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WO2018000339A1 - Nanobille magnétique enduite de cardiolipine modifiée et son procédé de préparation - Google Patents

Nanobille magnétique enduite de cardiolipine modifiée et son procédé de préparation Download PDF

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Publication number
WO2018000339A1
WO2018000339A1 PCT/CN2016/087910 CN2016087910W WO2018000339A1 WO 2018000339 A1 WO2018000339 A1 WO 2018000339A1 CN 2016087910 W CN2016087910 W CN 2016087910W WO 2018000339 A1 WO2018000339 A1 WO 2018000339A1
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WIPO (PCT)
Prior art keywords
cardiolipin
modified
modified cardiolipin
nano magnetic
nanomagnetic
Prior art date
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Ceased
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PCT/CN2016/087910
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English (en)
Chinese (zh)
Inventor
胡鹍辉
祝亮
邹定标
陈永棠
夏福臻
钱纯亘
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Shenzhen Yhlo Biotech Co Ltd
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Shenzhen Yhlo Biotech Co Ltd
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Priority to PCT/CN2016/087910 priority Critical patent/WO2018000339A1/fr
Priority to KR1020197002506A priority patent/KR102208218B1/ko
Publication of WO2018000339A1 publication Critical patent/WO2018000339A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G01N33/54326—Magnetic particles
    • G01N33/5434—Magnetic particles using magnetic particle immunoreagent carriers which constitute new materials per se
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/531—Production of immunochemical test materials
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/544—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being organic
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/571—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses for venereal disease, e.g. syphilis, gonorrhoea
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors

Definitions

  • the invention relates to the field of in vitro detection, in particular to a modified cardiolipin coated nano magnetic bead and a preparation method thereof.
  • An anticardiolipin antibody is an antibody that reacts with a variety of antigenic materials containing a phospholipid structure.
  • the antigen is a negatively charged phospholipid component that is involved in a variety of cell membranes. It is mainly found in patients with antiphospholipid syndrome, various autoimmune diseases and syphilis infections.
  • Antiphospholipid syndrome includes a variety of autoimmune diseases, more common in young people, the ratio of male to female incidence is about 2:8. Patients may have one or more manifestations that may affect multiple systems and organs, including: venous and arterial thrombosis, thrombocytopenia, habitual abortion, cardiomyopathy, heart disease, brain and kidney infarction, and pulmonary hypertension. Malignant APS can be characterized by progressive extensive thrombosis in the short term, resulting in multiple organ failure and even death. It can be secondary to systemic lupus erythematosus or other autoimmune diseases, but it can also occur alone (primary antiphospholipid syndrome).
  • Anti-phospholipid antibodies can also be produced in patients with syphilis.
  • Syphilis is a sexually transmitted disease caused by the spirochete syphilis. More than 5 million people are reported to be infected with syphilis each year, including 30,000 babies born through congenital infections. Syphilis can be lurking and hidden in patients for many years and can lead to a variety of clinical manifestations. Patients in the concealed period of syphilis have no clinical symptoms, and the secondary stage lasts for a lifetime in about two-thirds of untreated patients. Infected persons are not contagious during the concealment period, but children born to mothers in concealed periods may be infected with congenital syphilis.
  • Antiphospholipid antibody assays are widely used in the diagnosis of phospholipid syndrome and in the non-dense spiral test of syphilis. This detection has the advantage of being inexpensive, fast and convenient to perform on a large number of samples. In addition, since the concentration of antiphospholipid antibodies will gradually decrease with the successful treatment of syphilis, the specificity of syphilis infection Antibody Treponema antibodies can persist for years or even lifetimes. Therefore, antiphospholipid antibody test is considered to be a better choice for monitoring syphilis treatment.
  • the traditional method for detecting antiphospholipid antibodies is to apply cardiolipin to a specific solid such as a microplate by physical adsorption, and then combine the antiphospholipid antibodies in the sample to be tested with the cardiolipin attached to the plate. To achieve capture of antiphospholipid antibodies in the sample.
  • the concentration of the antiphospholipid antibody in the sample can be indirectly read by coloring the captured antiphospholipid antibody and measuring the luminescent concentration.
  • the cardiolipin immobilized by physical adsorption is easily dissociated and detached from the solid plate under the influence of external conditions such as solvent and heating, the stability of the test product prepared by the method is poor.
  • a modified cardiolipin coated nano magnetic bead comprising: modified cardiolipin and nano magnetic beads;
  • the modified cardiolipin is obtained by oxidizing and aminating a hydrophobic fatty acid side chain of a cardiolipin, the modified cardiolipin containing an amino group, and the modified cardiolipin is linked to the nanomagnetic beads through the amino group.
  • the surface of the nanomagnetic beads contains a carboxyl group that forms an amide ester structure with the carboxyl group to link the modified cardiolipin and the nanomagnetic beads together.
  • a method for preparing the modified cardiolipin coated nano magnetic beads comprising the following steps:
  • the cardiolipin and the peroxide are sufficiently reacted in the presence of the first solvent to obtain an intermediate product
  • the modified cardiolipin and the nano magnetic beads are mixed and fully reacted to obtain a modified cardiolipin coated nano magnetic bead.
  • the modified cardiolipin coated nano magnetic beads directly bond the modified cardiolipin to the nano magnetic beads through chemical bonds, and have the characteristics of strong stability and controllable connection amount.
  • Modified cardiolipin coating The nano magnetic beads can be directly used for the detection of antiphospholipid antibodies, and have higher stability than the detection products prepared by the conventional physical adsorption of cardiolipin.
  • FIG. 1 is a flow chart showing a method of preparing a modified cardiolipin coated nanomagnetic bead according to an embodiment.
  • the modified cardiolipin coated nanomagnetic beads of one embodiment include: modified cardiolipin and nano magnetic beads.
  • Cardiolipin is an ester composed of three glycerols, two phosphoric acids, and four long-chain unsaturated alkyl groups.
  • the structure contains two hydrophilic centers and four hydrophobic side chains.
  • cardiolipin The structural formula of cardiolipin is as follows:
  • the modified cardiolipin is obtained by oxidizing and aminating the hydrophobic fatty acid side chain of the cardiolipin, the modified cardiolipin contains an amino group, and the modified cardiolipin is linked to the nanomagnetic beads through the amino group.
  • the cardiolipin has four side chains, the four side chains can be simultaneously oxidized when the cardiolipin is modified, so the modified cardiolipin may contain a plurality of amino groups. Specifically, the modified cardiolipin may contain one to eight amino groups (-NH 2 ).
  • the modified cardiolipin contains one -NH 2 .
  • the surface of the nanomagnetic beads may contain at least one of a carboxyl group (-COOH) and a terminal epoxy group (-CH(O)CH 2 ).
  • the surface of the nanomagnetic beads contains a carboxyl group, and the amino group and the carboxyl group form an amide ester structure (-CO-NH-) to link the modified cardiolipin and the nanomagnetic beads together.
  • the modified cardiolipin coated nanomagnetic beads have the following structural formula:
  • the surface of the nanomagnetic beads contains a terminal epoxy group, and the amino group and the terminal epoxy group form a secondary amine structure (-NH-) to link the modified cardiolipin and the nanomagnetic beads together.
  • -NH- secondary amine structure
  • the modified cardiolipin coated nanomagnetic beads have the following structural formula:
  • the size of the cardiolipin molecule is very small, the space that can be modified is seriously insufficient, and modification of the hydrophilic phosphate ester center reduces the affinity of the cardiolipin and the antiphospholipid antibody, and even the antigen activity disappears.
  • the modified cardiolipin-coated nanomagnetic beads modify the hydrophilic side chain of the cardiolipin, retain the modified cardiolipin of the cardiolipin hydrophilic phosphate center, and utilize the amino and nano magnetic of the modified cardiolipin.
  • the beads combine to allow the modified cardiolipin to be firmly attached to the surface of the nanomagnetic beads.
  • the modified cardiolipin coated nano magnetic beads directly bond the modified cardiolipin to the nano magnetic beads through chemical bonds, and have the characteristics of stable and controllable connection amount.
  • the modified cardiolipin coated nano magnetic beads can be directly used for the detection of antiphospholipid antibodies, and has higher stability than the detection products prepared by the conventional physical adsorption of cardiolipin.
  • the preparation method of the above modified cardiolipin coated nano magnetic beads as shown in FIG. 1 comprises the following steps:
  • the fatty acid side chain of cardiolipin is oxidized by reaction of cardiolipin with peroxide.
  • the peroxide is peroxybenzoic acid, m-chloroperoxybenzoic acid, peroxyacetic acid or peroxypropionic acid.
  • the molar ratio of cardiolipin to peroxide is from 1:1 to 8.
  • the first solvent is dichloromethane, chloroform, chloroform, benzene or toluene.
  • S10 also includes the operation of purifying the intermediate product, which may be purified by liquid phase preparative chromatography. After purification, a modified cardiolipin having a purity of about 80% can be obtained.
  • reaction temperature is from 60 ° C to 100 ° C.
  • the hydrophobic fatty acid side chain of the cardiolipin is oxidized and aminated by peroxide and aqueous ammonia, so that the prepared modified cardiolipin contains an amino group.
  • the cardiolipin has four side chains, the four side chains can be simultaneously oxidized when the cardiolipin is modified, so the modified cardiolipin may contain a plurality of amino groups. Specifically, the modified cardiolipin may contain from 1 to 8 amino groups.
  • the modified cardiolipin contains one -NH 2 .
  • the mass concentration of ammonia water is 10% to 30%.
  • reaction temperature is from 60 ° C to 100 ° C.
  • the modified cardiolipin is linked to the nanomagnetic beads through the amino group.
  • the surface of the nanomagnetic beads may contain at least one of a carboxyl group (-COOH) and a terminal epoxy group (-CH(O)CH 2 ).
  • Nanomagnetic beads can be purchased directly, for example, the carboxyl magnetic beads of MagnaBind Company's Cat. No. 21353, MagnaMedics's product number MD01010, one of which may be selected, or a few may be mixed in a certain ratio.
  • S30 is: nanomagnetic beads, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCi) and 3-sulfonic acid-N-hydroxyl group
  • EDCi 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • Sulfo-NHS succinimide
  • the second solvent is DMSO, DMF, tetrahydrofuran or a phosphate buffer having a pH of 6.5 to 8.5, and the concentration of the nano magnetic beads is 5 mg/mL to 10 mg/mL, and 1-ethyl-3-(3-dimethylamino)
  • the concentration of propyl)carbodiimide is from 0.5 mg/mL to 1.5 mg/mL, and the concentration of 3-sulfonic acid-N-hydroxysuccinimide is from 0.5 mg/mL to 1.5 mg/mL.
  • the modified cardiolipin coated nanomagnetic beads obtained by the reaction of the modified cardiolipin and the nanomagnetic beads have the following structural formula:
  • S30 is: the nanometer magnetic beads and the modified cardiolipin are sufficiently reacted in the presence of a phosphate buffer solution having a pH of 6.5 to 8.5 to obtain a modified cardiolipin coated nanometer. Magnetic beads.
  • the concentration of the nano magnetic beads is 5 mg/mL to 10 mg/mL.
  • the modified cardiolipin coated nanomagnetic beads obtained by the reaction of the modified cardiolipin and the nano magnetic beads have the following structural formula:
  • the preparation method of the modified cardiolipin coated nano magnetic beads by modifying the hydrophobic side chain of the cardiolipin, obtaining the modified cardiolipin which retains the hydrophilic phosphate ester center of the cardiolipin, and using the modified cardiolipin
  • the amino group is combined with the nanomagnetic beads to firmly bond the modified cardiolipin to the surface of the nanomagnetic beads.
  • the preparation method of the modified cardiolipin coated nano magnetic beads directly bonds the modified cardiolipin to the nano magnetic beads through chemical bonds, and the prepared modified cardiolipin coated nano magnetic beads are stable and connected.
  • the controllable characteristics can be directly used for the detection of antiphospholipid antibodies, and has higher stability than the detection products prepared by the conventional physical adsorption of cardiolipin.
  • the modified cardiolipin coated nanomagnetic bead solution prepared in Examples 1 to 3 was separately taken, and 5 ⁇ L of the antiphospholipid antibody serum sample was added and incubated at 37 ° C for 30 minutes. After magnetic separation, the modified cardiolipin coated nanomagnetic beads were reconstituted to 200 ⁇ L, and the horseradish peroxidase-labeled secondary antibody was added. After incubation at 37 ° C for 30 minutes, the cells were washed successively, added with TMB substrate solution and incubated for 10 minutes. Add 100 ⁇ L of stop solution, The OD value was read on the microplate reader within 10 minutes to obtain the luminescence signal value of the sample.
  • Table 1 Examples 1 to 3 and control group (physical adsorption method) measure OD values of different samples
  • Example 1 It can be seen from Table 1 that the modified cardiolipin coated nano-magnetic beads prepared in Examples 1 to 3 are compared with the magnetic beads (control group) adsorbed by the physical adsorption method in the test of the anti-phospholipid antibody sample, Example 1
  • the modified erythrocyte-coated nano-magnetic beads prepared by ⁇ 3 had significantly lower luminescence signal values than the control group when the negative samples were measured (4 to 8 times lower), and the luminescence signal was significantly higher than that of the control group when measuring positive samples. Improvement (up to 5 to 10 times).
  • the modified cardiolipin coated nano magnetic beads prepared in Examples 1 to 3 have a significant improvement in detection sensitivity compared to the magnetic beads of the conventional physical adsorption method when measuring the antiphospholipid sample.

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  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
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  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
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Abstract

L'invention concerne une nanobille magnétique enduite de cardiolipine modifiée et son procédé de préparation. La nanobille magnétique enduite de cardiolipine modifiée comprend de la cardiolipine modifiée et une nanobille magnétique. La cardiolipine modifiée est obtenue par oxydation et amination d'une chaîne latérale d'acide gras hydrophobe de la cardiolipine, et contient un groupe aminé ; la cardiolipine modifiée est liée à la nanobille magnétique au moyen du groupe aminé.
PCT/CN2016/087910 2016-06-30 2016-06-30 Nanobille magnétique enduite de cardiolipine modifiée et son procédé de préparation Ceased WO2018000339A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2016/087910 WO2018000339A1 (fr) 2016-06-30 2016-06-30 Nanobille magnétique enduite de cardiolipine modifiée et son procédé de préparation
KR1020197002506A KR102208218B1 (ko) 2016-06-30 2016-06-30 변형된 카디오리핀으로 코팅된 마그네틱 나노비드 및 그 제조 방법

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111983221A (zh) * 2020-08-19 2020-11-24 深圳市卓润生物科技有限公司 表面修饰磁珠及其制备方法和应用

Citations (5)

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DE4241330A1 (de) * 1992-12-08 1994-06-09 Sabine Dr Lauer Testverfahren zur Differenzierung von gegen Cardiolipin (Anticardiolipin-Antikörper) und gegen einen Komplex aus Cardiolipin und ß2-Glykoprotein I gerichteten Antikörpern
CN101243321A (zh) * 2005-06-21 2008-08-13 美国政府健康及人类服务部，疾病控制和预防中心 用于检测抗-类脂抗体的方法、免疫测定法和装置
CN101360997A (zh) * 2005-11-18 2009-02-04 美国政府健康及人类服务部，疾病控制和预防中心 改性心磷脂及其应用
CN101498715A (zh) * 2009-03-11 2009-08-05 上海尧浩生物技术有限公司 抗心磷脂抗体检测试剂盒及其应用
CN101679463A (zh) * 2007-01-09 2010-03-24 脉管生物生长有限公司 制备氧化磷脂的改进方法

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WO1991010138A1 (fr) 1989-12-27 1991-07-11 Baxter Diagnostics Inc. Procede d'immobilisation de cardiolipine, de phosphatidylcholine et de cholesterol en phase solide et immunoanalyse
JP3359411B2 (ja) * 1994-03-07 2002-12-24 積水化学工業株式会社 抗リン脂質抗体測定用試薬の製造方法
GB0104057D0 (en) * 2001-02-20 2001-04-04 Babraham Inst Antiphospholipid antibody syndrome

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4241330A1 (de) * 1992-12-08 1994-06-09 Sabine Dr Lauer Testverfahren zur Differenzierung von gegen Cardiolipin (Anticardiolipin-Antikörper) und gegen einen Komplex aus Cardiolipin und ß2-Glykoprotein I gerichteten Antikörpern
CN101243321A (zh) * 2005-06-21 2008-08-13 美国政府健康及人类服务部，疾病控制和预防中心 用于检测抗-类脂抗体的方法、免疫测定法和装置
CN101360997A (zh) * 2005-11-18 2009-02-04 美国政府健康及人类服务部，疾病控制和预防中心 改性心磷脂及其应用
CN101679463A (zh) * 2007-01-09 2010-03-24 脉管生物生长有限公司 制备氧化磷脂的改进方法
CN101498715A (zh) * 2009-03-11 2009-08-05 上海尧浩生物技术有限公司 抗心磷脂抗体检测试剂盒及其应用

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111983221A (zh) * 2020-08-19 2020-11-24 深圳市卓润生物科技有限公司 表面修饰磁珠及其制备方法和应用
CN111983221B (zh) * 2020-08-19 2024-04-09 深圳市卓润生物科技有限公司 表面修饰磁珠及其制备方法和应用

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KR20190022762A (ko) 2019-03-06

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