CN117069919A - Organic porous adsorption material based on pentapterine quinone for blood purification and preparation method thereof - Google Patents
Organic porous adsorption material based on pentapterine quinone for blood purification and preparation method thereof Download PDFInfo
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- CN117069919A CN117069919A CN202311039845.7A CN202311039845A CN117069919A CN 117069919 A CN117069919 A CN 117069919A CN 202311039845 A CN202311039845 A CN 202311039845A CN 117069919 A CN117069919 A CN 117069919A
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- bilirubin
- adsorption
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- quinone
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- 238000001179 sorption measurement Methods 0.000 title claims abstract description 182
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 title claims abstract description 80
- 210000004369 blood Anatomy 0.000 title claims abstract description 33
- 239000008280 blood Substances 0.000 title claims abstract description 33
- 239000000463 material Substances 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000000746 purification Methods 0.000 title claims description 11
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 claims abstract description 412
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
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- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 9
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 claims description 9
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 8
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- 206010019663 Hepatic failure Diseases 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
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- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 2
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- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
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- NGDCLPXRKSWRPY-UHFFFAOYSA-N Triptycene Chemical compound C12=CC=CC=C2C2C3=CC=CC=C3C1C1=CC=CC=C12 NGDCLPXRKSWRPY-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G61/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
- C08G61/02—Macromolecular compounds containing only carbon atoms in the main chain of the macromolecule, e.g. polyxylylenes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
- B01J20/26—Synthetic macromolecular compounds
- B01J20/265—Synthetic macromolecular compounds modified or post-treated polymers
- B01J20/267—Cross-linked polymers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
- B01J20/28057—Surface area, e.g. B.E.T specific surface area
- B01J20/28066—Surface area, e.g. B.E.T specific surface area being more than 1000 m2/g
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
- B01J20/28069—Pore volume, e.g. total pore volume, mesopore volume, micropore volume
- B01J20/28076—Pore volume, e.g. total pore volume, mesopore volume, micropore volume being more than 1.0 ml/g
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/54—Ortho- or ortho- and peri-condensed systems containing more than five condensed rings
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
- C08G2261/10—Definition of the polymer structure
- C08G2261/12—Copolymers
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
- C08G2261/10—Definition of the polymer structure
- C08G2261/13—Morphological aspects
- C08G2261/135—Cross-linked structures
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Analytical Chemistry (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Polymers & Plastics (AREA)
- Medicinal Chemistry (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
Abstract
The invention discloses an organic porous adsorption material for purifying blood based on pentapterine quinone and a preparation method thereof, and relates to the technical field of preparation of adsorbents in functional polymer materials. The invention is based on the principle of molecular design, through designing the monomer pentapterine quinone which contains good space structure and can generate interaction force with endotoxin or bilirubin, the super-crosslinked organic polymer with good aperture structure is prepared by adopting the Friedel-crafts alkylation reaction which has mild reaction condition, low cost and easy industrialization, and because the super-crosslinked polymer contains excellent pore channel structure and oxygen atoms which can generate hydrogen bond interaction force with bilirubin, the mass transfer process of bilirubin is improved, the adsorption performance and selectivity of bilirubin are promoted, and further the super-crosslinked organic polymer has higher adsorption performance and better selectivity on bilirubin. Meanwhile, the material prepared by the invention can be used for making balls or blocks, is used as a high-efficiency adsorbent of a blood perfusion device, reduces the operation cost and risk, and has very good market application value.
Description
Technical Field
The invention relates to the technical field of preparation of adsorbents in functional polymer materials, in particular to an organic porous adsorption material for purifying blood based on pentapterine quinone and a preparation method thereof.
Background
Bilirubin is produced by the metabolism of hemoglobin, is easily combined with serum albumin in blood to form direct bilirubin, circulates to the liver through blood, and is finally hydrolyzed and discharged by enzymes in the liver. However, when the liver is severely damaged by various factors (such as viruses, alcohol, medicines and the like), a great deal of necrosis of liver cells is caused, so that liver failure is caused, the metabolic functions of toxins such as bilirubin and the like participated by the liver are reduced, and great damage is caused to human health.
Aiming at the important problem of liver function diseases, the main clinical treatment methods at present are liver transplantation and blood purification. Among them, liver transplantation is an effective treatment method for clinical liver diseases, but the practical clinical application of liver transplantation is greatly limited by the shortage of liver, low treatment safety, easy complications, difficulty in paying the cost of patients, ethical issues and the like. Thus, the primary means of treating liver failure clinically today is blood purification.
Blood purification is a therapeutic method for removing body toxins by artificial means, and can be subdivided into hemodialysis, plasmapheresis, hemoperfusion, etc. according to the mechanism and the type of impurities removed. The hemodialysis refers to a treatment method for removing body toxins through the principle of 'diffusion' of a semi-permeable membrane after purifying blood of a patient in an extracorporeal membrane type purification device and then conveying the blood back into a human body. Since the semipermeable membrane applied in the hemodialysis process only allows ions and small molecular substances to pass through, the semipermeable membrane is generally used for removing the small molecular substances in blood, and has poor removal effect on medium and large molecules in blood. The plasma exchange means that the blood in the patient is led to the outside of the body, the toxic substances in the blood plasma are separated by a plasma separator, and then the toxic substances in the blood of the patient are removed by replacing the toxic substances in the blood plasma of a healthy human body, and the removal rate is higher. However, this method causes allergic reaction due to the introduction of a large amount of exogenous plasma deficient in immunoglobulin and various coagulation substances during the treatment, and causes problems such as electrolyte disorder and arrhythmia of the human body.
In view of the above, hemodialysis and plasmapheresis are difficult to meet the overall needs of the human health industry, and therefore development of therapeutic means that can compensate for the deficiency of hemodialysis and plasmapheresis is highly desired. In recent years, blood perfusion is widely favored because it removes endogenous and exogenous toxins in the blood by the principle of efficient adsorption, and has no serial rejection and disease risk from the extraneous plasma. The current common blood perfusion adsorbents include active carbon materials, resin materials, novel porous materials and the like. Wherein, the adsorption capacity of the activated carbon material and the resin material is low, and side reactions such as hemolysis and the like are easy to be caused in the use process, so that the clinical practical application cannot be satisfied. The novel porous material has been paid attention to in recent years because of its advantages such as a special pore size structure, good mechanical properties, excellent adsorption properties, etc. However, in the novel porous materials, metal Organic Frameworks (MOFs), porous Aromatic Frameworks (PAFs) and Supermolecular Organic Frameworks (SOFs) are high in preparation cost, complex in reaction condition, difficult to mass produce, and cannot meet practical application requirements.
The present application has been made for the above reasons.
Disclosure of Invention
For the above reasons, in view of the problems or drawbacks of the prior art, it is an object of the present application to provide an organic porous adsorbent material for purifying blood based on pentamethylene quinone and a method for preparing the same, which solve or at least partially solve the above technical drawbacks of the prior art: the application selects the pentapterine quinone with H-shaped skeleton structure and oxygen heteroatom as monomer, prepares the pentapterine quinone-based super-crosslinking organic polymer through the Friedel-crafts alkylation reaction, and is used for bilirubin adsorption. The application improves the absorption amount of bilirubin by optimizing the pore canal structure of the adsorbent and the interaction force between the bilirubin and the adsorbent.
In order to achieve one of the above objects of the present application, the present application adopts the following technical scheme:
the preparation method of the organic porous adsorption material for purifying blood based on the pentapterine quinone comprises the following specific synthetic technical routes: the preparation method comprises the steps of taking the pentamethylene quinone with an H-type structure as a monomer, taking methylene dichloride as a solvent and a cross-linking agent, taking anhydrous aluminum trichloride as a catalyst, connecting the monomer with the monomer by methylene, and preparing the pentamethylene quinone by a solvent weaving method.
The method specifically comprises the following steps:
Under inert atmosphere and airtight condition, monomer pentapterine quinone is dissolved in methylene dichloride to obtain pentapterine quinone solution, and then anhydrous aluminum chloride AlCl is added into the pentapterine quinone solution 3 The obtained mixture is reacted for 12 hours at 0 ℃,30 ℃,40 ℃ and 60 ℃ in sequence, and finally the temperature is raised to 80 ℃ for 24 hours; after the reaction is completed, cooling the reaction to room temperature, quenching and suction filtering to obtain a solid product; and (3) washing and Soxhlet extraction are sequentially carried out on the solid product, and finally, vacuum drying is carried out, so that black powder is obtained, namely the organic porous adsorption material for purifying blood based on the pentapterine quinone.
Specifically, according to the technical scheme, the solvent braiding method is that under the condition of nitrogen, the dichloromethane solution of the aromatic compound is catalyzed by anhydrous aluminum trichloride, and the solvent braiding is carried out to obtain the super-crosslinked polymer with high specific surface area.
Further, according to the technical scheme, the inert atmosphere is an argon atmosphere or a nitrogen atmosphere.
Further, according to the technical scheme, the molar ratio of the monomer pentapterinenquinone to the catalyst is 1: (20-30). In a preferred embodiment of the invention, the mole ratio of the pentapterinenquinone to the catalyst is 1:24.
Further, according to the technical scheme, the dosage of the dichloromethane is not particularly limited, so long as the dissolution of the monomer and the reaction are not affected. For example, the monomeric pentamethylene quinone to methylene chloride may be used in an amount of (0.001 to 0.005) moL: (10-20) mL. In a preferred embodiment of the invention, the monomer, the ratio of the amount of the pentapterinenquinone to the amount of dichloromethane, is 0.002moL:10mL.
Specifically, according to the technical scheme, the anhydrous aluminum trichloride plays a role of a catalyst in the invention.
Specifically, according to the technical scheme, the anhydrous aluminum trichloride selected by the reaction has high activity and the reaction process is an exothermic process, so that the problems caused by catalyst selection and enthalpy change process can be well solved by a gradual heating method, and the reaction is full.
Further, in a preferred embodiment of the present invention, the above-described technical scheme is performed by quenching with methanol.
Further, in a preferred embodiment of the present invention, the soxhlet extraction is performed at 75 ℃ for 24 hours.
Further, in a preferred embodiment of the present invention, the vacuum drying is performed at 80 ℃ for 24 hours under vacuum.
Further, according to the technical scheme, the monomer pentapterin quinone is prepared by the following steps:
under inert atmosphere, adding anthracene, p-benzoquinone and tetrachlorobenzoquinone into acetic acid according to a proportion to dissolve, and condensing and refluxing the obtained mixed solution at 110-120 ℃ for 15-20 hours; and after the reaction is finished, filtering, washing and vacuum drying the obtained product to obtain the monomer pentapterinenquinone.
Preferably, in the above technical solution, the inert atmosphere is an argon atmosphere or a nitrogen atmosphere.
Preferably, in the above technical solution, in a preferred embodiment of the present invention, the molar ratio of anthracene, p-benzoquinone and tetrachlorobenzoquinone is 2:1:2.
preferably, in the above technical scheme, the amount of the acetic acid is not particularly limited, so long as the dissolution of anthracene, p-benzoquinone and tetrachlorobenzoquinone and the reaction are not affected. For example, the ratio of the total amount of anthracene, p-benzoquinone, and tetrachlorobenzoquinone to acetic acid may be (0.05-0.2) moL:100mL. In a preferred embodiment of the invention, the ratio of the total amount of anthracene, p-benzoquinone, and tetrachlorobenzoquinone to the amount of dichloromethane is 0.1moL:100mL.
Preferably, in a preferred embodiment of the present invention, the temperature of the condensation reflux reaction is 118 ℃ for 16 hours
Preferably, according to the technical scheme, the washing is carried out by using anhydrous diethyl ether and then using the anhydrous ethanol for washing for several times. Further, in a preferred embodiment of the present invention, the vacuum drying is performed at 80 ℃ for 24 hours under vacuum.
The second object of the present invention is to provide a pentapterine quinone-based organic porous adsorbent material for blood purification prepared by the above method.
Further, according to the technical scheme, the specific surface area of the organic porous adsorption material for purifying blood based on the pentapteriquinone is 780-1900m 2 /g。
A third object of the present invention is to provide the use of the organic porous adsorption material prepared by the above method in blood purification, in particular in adsorption of bilirubin by extracorporeal blood perfusion.
An adsorbent for purifying blood or removing bilirubin, comprising the organic porous adsorption material prepared by the method.
The invention selects the triptycene quinone with a special three-dimensional structure as a reaction monomer, and the super-crosslinked polymer HCP-6 prepared by a solvent weaving method has high specific surface area 1900m 2 /g and large pore volume 2.80cm 3 And/g, the porous structure is excellent. The adsorption experiment of bilirubin shows that the maximum adsorption capacity of free bilirubin can reach 931mg/g, and the albumin removing rate of HCP-6 to 256 mu M concentration is only 0.8%, and the bilirubin is selectively adsorbed in the bilirubin and albumin combination liquid. The adsorption mechanism is mainly that the superior pore canal structure of the super-crosslinked polymer HCP-6 prepared by a solvent weaving method captures the pore canal of bilirubin, and benzene ring and carbonyl in the HCP-6 respectively accumulate pi-pi with pyrrole groups in the bilirubin and imine in the pyrrole groups Hydrogen bonding interactions occur. In addition, HCP-6 has good recyclability and excellent biocompatibility.
Compared with the prior art, the invention has the following beneficial effects:
1. the HCP-6 of the invention has the highest specific surface area (1900 m) 2 /g) and a maximum pore volume (2.80 cm 3 /g)。
2. The HCP-6 has an excellent pore diameter structure, and a large number of benzene rings and carbonyl groups are contained in the structural unit, so that the HCP-6 can be in pore adsorption, pi-pi stacking and hydrogen bond interaction with bilirubin, the adsorption quantity of free bilirubin is 160mg/g, and the adsorption balance time of bilirubin is 30min. The adsorption process of HCP-6 on bilirubin is more in accordance with a quasi-second-level kinetic model, and the maximum adsorption quantity of the super-crosslinked polymer on bilirubin is researched through an adsorption isotherm, so that the saturated adsorption quantity of HCP-6 on bilirubin can reach 931mg/g.
3. The invention researches competitive adsorption of HCP-6 and bovine serum albumin, and even under the condition that the molar ratio of bilirubin to bovine serum albumin is 2:1 and 1:1, the adsorption amount of HCP-6 to bilirubin still can reach 120mg/g and 118mg/g. Its high selective adsorption is attributable to HCP-6 having an average pore size greater than bilirubin molecules and less than bovine serum albumin, and hydrogen bonding interactions with bilirubin. The removal rate of HCP-6 from bovine serum albumin was tested and was only 0.8% even at a molar BSA level of 256. Mu. MoL.
4. After the HCP-6 of the invention is adsorbed for 5 times on bilirubin circulation, the adsorption quantity still has the retention rate of more than 82 percent.
5. The HCP-6 of the invention has lower cytotoxicity and low hemolysis rate.
Drawings
FIG. 1 is a schematic representation of the synthesis of a pentapterinenquinone monomer of example 1;
FIG. 2 is a schematic representation of the synthesis of the super cross-linked polymer HCP-4 of comparative example 1;
FIG. 3 is a schematic representation of the synthesis of the super cross-linked polymer HCP-5 of comparative example 2;
FIG. 4 is a schematic representation of the synthesis of the super cross-linked polymer HCP-6 of example 2;
FIG. 5 is an H spectrum of a pentapterinenquinone monomer prepared in example 1;
FIG. 6 is a FT-IR spectrum of a super cross-linked polymer HCP 4-6;
FIG. 7 is a schematic diagram of a super cross-linked polymer HCP 4-6 13 C solid nuclear magnetic spectrum, "+" represents rotating sidebands;
FIGS. 8 (a), (b) SEM images of HCP-4; (c) and (d) SEM images of HCP-5; (e) SEM images of HCP-6;
FIGS. 9 (a), (b) are TEM images of HCP-4; (c) and (d) TEM images of HCP-5; (e) TEM image of HCP-6;
FIG. 10 is a PXRD pattern for the super cross-linked polymer HCP 4-6;
FIG. 11 is a TGA diagram of the super-crosslinked polymer HCP 4-6;
FIG. 12 (a) is a graph showing the nitrogen adsorption-desorption of the super cross-linked polymer HCP 4-6 prepared by various synthesis methods; (b) Pore size distribution curves of the super cross-linked polymers HCP 4-6 prepared by different synthesis methods;
FIG. 13 (a) is a graph of ultraviolet absorbance spectra of bilirubin solutions of different concentrations; (b) a free bilirubin standard curve;
FIG. 14 is a graph of the adsorption kinetics of the super cross-linked polymer HCP 4-6;
FIG. 15HCP-4 line-fitting to quasi-first and quasi-second order kinetic equations of bilirubin adsorption;
FIG. 16HCP-5 line-fitting to quasi-first and quasi-second order kinetic equations of bilirubin adsorption;
FIG. 17HCP-6 line-fitting to quasi-first and quasi-second order kinetic equations of bilirubin adsorption;
FIG. 18 Langmuir and Freundlich fit curves for the super-crosslinked polymer HCP4-6 for bilirubin adsorption;
FIG. 19 Langmuir straight line fit and Freundlich straight line fit of the super-crosslinked polymer HCP4-6 to bilirubin adsorption;
FIG. 20 (a) is a graph of ultraviolet absorbance spectra of Bovine Serum Albumin (BSA) and bilirubin binding solutions at different concentrations; (b) Bilirubin and Bovine Serum Albumin (BSA) conjugate solution standard curve with a molar ratio of 2:1;
FIG. 21 (a) is a graph of ultraviolet absorbance spectra of Bovine Serum Albumin (BSA) and bilirubin binding solutions at different concentrations; (b) Bilirubin and Bovine Serum Albumin (BSA) conjugate solution standard curve with a molar ratio of 1:1;
FIG. 22 adsorption kinetics curves for the super-crosslinked polymer HCP-6 in different BSA bilirubin binding solutions;
FIG. 23HCP-6 line-fits a quasi-first order kinetic equation for adsorption of different BSA bilirubin binding solutions;
FIG. 24HCP-6 line-fits a quasi-second order kinetic equation for adsorption of different BSA bilirubin binding solutions;
FIG. 25HCP-6 removal of different molar amounts of BSA;
FIG. 26 is a schematic illustration of the mechanism of HCP-6 to bilirubin adsorption;
FIG. 27 effect of cycle number on bilirubin adsorption amount;
FIG. 28 viability of fibroblasts at different concentrations of polymer;
FIG. 29 haemolysis rates under different concentrations of polymer.
Detailed Description
The invention discloses an organic porous adsorption material based on pentapterine quinone for blood purification and a preparation method thereof. The invention is based on the principle of molecular design, through designing the monomer pentapterine quinone which contains good space structure and can generate interaction force with endotoxin (bilirubin), and adopting the Friedel-crafts alkylation reaction which has mild reaction condition, low cost and easy industrialization, the super-crosslinked organic polymer with good aperture structure is prepared, and because the super-crosslinked polymer contains excellent pore channel structure and oxygen atoms which can generate hydrogen bond interaction force with bilirubin, the mass transfer process of bilirubin is improved, the adsorption performance and selectivity of bilirubin are promoted, and further the super-crosslinked organic polymer has higher adsorption performance and better selectivity on bilirubin. Meanwhile, the organic porous adsorption material prepared by the invention is a super-crosslinked polymer, has a large gap in the market at present, and most importantly, has better adsorption performance on bilirubin, so that the invention has a considerable development prospect in the field of bilirubin adsorption materials. The invention can be used for making balls or blocks, can be used as a high-efficiency adsorbent of a blood perfusion device, reduces the operation cost and risk, and has good market application value.
The invention is described in further detail below by way of examples. The present embodiment is implemented on the premise of the present technology, and a detailed embodiment and a specific operation procedure are now given to illustrate the inventive aspects of the present invention, but the scope of protection of the present invention is not limited to the following embodiments.
The equipment and materials used in the present invention are commercially available or are commonly used in the art. The methods in the following examples are conventional in the art unless otherwise specified.
The anthracene used in the following examples or application examples of the present invention has a chemical formula of C 14 H 10 Purity AR, available from alaa Ding Shiji (Shanghai) limited.
The chemical formula of the tetrachlorobenzoquinone adopted in the following examples or application examples of the present invention is C 6 Cl 4 O 2 Purity was 98% and was purchased from alaa Ding Shiji (Shanghai) limited.
The p-benzoquinone used in the following examples or application examples of the present invention has a chemical formula of C 6 H 4 O 2 The purity was AR, purchased from national pharmaceutical group chemical Co.
The dimethoxymethane used in the following examples or application examples of the present invention has the chemical formula C 3 H 8 O 2 Purity was 98% and was purchased from alaa Ding Shiji (Shanghai) limited.
Bilirubin used in the following examples or application examples of the present invention has the chemical formula C 33 H 36 N 4 O 6 Purity 98% and was purchased from beijing solebao limited.
Bovine serum albumin, abbreviated BSA, used in the following examples or application examples of the present invention, was obtained in 97% purity from beijing solibao.
The phosphate buffer solution used in the following examples or application examples of the present invention, abbreviated as PBS, was obtained in 99% purity from Guangzhou Shuo Spectrum Biotechnology Co.
Example 1
The synthesis method of the pentapterine quinone monomer comprises the following steps:
anthracene (7.12 g, 0.040mol), p-benzoquinone (2.16 g, 0.020mol) and tetrachlorobenzoquinone (0.04 mol, 0.040mol) were added to 100mL of acetic acid under nitrogen atmosphere, and the reaction was condensed at 118℃under reflux for 16 hours. The obtained product is filtered by suction, and washed for several times by using absolute ethyl ether and absolute ethyl alcohol in sequence, and the final product is yellow powder. Drying for 24 hours at the temperature of 60 ℃ in vacuum, and obtaining the final product, namely the pentaptericenquinone monomer. The synthetic scheme is shown in figure 1.
Example 2
The preparation method of the organic porous adsorption material HCP-6 for purifying blood based on the pentamethylene quinone of the embodiment comprises the following steps:
Under nitrogen and closed conditions, monomeric pentapterinenquinone (0.92 g, 0.002mol) was added to 10mL of methylene chloride solution, magnetically stirred for a period of time until dissolved, then catalyst AlCl was added 3 (6.4 g,0.048 mol) at 0deg.C for 12 hours, 30deg.C for 12 hours, 40deg.C for 12 hours, 60deg.C for 12 hours, and raised to 80deg.C for 24 hours. After the reaction was completed, the reaction was cooled to room temperature, quenched with methanol, and then the solid product was removed by suction filtration, washed with water, washed with methanol, and subjected to soxhlet extraction at 75 ℃ for 24 hours. Finally, drying is carried out for 24 hours under the vacuum condition at 80 ℃, and the product is black powder. The synthetic scheme is shown in FIG. 4.
Comparative example 1
A method for preparing a super cross-linked polymer HCP-4 by using an external cross-linking agent weaving method of the comparative example comprises the following steps:
pentagon (0.92 g, 0.002mol) was added to 10mL of dichloroethane at room temperature, magnetically stirred for a period of time until dissolved, and anhydrous FeCl as catalyst was added 3 (1.59 g, 0.010mol) and slowly dropwise adding external cross-linking agent dimethoxymethane (FDA) (0.76 g, 0.010mol), after completion of the dropwise addition, the reaction was allowed to warm to 45℃for 5 hours and 80℃for 19 hours. Completion of the reaction After cooling the reaction to room temperature, quenching the reaction with methanol, then removing the solid product by suction filtration, and subjecting the solid product to water washing, methanol washing, and soxhlet extraction at 75 ℃ for 24 hours. Finally, the mixture was dried under vacuum at 80℃for 24 hours, the product being a brown powder. The synthetic scheme is shown in fig. 2.
Comparative example 2
A method for preparing a super cross-linked polymer HCP-5 using Scholl coupling of this comparative example, comprising the steps of:
pentagon (0.92 g,0.002 mol) was added to 10mL chloroform under nitrogen atmosphere, magnetically stirred for a period of time until dissolved, then catalyst AlCl was added 3 (6.4 g,0.064 mol) and the reaction was allowed to warm to 80℃for 24 hours. After the reaction was completed, the reaction was cooled to room temperature, quenched with methanol, then the solid product was removed by suction filtration, washed with water, washed with methanol, and soxhlet extracted at 75 ℃ for 24 hours. Finally, drying the mixture for 24 hours under the vacuum condition at 80 ℃ to obtain a brown-black powder. The synthetic scheme is shown in FIG. 3.
Basic characterization of the Pentagon quinone monomer and the hypercrosslinked Polymer HCP 4-6
FIG. 5 shows the presence of pentapteriquinone in CDCl 3 Wherein 7.4ppm is H at point a on the pentapteriquinone, 7.0ppm is H at point b on the pentapteriquinone, and 5.8ppm is H at point c on the bridgehead carbon. Nuclear magnetism indicates that the monomer has been successfully synthesized.
To investigate whether the super cross-linked polymer HCP 4-6 synthesized based on the pentapterine quinone was successfully synthesized, the basic structural characterization of the polymer was performed by infrared absorption spectroscopy. As shown in FIG. 6, in which 3480cm was found to be apparent in the infrared absorption spectrum of HCP 4-6 -1 、2930cm -1 、2850cm -1 And 1620cm -1 Characteristic peaks exist nearby and are respectively connected with-OH and-CH 2 -stretching vibration peaks and vibration peaks of benzene ring skeleton are in one-to-one correspondence, wherein-OH vibration peaks are derived from water peaks which cannot be completely removed, -CH 2 The stretching vibration peak is a methylene structure generated in the crosslinking process, and the vibration peak of the benzene ring framework is derived from the benzene ring framework in the pentapterine quinone monomer structure. To sum upThe super cross-linked polymer is successfully synthesized.
By solid body 13 As shown in FIG. 7, for HCP-4, 180ppm represents the g-site carbon atom in the monomer, 144ppm represents the b-site carbon atom in the monomer, e-site carbon atom in the monomer, 135ppm represents the d-site carbon atom in the monomer, 125ppm represents the C-site carbon atom in the monomer, 48ppm is the a-site bridgehead carbon in the monomer, and a carbon signal around 37ppm is attributed to a carbon atom in the methylene group formed during crosslinking. For HCP-5, 180ppm represents the g-site carbon atom in the monomer, 142ppm represents the b-site carbon atom in the monomer, e-site carbon atom in the monomer, 125ppm represents the c-site carbon atom in the monomer, and 48ppm is the a-site bridgehead carbon in the monomer. For HCP-6, 180ppm represents the g-point carbon atom in the monomer, 141ppm represents the b-e-point carbon atom in the monomer, 131ppm represents the c-d-point carbon atom in the monomer, 48ppm is the a-bridgehead carbon in the monomer, and a carbon signal around 37ppm is attributed to a carbon atom in the methylene group formed during crosslinking. Thus, we can demonstrate successful synthesis of the super cross-linked polymer HCP 4-6.
FIG. 8 shows the microscopic morphology of the super cross-linked polymer HCP4-6 under a field emission scanning electron microscope (FE-SEM). The polymer prepared by the three different synthesis methods has no obvious difference in morphology under the condition of the size proportion of 1 mu m to 10 mu m, is in the shape of a plurality of irregular blocks and particles, and completely accords with the irregular morphology characteristics of the super-crosslinked polymer.
The pore structure and the microscopic morphology of the super-crosslinked polymer HCPs 4-6 were characterized by a transmission electron microscope, as shown in FIG. 9, and the super-crosslinked polymer HCPs 4-6 had porous structures at 50nm and 100 nm.
Whether the super-crosslinked polymer HCP4-6 has a crystal structure or not is examined by an X-ray diffractometer, and as shown in FIG. 10, the three super-crosslinked polymer PXRD patterns have steamed bread peaks at about 20 degrees, and no characteristic peaks similar to covalent triazine frames appear, which indicates that the super-crosslinked polymer HCP4-6 has an amorphous structure, which is consistent with that shown in FIG. 8 in a field emission scanning electron microscope.
The thermal stability of the super-crosslinked polymer HCP4-6 prepared by different synthesis methods is explored through thermogravimetric analysis (TGA), as shown in FIG. 11, the quality of the super-crosslinked polymer HCP4-6 is reduced at about 100 ℃, the main reasons are that the polymer pore canal contains water molecules, small molecular solvents and the like, and the loss of the polymer only reaches 10wt% at about 400 ℃, which proves that the HCP4-6 has good thermal stability. The thermal weight loss rate of the three polymers at 800 ℃ was only 30wt%, indicating that the super cross-linked polymers HCP4-6 all had high thermal stability.
Pore structure study of the super Cross-Linked Polymer HCP4-6
Under 77.3K, by BET specific surface area meter, N 2 As adsorption molecules, properties such as specific surface area and pore structure of three types of super cross-linked polymers were investigated. As can be seen from FIG. 12 (a), three super-crosslinked polymers are crosslinked at low pressure (P/P0<0.001 Under N) 2 The adsorption curve rises sharply, which means that a large number of microporous structures exist in all three polymers, namely, the pore diameter is smaller than 2nm, and the larger the corresponding ordinate adsorption amount is, the higher the micropore content is. Under medium pressure conditions, the nitrogen adsorption curve and the nitrogen desorption curve do not completely coincide, and a significant hysteresis loop appears, which indicates that mesopores exist in the polymer, i.e. the pore diameter is between 2 and 50nm. Of these, only HCP-6 had significantly elevated adsorption isotherms in the medium-high pressure zone (P/P0=0.8-1.0), indicating the presence of macropores in the polymer HCP-6, i.e., pore sizes greater than 50nm. The pore size distribution of the polymer can be calculated by NLDFT (non-local Density functional theory), as shown in FIG. 12 (b), it can be seen that the pore size of the super-crosslinked polymer HCP4-6 is mainly distributed in the region below 2nm, indicating that the polymer has micropores, and HCP4-6 has pores between 2-50nm, indicating that the polymer has mesopores. Table 1 shows parameters in terms of specific surface area and pore structure of the super-crosslinked polymer HCP4-6, wherein HCP-6 has the highest BET specific surface area of 1900m 2 Per g, highest pore volume 2.80cm 3 The main reasons of the method are that no external cross-linking agent exists in the preparation process of HCP-6, dichloromethane has relatively low activity in the reaction process, and the solvent weaving method has very slow polymerization rate, so that the method is beneficial to the construction of a pore structure in the preparation process.
TABLE 1 pore Structure parameters of HCPs 4-6
Application examples and comparative examples
The bilirubin standard curve is measured by an ultraviolet spectrophotometer
Dissolving 10mg of bilirubin powder in a small amount of 0.1mol/L NaOH solution by ultrasonic vibration, fixing the volume to 10mL by using 1M PBS buffer solution, preparing 1000mg/L bilirubin solution, and shaking uniformly for later use. Then diluted with 1M PBS buffer solution to prepare bilirubin solutions with the concentration of 40mg/L, 30mg/L, 20mg/L, 10mg/L and 5mg/L in sequence. The baseline was scanned with PBS buffer as a blank, and bilirubin solutions of different concentrations were tested for their corresponding absorbance at a wavelength of 438nm, and a bilirubin standard curve was drawn (bilirubin was readily decomposed by light and placed in a darkroom for immediate use). Drawing an ultraviolet absorption spectrum from the relationship between the wavelength (abscissa) and absorbance (ordinate), as shown in fig. 13 (a); the bilirubin standard curve is plotted from the linear relationship between concentration (abscissa) and absorbance (ordinate), as shown in fig. 13 (b). Bilirubin standard curve equation y=0.0673X-0.0074, r 2 = 0.9996, the linear fit was good.
Adsorption kinetics curves for the second super Cross-Linked Polymer HCP4-6
Taking the super cross-linked polymer HCP-4 as an example, the test method of HCP4-6 is as follows: 15mg of bilirubin powder is weighed, dissolved in 3mL of 0.1mol/L NaOH solution by ultrasonic vibration, and is fixed to 100mL by using 1M PBS buffer solution, 150mg/L bilirubin solution is prepared, and the solution is uniformly shaken for later use. Adding 10mL of bilirubin solution into 9 brown triangular flasks respectively, adding 8mg of bilirubin adsorbent super-crosslinked polymer HCP-4 into each brown triangular flask, covering a stopper, placing the solution in a constant temperature shaking table (keeping the temperature at 37 ℃) and adsorbing under the condition of 175rpm of the shaking table and light shielding, taking out the corresponding brown triangular flask at different moments (5 min, 10min, 15min, 20min, 25min, 30min, 40min, 60min and 120 min) respectively, diluting the solution by a needle type filter head with 0.45um, testing the absorbance by an ultraviolet spectrophotometer, substituting a bilirubin standard curve, calculating to obtain the corresponding bilirubin concentration, repeating each experiment three times, and calculating the adsorption amount of the super-crosslinked polymer to the bilirubin solution at different moments through one experiment.
Wherein:
q e when the bilirubin adsorbent reaches adsorption equilibrium for bilirubin solution, the amount of bilirubin adsorbed by the adsorbent (mg/g) is obtained.
C 0 -initial concentration of free bilirubin solution (mg/L).
C t -concentration of bilirubin solution at adsorption equilibrium (mg/L).
V- -volume of free bilirubin solution (L).
m- - - -mass of bilirubin adsorbent (g).
In addition, the bilirubin adsorption process of the bilirubin adsorbent is studied by fitting a quasi-first-order kinetic equation and a quasi-second-order kinetic equation.
The quasi-first order kinetic equation is:
ln(q e -q t )＝lnq e -K 1 t
a second formula;
wherein:
q e when the bilirubin adsorbent reaches adsorption equilibrium for bilirubin solution, the amount of bilirubin adsorbed by the adsorbent (mg/g) is obtained.
q t -the amount of bilirubin adsorbed by the adsorbent at time t (mg/g).
K 1 -a quasi-first order adsorption rate constant.
t- -adsorption time (min).
The quasi-second order kinetic equation is:
q e when the bilirubin adsorbent reaches adsorption equilibrium for bilirubin solution, the amount of bilirubin adsorbed by the adsorbent (mg/g) is obtained.
q t The term "bilirubin" refers to the amount of bilirubin adsorbed by the adsorbent (mg/g) at time t.
K 2 -a quasi-secondary adsorption rate constant.
t- -adsorption time (min).
FIG. 14 shows the adsorption kinetics of the super-crosslinked polymer HCP4-6 to free bilirubin, from which it can be seen that HCP-4 reaches an adsorption equilibrium during 60min during bilirubin adsorption at an adsorption rate of 100mg/g; in the process of adsorbing bilirubin, HCP-5 reaches adsorption equilibrium within 40min, and the adsorption quantity is 60mg/g; HCP-6 has extremely fast adsorption rate before 25min, the adsorption quantity reaches 135mg/g after 5min, the adsorption balance is reached after 30min, and the adsorption quantity reaches 160mg/g. Compared with HCP-4 and HCP-5, the HCP-6 has short adsorption equilibrium time and high adsorption quantity. According to Table 1, the specific surface area of the super cross-linked polymer (HCP-6) prepared by the solvent plaiting method based on the pentapterene is as high as 1900m 2 Per g, wherein the specific surface area of the super cross-linked polymer HCP-4 prepared by the external cross-linking agent braiding method is 1215m 2 Per g, specific surface area 781m of the super cross-linked polymer HCP-5 prepared by Scholl coupling 2 The high specific surface area further indicates that the adsorption sites exposed in the pores are rich, which is favorable for the adsorption process and diffusion mechanism of bilirubin in the polymer, so that the adsorption rate of HCP-6 is higher than that of HCP-4 and HCP-5. At the same time, HCP-6 exhibited a pore volume size (2.80 cm 3 Each of the two groups/g) was greater than HCP-4 (0.86 cm) 3 /g) and HCP-5 (0.30 cm) 3 Per g), whereas pore volume size indicates an abundance of pore structures, a high pore volume of HCP-6 favors bilirubin adsorption and thus exhibits a higher adsorption capacity. The invention introduces more proper aperture structure and oxygen atom which can generate hydrogen bond interaction force with bilirubin molecule into HCP-6, which is beneficial to the absorption and diffusion of bilirubin in super-crosslinked polymer, thus having higher bilirubin absorption performance.
The adsorption mechanism of the polymer HCP4-6 to bilirubin is further discussed through quasi-first order kinetic simulation and quasi-second order kinetic simulation. FIGS. 15, 16 and 17 are, respectively, a quasi-first order mechanical fit and a quasi-second order kinetic fit of HCP-4, HCP-5 and HCP-6 to bilirubin, with Table 2 being a quasi-first order Dynamics and quasi-secondary dynamics related data. By comparing fitting parameters R of the quasi-primary dynamics and the quasi-secondary dynamics 2 Quasi-second order kinetic fitting parameters R of three super-crosslinked polymers were found 2 Are all higher than the quasi-first-order dynamics fitting parameter R 2 The adsorption process of the super-crosslinked polymer HCP4-6 on bilirubin is more in accordance with a quasi-secondary kinetic model, namely the adsorption process mainly takes chemical adsorption as a main part, and in addition, the saturated adsorption quantity q of the HCP4-6 on the bilirubin is calculated according to the quasi-secondary kinetic simulation theory e And the bilirubin adsorption quantity q obtained by experiments e Is close to each other. In addition, HCP-6 has a higher adsorption rate constant (5.52X10) -3 g.mg -1 min -1 ) The unique pore structure and oxygen atoms are shown to be beneficial to the adsorption and diffusion of bilirubin. As HCP4-6 accords with a quasi-second-level kinetic equation on the bilirubin adsorption mechanism, the three super-crosslinked polymers are proved to have the phenomena of electron sharing, electron transfer and hydrogen bond formation in the bilirubin adsorption process.
TABLE 2 adsorption kinetics parameters for the super Cross-Linked Polymer HCP4-6
(III) super cross-linked Polymer HCP4-6 examination of bilirubin adsorption isotherm
Super cross-linked polymer HCP-4 bilirubin adsorption isotherm test: 200mg/L, 300mg/L, 400mg/L, 500mg/L, 600mg/L, 700mg/L and 800mg/L bilirubin solutions were prepared, 9mL of each solution was placed in 7 50mL brown triangular flasks, 6mg of the super-crosslinked polymer HCP-4 was added, the flask was capped, and the flask was placed in a constant temperature shaker (maintaining the temperature at 37 ℃ C.) and adsorbed for 2 hours at a shaker speed of 175rpm and in the dark until adsorption equilibrated. Taking a certain amount of bilirubin solution by a 0.45um needle filter, diluting, testing the absorbance by an ultraviolet spectrophotometer, substituting the absorbance into a bilirubin standard curve, calculating to obtain bilirubin concentration, and calculating the adsorption amount of the super-crosslinked polymer HCP-4 on bilirubin solutions with different initial concentrations.
Super cross-linked polymer HCP-5 bilirubin adsorption isotherm test: 200mg/L, 250mg/L, 300mg/L, 350mg/L, 400mg/L, 450mg/L and 500mg/L bilirubin solutions were prepared, 9mL of each solution was placed in 7 50mL brown triangular flasks, 6mg of the super-crosslinked polymer HCP-5 was added, the flask was capped, and the flask was placed in a constant temperature shaker (maintaining the temperature at 37 ℃ C.) and adsorbed for 2 hours at a shaker speed of 175rpm and in the dark until adsorption equilibrated. Taking a certain amount of bilirubin solution by a 0.45um needle filter, diluting, testing the absorbance by an ultraviolet spectrophotometer, substituting the absorbance into a bilirubin standard curve, calculating to obtain bilirubin concentration, and calculating the adsorption amount of the super-crosslinked polymer HCP-5 to bilirubin solutions with different initial concentrations.
Super cross-linked polymer HCP-6 bilirubin adsorption isotherm test: 200mg/L, 300mg/L, 400mg/L, 500mg/L, 600mg/L, 700mg/L, 800mg/L and 1000mg/L of bilirubin solution are prepared, 9mL of each solution is put into 8 50mL brown triangular flasks, 6mg of super-crosslinked polymer HCP-6 is added, after the bottle stopper is covered, the solution is placed in a constant temperature shaking table (keeping the temperature at 37 ℃) and adsorbed for 2 hours under the condition that the rotation speed of the shaking table is 175rpm and the condition of avoiding light until adsorption is balanced. Taking a certain amount of bilirubin solution by a 0.45um needle filter, diluting, testing the absorbance by an ultraviolet spectrophotometer, substituting the absorbance into a bilirubin standard curve, calculating to obtain bilirubin concentration, and calculating the adsorption amount of the super-crosslinked polymer HCP-6 on bilirubin solutions with different initial concentrations.
The thermodynamic properties of the HCP4-6 adsorption process were studied by introducing a Langmuir isothermal adsorption model and a Freundlich isothermal adsorption model.
The Langmuir isothermal adsorption model equation is:
wherein: q e When the bilirubin adsorbent reaches adsorption equilibrium for bilirubin solution, the amount of bilirubin adsorbed by the adsorbent (mg/g) is obtained.
C e Bilirubin adsorbent for bilirubin solutionBilirubin concentration (mg/L) at adsorption equilibrium.
K L -Langmuir isothermal adsorption coefficient.
q max -simulated maximum adsorption of bilirubin by bilirubin adsorbent.
The Freundlich isothermal adsorption model equation is:
wherein: q e When the bilirubin adsorbent reaches adsorption equilibrium for bilirubin solution, the amount of bilirubin adsorbed by the adsorbent (mg/g) is obtained.
C e -bilirubin concentration (mg/L) at which the bilirubin adsorbent reaches adsorption equilibrium for the bilirubin solution.
K F -Freundlich (friedrich) adsorption coefficient.
1/n- - - -Freundlich (Friedel-crafts) constant, which indicates the adsorption strength.
Adsorption isotherm of super cross-linked polymer HCP4-6 for adsorbing bilirubin
Based on an adsorption isotherm model, fitting is carried out by adopting two modes of a curve and a straight line, and the adsorption mechanism of three super-crosslinked polymers on bilirubin is estimated. Fig. 18 is a Langmuir and Freundlich fitting curve of the super-crosslinked polymer HCP4-6 for bilirubin adsorption, and fig. 19 is a Langmuir and Freundlich straight line fitting of the super-crosslinked polymer HCP4-6 for bilirubin adsorption. As can be seen from the figure, as the initial bilirubin concentration increases, the adsorption capacity of the three super-crosslinked polymers for bilirubin also increases gradually. However, as the concentration reaches a certain value, the adsorption amount of bilirubin by the three super-crosslinked polymers will reach saturation.
Table 3 lists parameters such as the adsorption thermodynamic equation for bilirubin for three super-crosslinked polymers. By comparing the fitting coefficients R for the Langmuir and Freundlich models 2 Indicating the adsorption of bilirubin by three super-crosslinked polymersThe method is more in line with a Langmuir isothermal adsorption model, namely, the adsorption process of three super-crosslinked polymers on bilirubin is monolayer adsorption. And the maximum adsorption quantity of three super-crosslinked polymers to bilirubin is calculated by a five Langmuir isothermal adsorption model. Wherein the HCP-6 has higher maximum absorption capacity (931 mg/g) to bilirubin than HCP-4 (617 mg/g) and HCP-5 (338 mg/g), which indicates that HCPs prepared by the solvent-based method have excellent pore structure, are favorable for spreading of a monolayer of bilirubin on the surface thereof, and further promote the absorption of bilirubin. The maximum absorption amounts of HCP-4, HCP-5 and HCP-6 to bilirubin are 617mg/g, 338mg/g and 931mg/g, respectively.
TABLE 3 adsorption isotherm parameters for the super cross-linked polymers HCP 4-6
(IV) competitive adsorption of the super Cross-linked Polymer HCP-6 with bovine serum Albumin
Drawing competitive adsorption standard curve of bilirubin and bovine serum albumin
Standard curve determination of binding solution at a molar ratio of bilirubin to Bovine Serum Albumin (BSA) of 2:1: 15mg bilirubin (256 mu mol) is weighed into a beaker wrapped by tinfoil paper, a small amount of 0.1mol/L NaOH solution is added, after ultrasonic vibration until the bilirubin is fully dissolved, a proper amount of 1M PBS buffer solution is added, and 0.87g bovine serum albumin (128 mu mol) is added, after the bilirubin is fully dissolved, the mixture is transferred into a 100mL brown volumetric flask, and the volume is fixed to 100mL by using 1MPBS buffer solution, or a bilirubin and bovine serum albumin combination solution with a molar ratio of 2:1 is obtained. Then diluting with 1M PBS buffer solution, sequentially preparing binding solutions with the concentration of 30mg/L, 20mg/L, 15mg/L, 10mg/L and 5mg/L, respectively measuring the absorbance of the binding solutions with different concentrations at the wavelength of 460nm, and drawing a standard curve of the bilirubin and bovine serum albumin binding solution with the molar ratio of 2:1 based on the absorbance value and the corresponding concentration. The ultraviolet absorption spectra of binding solutions of different concentrations are shown in FIG. 20 (a), and the standard curve of bilirubin and bovine serum albumin binding solution with a molar ratio of 2:1 is shown in FIG. 20 (b). Standard curve equation y=0.0653x+0.0244, r 2 = 0.9972, the linear fit was good.
Standard curve determination of bilirubin and Bovine Serum Albumin (BSA) binding solution at a molar ratio of 1:1: the standard curve of binding solution of bilirubin and Bovine Serum Albumin (BSA) at a molar ratio of 1:1 is shown in FIG. 21 (b), and the ultraviolet absorption spectrum of binding solution at different concentrations is shown in FIG. 21 (a) by the same method. Standard curve equation y=0.0783X-0.0101, r 2 = 0.9991, the linear fit was good.
According to the invention, the super-crosslinked polymer HCP-6 with the highest adsorption amount to free bilirubin is screened out and used as an adsorbent, and the competitive adsorption capacity of the adsorbent HCP-6 for bilirubin in bilirubin and albumin binding solution with the molar ratio of 1:1 and 2:1 is respectively explored. FIG. 22 shows adsorption kinetics curves of the super-crosslinked polymer HCP-6 in different BSA-conjugated bilirubin solutions, from which it can be seen that adsorption of bilirubin by HCP-6 reaches adsorption equilibrium after 30min at an adsorption amount of 120mg/g when the molar ratio of bilirubin to albumin is 2:1; when the molar ratio of bilirubin to albumin is 1:1, the adsorption of bilirubin by HCP-6 reaches adsorption equilibrium after 40min, and the adsorption amount is 118mg/g. The analysis results revealed that HCP-6 had a high adsorption amount and a rapid adsorption rate of bilirubin despite the presence of albumin, and that the main reason was that the average pore size of the super-crosslinked polymer HCP-6 was larger than the bilirubin molecular size and smaller than the albumin size, and exhibited a high selective adsorption of bilirubin. In addition, there are hydrophobic interactions, pi-pi interactions, and hydrogen bonding forces (introducing O heteroatoms) between the super-crosslinked polymer and bilirubin, providing sufficient affinity to adsorb bilirubin in albumin-bound bilirubin solutions. Meanwhile, the comparison experiment shows that under the condition that albumin exists, the adsorption quantity of HCP-6 to bilirubin is greatly reduced; and when albumin is in a supersaturated state with respect to bilirubin, the amount of absorption of bilirubin by HCP-6 is further reduced.
Further, the adsorption mechanism of the super cross-linked polymer HCP-6 to different BSA bilirubin binding solutions was investigated by a three-quasi-first order kinetic simulation and a four-quasi-second order kinetic simulation. FIGS. 23 and 24 are HCP-6 versus different BSA gall reds, respectivelyAnd (3) performing linear fitting of a quasi-first-order kinetic equation and linear fitting of a quasi-second-order kinetic equation of the adsorption of the element combined solution. Table 4 shows the adsorption kinetics parameters of HCP-6 for different BSA bilirubin binding solutions. Contrast the correlation coefficient R of the quasi-first-order rate equation 2 And correlation coefficient R of quasi-second-order rate equation 2 This shows that the adsorption process of the super-crosslinked polymer HCP-6 on bilirubin is more in accordance with a quasi-secondary kinetic model, and the adsorption is mainly chemical adsorption.
TABLE 4 adsorption kinetics of the super-crosslinked Polymer HCP-6 on different BSA bilirubin binding solutions
The ideal bilirubin blood adsorbent should have low adsorptivity to albumin, and HCP-6 has a certain meaning to the removal rate of pure BSA solution. As can be seen from FIG. 25, the removal rate of HCP-6 for BSA was only 0.5% at 128. Mu. MoL of BSA, and the removal rate of HCP-6 for BSA was also only 0.8% at 256. Mu. MoL of BSA. Indicating that the super cross-linked polymer HCP-6 has low adsorption to albumin.
Exploration of adsorption mechanism of super cross-linked polymer HCP-6
The adsorption mechanism of the super-crosslinked polymer HCP-6 on bilirubin is explored by deeply analyzing the pore structure of the super-crosslinked polymer HCP-6 and the measured adsorption result. As can be seen from the pore size and pore size distribution diagram of HCP-6 (FIG. 12), HCP-6 prepared by solvent-weaving method has micropores and mesopores, the average pore size is mainly distributed at 2nm, and bilirubin molecule diameter is 1.94X10.91X10.67 nm, which is beneficial to bilirubin adsorption process. Calculating HCP-6 specific surface area to 1900m by adopting non-local functional theory 2 Per gram, pore volume of 2.80cm 3 And/g, the abundant pore structure provides more adsorption sites for bilirubin adsorption, so that the bilirubin adsorption device has certain advantages in adsorption rate and adsorption quantity, and the expected adsorption result is matched with the data obtained by experiments. The selective adsorption result of HCP-6 in the bilirubin and albumin combination liquid is analyzed, the adsorption amount of HCP-6 on albumin is far lower than that of bilirubin,even negligible, the result can be derived from the pore size of HCP-6 and the difference in molecular size between bilirubin and albumin, the average pore size of HCP-6 being slightly larger than bilirubin molecular size and much smaller than albumin size, thus exhibiting extremely high selective adsorption.
For better mechanism of the reduction adsorption process, the inventor further analyzes the structure and the performance of the super-crosslinked polymer. As can be obtained from the infrared and nuclear magnetic patterns, HCP-6 contains a large number of large pi bonds and carbonyl structures, the existence of the large pi bonds is favorable for the flow of electron cloud, and electron sharing and electron transfer exist between the HCP-6 and bilirubin, and the HCP-6 has pi-pi stacking expression form; the presence of carbonyl structure in HCP-6 can easily form hydrogen bond with carboxyl in bilirubin and imine in pyrrole, and can raise the interaction force between adsorbent and adsorbate, so that HCP-6 has higher adsorption capacity to bilirubin. In summary, HCP-6 facilitates adsorption of bilirubin, both in pore size structure and in performance, and competitive adsorption exhibits excellent selectivity. FIG. 26 is a schematic illustration of the mechanism of adsorption of bilirubin by HCP-6.
(fifth) cyclicity of the super Cross-linked Polymer HCP-6
Super cross-linked polymer adsorption bilirubin circulation experiment
To investigate the reusability of the super-crosslinked polymer HCP-6, 100mL of a bilirubin solution with a concentration of 200mg/L was prepared, 30mL of the bilirubin solution was placed in 3 50mL brown triangular flasks, 30mg of the super-crosslinked polymer HCP-6 was added to each brown triangular flask, and after 2 hours of adsorption, the amount of bilirubin adsorbed was measured. Then preparing 0.1mol/L NaOH solution as a desorption agent of bilirubin, eluting for a plurality of times until the filtrate is colorless, and drying the super-crosslinked polymer HCP-6 for 24 hours under the vacuum condition at 80 ℃ to perform a cyclicity experiment. The cycle was repeated 5 times, and the amount of bilirubin adsorbed each time was recorded.
FIG. 27 is a cyclic adsorption histogram of the super cross-linked polymer HCP-6. As can be seen from the figure, the adsorption efficiency of HCP-6 on bilirubin is still high after 5 cycles of adsorption, and the adsorption quantity of bilirubin still reaches 82% retention rate. In summary, the super cross-linked polymer HCP-6 has excellent recyclability.
(six) super Cross-Linked Polymer HCP-6 cytotoxicity
Super crosslinked Polymer cytotoxicity experiment
The super-crosslinked polymer HCP-6 was co-cultured with (NIH) mouse fibroblasts and the cytotoxicity was evaluated by MTT method. The specific operation is as follows: the corresponding mouse fibroblasts were inoculated in an alpha-MEM medium and cultured in a constant temperature incubator (maintained at 37 ℃) for 24 hours. The next day, the super cross-linked polymer HCP-3 was placed in fresh alpha-MEM medium and diluted to six groups of different concentrations (0 ug/mL, 100ug/mL, 200ug/mL, 300ug/mL, 400ug/mL, 500 ug/mL) followed by a cell density of 4X 10 5 CFU/mL of mouse fibroblasts were added to the super cross-linked polymer HCP-3 medium with different concentrations for 24 hours (constant temperature at 37 ℃), after which MTT solution (50 uL,5 mg/mL) was added to each well, and after incubation continued for a period of time (4 hours) at 37 ℃, DMSO (dimethyl sulfoxide) was added, and finally absorbance of the sample wells at 592nm was measured with a microplate reader (Molecular Devices). Cell viability was calculated using equation seven.
Wherein: OD (optical density) sample -absorbance of the sample.
OD negative control Absorbance of the control group.
Lower cytotoxicity is a prerequisite for acceptable bilirubin adsorbents, and therefore, studying cytotoxicity is of profound significance for super cross-linked polymer adsorbents. The invention designs the cytotoxicity of the fibroblast under the condition of different concentrations of polymers through the survival rate of the fibroblast. As shown in fig. 28, the relative viability of the cells decreased slightly with increasing concentration of the adsorbent sample. Even when the concentration of the polymer is as high as 500ug/mL, the survival rate of the fibroblasts can still reach about 90%, which indicates that the super-crosslinked polymer HCP-6 has good biocompatibility.
(seventh) hypercrosslinked Polymer HCP-6 hemolysis
Super crosslinked Polymer biocompatibility experiment
The extent of damage to erythrocytes by the hypercrosslinked polymer HCP-6 was evaluated by hemolysis. During the experiment, physiological saline (NaCl) was used as a negative control and deionized water was used as a positive control. The experimental procedure was as follows: 1ml of fresh blood of rats was centrifuged at 3000rmp for 10min at 4℃and the centrifuged erythrocytes were collected (upper plasma removed), washed several times with physiological saline and diluted with physiological saline to a 10% dispersion. The super-crosslinked polymer HCP-3 was prepared as solutions of different concentrations (100 ug/mL, 200ug/mL, 300ug/mL, 400ug/mL, 500 ug/mL) with physiological saline, and 0.5mL of the solutions of different super-crosslinked polymer concentrations were mixed with 0.5mL of the erythrocyte dispersion, respectively. After incubation at 37℃for 4 hours, centrifugation was carried out at 4000rpm for 10min and absorbance at 570nm was measured using a microplate reader (Molecular Devices). The hemolysis rate was calculated using eight.
Wherein:
OD s -testing the absorbance of the sample super cross-linked polymer.
OD pc -absorbance of positive control (deionized water).
OD nc Negative control (physiological saline) absorbance.
As a bilirubin adsorbent, the material needs to have good biocompatibility, and the hemolysis rate is an important measure for verifying whether the material has good biocompatibility. As shown in FIG. 29, even when the polymer concentration was as high as 500ug/mL, the hemolysis rate did not exceed the prescribed 5%, indicating that the super-crosslinked polymer HCP-6 had good biocompatibility.
Claims (10)
1. The preparation method of the organic porous adsorption material for purifying blood based on the pentapterine quinone is characterized by comprising the following steps of: the preparation method is characterized in that the preparation method comprises the steps of taking a pentamethylene quinone with an H-type structure as a monomer, taking methylene dichloride as a solvent and a cross-linking agent, taking anhydrous aluminum trichloride as a catalyst, connecting the monomer with the monomer by methylene, and preparing the product by a solvent weaving method.
2. The method according to claim 1, characterized in that: the method specifically comprises the following steps:
under inert atmosphere and airtight condition, monomer pentapterine quinone is dissolved in methylene dichloride to obtain pentapterine quinone solution, and then anhydrous aluminum chloride AlCl is added into the pentapterine quinone solution 3 The obtained mixture is reacted for 12 hours at 0 ℃,30 ℃,40 ℃ and 60 ℃ in sequence, and finally the temperature is raised to 80 ℃ for 24 hours; after the reaction is completed, cooling the reaction to room temperature, quenching and suction filtering to obtain a solid product; and (3) washing and Soxhlet extraction are sequentially carried out on the solid product, and finally, vacuum drying is carried out, so that black powder is obtained, namely the organic porous adsorption material for purifying blood based on the pentapterine quinone.
3. The method according to claim 2, characterized in that: the molar ratio of the monomer pentapterinenquinone to the catalyst is 1: (20-30).
4. A method according to claim 3, characterized in that: the mole ratio of the pentapterin quinone to the catalyst is 1:24.
5. the method according to claim 1 or 2, characterized in that: the monomer, the penterequinone, is prepared by the following steps:
under inert atmosphere, adding anthracene, p-benzoquinone and tetrachlorobenzoquinone into acetic acid according to a proportion to dissolve, and condensing and refluxing the obtained mixed solution at 110-120 ℃ for 15-20 hours; and after the reaction is finished, filtering, washing and vacuum drying the obtained product to obtain the monomer pentapterinenquinone.
6. The method according to claim 5, wherein: the molar ratio of anthracene, p-benzoquinone and tetrachlorobenzoquinone is 2:1:2.
7. The organic porous adsorbing material for purifying blood based on the pentamethylene quinone prepared by the method of any one of claims 1 to 6.
8. The organic porous adsorbent material for purifying blood based on pentamethylene quinone according to claim 7, wherein: the specific surface area of the organic porous adsorption material is 780-1900m 2 /g。
9. Use of the organic porous adsorption material prepared by the method of any one of claims 1 to 6 or the organic porous adsorption material of claim 7 or 8 in blood purification.
10. An adsorbent for blood purification or bilirubin removal comprising the organic porous adsorbent material prepared by the method of any one of claims 1-6 or the organic porous adsorbent material of claim 7 or 8.
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