monosaccharide composition analysis of ⁇ -1,3/1,6-glucan of the present invention.
  • FTIR Fourier transform infrared spectroscopy
  • Fig. 3 is a nuclear magnetic resonance carbon spectrum ( 13 C-NMR) chart of ⁇ -1,3/1,6-glucan of the present invention.
  • Figure 4 is a graph showing the effect of ⁇ -1,3/1,6-glucan on promoting phagocytosis of neutral red by macrophages of the present invention.
  • Fig. 5 is a graph showing the effect of ⁇ -1,3/1,6-glucan on the proliferation of B lymphocytes (5A) and T lymphocytes (5B) according to the present invention.
  • Figure 6 shows that ⁇ -1,3/1,6-glucan inhibits the growth of breast cancer (6B) in murine 4T1 breast cancer (6A) and human breast cancer MDA-MB-231, and effectively increases The effect of the therapeutic effect of clinically used chemotherapy drug paclitaxel.
  • the ⁇ -1,3/1,6-glucose prepared in this example has a purity of 97.5 wt% and a protein content of 2% wt.
  • High-performance gel permeation chromatography (HPGPC) and eighteen-angle laser scatterometry (MALLS) and differential display are used.
  • the detector (RI) was analyzed in combination and its molecular weight distribution was between 1.1 kDa and 50 kDa.
  • the monosaccharide composition analysis results of the product of the present invention showed that the monosaccharide composition of the obtained polysaccharide had only glucose, indicating that it was glucan.
  • the infrared spectrum of the product of the present invention show, OH stretching vibration of a polysaccharide hydroxyl group 3347cm -1, 2917cm -1 is the stretching vibration peak of the sugar ring CH, 1646cm -1 in a small amount of NH stretching vibration protein
  • the peak, 1371 cm -1 is the variable angular vibration peak of CH; 1152 cm -1 , 1072 cm -1 and 1030 cm -1 are the asymmetric stretching vibration peaks of D-glucopyranose ring respectively; 896 cm -1 is the characteristic stretching of ⁇ -terminal CH
  • the vibration peak, from which it can be judged that the product of the present invention is a ⁇ -D-glucopyranose.
  • Table 1 shows the results of methylation analysis of the products of the present invention. From the data in the table, it is known that Glc (1 ⁇ , ⁇ 3) Glc (1 ⁇ , ⁇ 6) Glc (1 ⁇ and ⁇ 3,6) Glc (1) exists between each glucose (Glc) in the glucan product of the present invention.
  • ⁇ Four kinds of linkage means that the dextran is a dextran with 1 ⁇ 3 linkage as the main chain and 1 ⁇ 6 linkage as the branch.
  • Figure 3 is a 13 C-NMR spectrum of the product of the present invention. As can be seen from Fig. 3, there is no signal in the range of ⁇ 170 to 176 ⁇ 10 -6 , indicating that there is no signal between uronic acid and acetyl group in the sample, and ⁇ 16 ⁇ 18 ⁇ 10 -6 , indicating that there is no methyl sugar in the sample.
  • the signal attribution of the product of the invention is shown in Table 2. From the data in Table 2, the obtained product was ⁇ -1,3/1,6-glucose.
  • Macrophages (Raw264.7) were cultured in high glucose DMEM medium containing 10% fetal bovine serum, and the cell concentration was adjusted, and the cells were seeded in a 96-well cell culture plate to have a cell concentration of 2 ⁇ 10 4 /well. Then, different concentrations of samples were added to make ⁇ -1,3/1,6-glucose final concentrations of 5 ⁇ g/mL, 25 ⁇ g/mL, 50 ⁇ g/mL, and 100 ⁇ g/mL, respectively, with blank medium as control.
  • the above experiments were repeated 3 times, and the average was taken for statistical analysis of the results. From the results of Fig. 4, it can be seen that the product of the present invention has a significant promoting effect on macrophage phagocytosis neutral red as the concentration increases from 1 to 100 ⁇ g/mL.
  • mice After the Kunming mice were sacrificed by cervical vertebrae, 75% alcohol was disinfected for 3-5 minutes. The mice were dissected from the ultra-clean table. The spleens of the mice were removed, washed with PBS, ground into individual cells, and counted under a microscope to 4 ⁇ 10 7 cells/mL. The density was inoculated into a 96-well plate. After 4 hours, different concentrations of ⁇ -1,3/1,6-glucan (1,5,25, 50, 100 ⁇ g/ml) were added, and the administration group was LPS+glucan.
  • the experimental results are shown in Fig. 5.
  • the dextran can effectively increase the responsiveness of spleen lymphocytes to LPS and ConA at a concentration of 1-200 ug/ml, indicating that dextran has a significant effect on promoting spleen lymphocyte proliferation.
  • mice Mouse Lewis lung cancer cells (LLC) were cultured under appropriate conditions, and when the cells were grown to log phase, the cells were resuspended, counted, inoculated, and passaged in vivo.
  • the mice were subcutaneously inoculated with 1 mm 3 tumor mass in the right forelimb of the right forelimb, and the tumors were grown to a size of about 10 mm 3 .
  • the mice were randomly divided into groups according to their body weight.
  • the blank group was given 20 mL/kg/day saline.
  • the dose of glucan in the drug-administered group was 1, 4, 10 mg/kg/day, and cyclophosphamide (30 mg/kg/day) was used as the positive control group. 21 days. The tumor weight was measured twice a week and the tumor volume was calculated. After the mice were sacrificed by cervical dislocation, the tumor pieces were taken out and weighed, and the lung tissues were taken out to observe the number of tumor metastatic nodules.
  • dextran can effectively inhibit tumor growth, the tumor inhibition rate is 32.9%, and cyclophosphamide has a tendency to lose weight during the course of administration, but the weight of the dextran group does not decrease significantly. It shows that the dextran drug is safe and non-toxic, and has protective effects on animals.
  • dextran can significantly inhibit the spontaneous lung metastasis of Lewis lung cancer, and the inhibition efficiency is 40.6%, indicating that dextran has an effective inhibitory effect on tumor metastasis and invasion.
  • the mouse breast cancer cell line 4T-1 was resuscitated by liquid nitrogen, and cultured in DMEM medium containing 10% fetal bovine serum; the cultured cells were expanded to reach the desired cell volume, and the cells were digested and collected; 10% fetal bovine was used.
  • the serum DMEM medium was diluted into 5 million/ml cell suspension, and 0.2 ml was inoculated into the right forelimb axillary portion of the mouse after routine disinfection. The diameter of the transplanted tumor was measured with a vernier caliper.
  • mice were randomly divided into groups of 12-15 each; the saline negative control group; the positive control paclitaxel group: paclitaxel 25 mg/kg, paclitaxel 12.5 mg/kg Glucan group: 1 mg/kg, 4 mg/kg; combined drug group was paclitaxel and dextran combination: paclitaxel 12.5 mg/kg +1 mg/kg, paclitaxel 12.5 mg/kg+4 mg/kg.
  • paclitaxel was intraperitoneally administered and administered every other day.
  • Glucan is administered intraperitoneally and administered daily.
  • the negative control group was intraperitoneally injected with the same volume of physiological saline, and the results are shown in Tables 5 and 6.
  • the data in Table 5 shows that seaweed ⁇ -1,3/1,6-glucan showed significant antitumor effect at 1 mg/kg alone, and the tumor inhibition rate was 25%.
  • 1 and 4 mg/kg of ⁇ -1,3/1,6-glucan significantly increased the antitumor effect of paclitaxel, and the tumor inhibition rate of 12.5 mg/kg paclitaxel was 26 % rose to 39% and 44%, indicating that seaweed ⁇ -1,3/1,6-glucan has an effect of increasing the antitumor effect of paclitaxel.
  • Lymphocytes of the spleen are mainly divided into T and B lymphocytes and a small amount of NK cells, which complete the cellular and humoral immune functions and the killing effect of tumor cells.
  • the results in Table 6 indicate that the seaweed ⁇ -1,3/1,6-glucan alone administration group has a significant effect of increasing the spleen index, P ⁇ 0.01; the increase of the spleen index indicates the lymphocyte proliferation of the spleen.
  • Figure 6A is a visual representation of the size of the tumor obtained during the experiment. The inhibitory effect of glucan on breast tumors was clearly observed, and glucan increased the anti-breast cancer effect of paclitaxel.
  • Liquid nitrogen was used to resuscitate human breast cancer cell line MDA-MB-231, cultured in DMEM medium containing 10% fetal bovine serum; cell fusion reached 80% or more, 0.25% trypsin digestion, passaged at a ratio of 1:3, 4th Cell generation was collected, and 10 7 cells were subcutaneously inoculated into each mouse.
  • the tumor grew to a diameter of approximately 1-1.5 cm, the tumor tissue was isolated, and the nude mice were inoculated into the armpits with a size of 1 mm 3 by scissors. The diameter of the transplanted tumor was measured with a vernier caliper.
  • mice were randomly divided into groups of 10-12 each; the saline negative control group; the positive control 5-Fu (5-fluorouracil) group: 5 mg/kg Glucan group: 0.5 mg/kg, 1 mg/kg; 5 mg/kg; administered for 21 days. 5-Fu was injected intraperitoneally and administered every other day; administration was given for 21 days. Three doses of dextran were administered intraperitoneally, intraperitoneally, daily for 21 days. The negative control group was intraperitoneally injected with the same volume of normal saline.
  • the experimental results are shown in Fig. 6B.
  • the algae ⁇ -1,3/1,6-glucan has a significant inhibitory effect on the weight of breast cancer tumors in immunodeficient nude mice at different doses, at a low dose of 0.5 mg.
  • the tumor inhibition rate was 25% at /kg/day, and the tumor inhibition rate of breast cancer was 20-25% at doses of 0.5 mg/mg, 1.0 mg/kg, and 5.0 mg/kg.
  • the concentration of the ⁇ -1,3/1,6-glucan prepared by the present invention is from 1 to 200 ⁇ g/mL, it has the effect of promoting macrophage phagocytosis of neutral red and proliferation of T and B lymphocytes. It is shown to have significant immunopotentiating activity.
  • In vivo mouse experiments showed that at 0.5 mg/kg/day, it significantly inhibited tumor growth and lung tumor metastasis in lung cancer and breast cancer mice, and increased the spleen index of immune organs in tumor-bearing mice. Enhance the potential of anti-tumor drugs.

Abstract

L'invention concerne un glucane et un procédé de préparation de ce dernier, et une application dans la préparation de médicaments et d'aliments fonctionnels stimulants immunitaires et antitumoraux. Le procédé comprend les étapes suivantes : séchage et broyage d'algues brunes de l'Antarctique ; et après dégraissage, extraction de l'eau, précipitation par du chlorure de calcium, et purification par une résine échangeuse d'anions, obtention d'un glucane ayant un β-1,3-glucose en tant que chaîne principale, un β-1,6-glucose en tant que chaîne ramifiée, et un poids moléculaire de 1,1 kDa à 50 kDa. Le β-glucane préparé selon la présente invention présente des activités de stimulation immunitaire indiquées par des analyses in vitro d'absorption de rouge neutre par les macrophages, et de prolifération des lymphocytes T et B, et il a aussi des fonctions de suppression de la croissance tumorale, d'inhibition des métastases tumorales, et une augmentation de l'indice splénique des organes du système immunitaire de souris porteuses de tumeur indiquée par des expériences.
PCT/CN2016/095989 2015-07-14 2016-08-19 Glucane et procédé de préparation de ce dernier, et application dans la préparation de médicaments et d'aliments fonctionnels stimulants immunitaires et antitumoraux. WO2017008768A1 (fr)

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CN113512130A (zh) * 2021-04-20 2021-10-19 汉邦环宇多糖生物科技（河源）有限公司 一种葡聚糖硫酸酯的超滤分级及其抗凝血活性测定方法
CN113831421A (zh) * 2021-10-14 2021-12-24 黄河三角洲京博化工研究院有限公司 一种灰树花菌丝体多肽和β-葡聚糖的联合制备方法
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WO2019024962A1 (fr) 2017-08-04 2019-02-07 Dittrich Klemens Adaptateur pour une station de charge de terminaux de télécommunication
DE102017122691A1 (de) 2017-08-04 2019-02-07 Klemens Dittrich Adapter für eine Ladestation für Telekommunikationsendgeräte
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EP3985030A4 (fr) * 2019-06-14 2023-07-12 CP Pharmaceutical Qingdao Co., Ltd. Composition de b-glucane et son utilisation
CN113512130A (zh) * 2021-04-20 2021-10-19 汉邦环宇多糖生物科技（河源）有限公司 一种葡聚糖硫酸酯的超滤分级及其抗凝血活性测定方法
CN113831421A (zh) * 2021-10-14 2021-12-24 黄河三角洲京博化工研究院有限公司 一种灰树花菌丝体多肽和β-葡聚糖的联合制备方法
CN114807270A (zh) * 2022-03-04 2022-07-29 山东大学 一种利用黑根霉发酵制备的牛蒡根多糖及其生产工艺和应用
CN114807270B (zh) * 2022-03-04 2023-09-22 山东大学 一种利用黑根霉发酵制备的牛蒡根多糖及其生产工艺和应用

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