Sulfonium salt cationic adsorbent as well as preparation method and application thereof

Abstract

The invention provides a sulfonium salt cationic adsorbent as well as a preparation method and application thereof. The preparation method of the sulfonium salt cationic adsorbent comprises the following steps: firstly, carrying out ring-opening polymerization reaction on a methionine monomer to form a methionine polymer; a bacterium adsorbent is further prepared on the basis of the methionine polymer with bacterium selectivity. According to the first route, the methionine polymer base material and a halogen-containing compound are subjected to a cross-linking reaction, and a cross-linked sulfonium salt structure is formed; and the route II comprises the following steps: modifying the methionine polymer base material by using a compound containing a functional group to introduce an active functional group capable of further reaction into a side chain of the methionine polymer base material, and then carrying out cross-linking reaction on the modified thiomethionine polymer and a cross-linkable compound to form a cross-linked sulfonium salt structure. Or mixing and reacting the modified methionine polymer and the loadable matrix to cover a layer of sulfonium salt polymer on the surface of the matrix. The adsorbent can effectively adsorb bacteria and cannot cause thrombus and blood coagulation.

Description

Technical Field

[0001] The invention relates to the field of medical polymer materials, and in particular to a sulfonium salt cation adsorbent and a preparation method and application thereof. Background Art

[0002] Bloodstream infections represent a public health challenge due to their potential for long-term complications and high mortality rates resulting from delayed treatment, which can lead to conditions such as severe bacteremia. Gram-positive bacteria generally exhibit a more complex virulence factor profile than Gram-negative bacteria in bloodstream infections. Typical virulence factors of Gram-positive bacteria include bacterial cell wall components, exoenzymes, and exotoxins, all of which may trigger an aberrant immune response and excessive cytokine release. Due to the lack of effective treatment measures, MRSA-associated bloodstream infections may result in recurrent infections, increased mortality, and prolonged hospital stays.

[0003] Drug intervention remains the standard approach for managing MRSA bloodstream infections. However, clinical antibiotics such as vancomycin and daptomycin have specific toxic side effects and exacerbate bacterial resistance. Alternative approaches, such as non-drug blood purification using nanoparticles, porous framework materials, and porous microspheres, focus primarily on removing small molecule toxins such as cytokines, bilirubin, and endotoxins, but are limited in pathogen clearance. Therefore, the development of highly selective and safe methods for bloodstream bacterial clearance remains scarce. Summary of the invention

[0004] In view of this, the present invention provides a sulfonium salt cationic adsorbent and a preparation method and application thereof. The sulfonium salt cationic adsorbent provided by the present invention has an extremely fast adsorption rate for bacteria in the blood, and has excellent blood compatibility, does not cause thrombosis and coagulation, and is expected to be used for the rapid removal of microbial toxicity in the blood in the early stage of trauma, and to block the subsequent generation of inflammatory storms.

[0005] The present invention provides a method for preparing a sulfonium salt cationic adsorbent, comprising the following steps:

[0006] S1: Under the action of the initiator, the methionine monomer undergoes a ring-opening polymerization reaction to form a methionine polymer;

[0007] in,

[0008] The methionine monomer is at least one of D,L-methionine, D-methionine and L-methionine;

[0009] The methionine polymer is at least one of formula (1-1), formula (1-2) and formula (1-3):

[0010]

[0011] S2: cross-linking the methionine polymer with a halogen-containing compound to obtain a sulfonium salt cationic adsorbent;

[0012] in,

[0013] The halogen-containing compound is selected from at least one of formulas a1 to a13:

[0014]

[0015] In the above formulas a1 to a13, the multiple X in each compound are independently selected from: I, Br, Cl or epoxy group, and the multiple X in each compound are not epoxy groups at the same time;

[0016] Or including the following steps:

[0017] K1: Under the action of the initiator, the methionine monomer undergoes a ring-opening polymerization reaction to form a methionine polymer;

[0018] in,

[0019] The methionine monomer is at least one of D,L-methionine, D-methionine and L-methionine;

[0020] The methionine polymer is at least one of formula (1-1), formula (1-2) and formula (1-3):

[0021]

[0022] K2: reacting the methionine polymer with a compound containing a functional group to obtain a methionine polymer modified substance;

[0023] in,

[0024] The compound containing a functional group is selected from at least one of iodoacetic acid, iodoacetylene, 4-(2-bromoethyl)phenylboronic acid, allyl iodide and trifluoromethanesulfonate azide;

[0025] The methionine polymer modified substance is selected from at least one of formula (1-1-1) to formula (1-3-5):

[0026]

[0027] K3: mixing the methionine polymer modified substance with the object to be combined to obtain a sulfonium salt cation adsorbent;

[0028] in,

[0029] The object to be combined is a cross-linkable compound or a loadable matrix;

[0030] The cross-linkable compound is at least one of a polyhydroxy compound, a polyamine compound and a compound containing multiple double bonds;

[0031] The loadable matrix is ​​at least one of polymer microspheres, molecular sieves and magnetic beads.

[0032] Preferably, in step S2, the halogen-containing compound is selected from at least one of 1,3,5-tribromobenzene, 1,4-bis(bromomethyl)-2,5-diiodobenzene, 1,3,4,6-tetrabromobenzene, 1,3,4,5,6-pentabromobenzene, perbromobenzene, 1,3,5-tri(bromomethyl)benzene, hexaperbromomethylbenzene, 1,4-dibromo-2,5-bis(bromomethyl)benzene, iodoform and tetrabromomethane;

[0033] In step K3, the cross-linkable compound is selected from at least one of branched polyethyleneimine and polydipentaerythritol hexaacrylate;

[0034] The polymer microspheres are at least one of polystyrene microspheres and polyvinyl alcohol microspheres.

[0035] Preferably, in step S1, the initiator is at least one of a monoamine-containing compound, a hexamethylsilylamine-containing lithium compound and a tertiary amine-containing compound;

[0036] In step K1, the initiator is at least one of a monoamine-containing compound, a hexamethylsilylamine-containing lithium compound and a tertiary amine-containing compound.

[0037] Preferably, in step S1, the initiator is at least one of n-hexylamine, lithium bis(trimethylsilyl)amide, ethylenediamine, butanediamine, aniline and dendritic polyamide;

[0038] In step K1, the initiator is at least one of n-hexylamine, lithium bis(trimethylsilyl)amide, ethylenediamine, butanediamine, aniline and dendritic polyamide.

[0039] Preferably, in step S1, the temperature of the ring-opening polymerization reaction is 15 to 60° C., and the time is 2 to 48 hours;

[0040] In step K1, the temperature of the ring-opening polymerization reaction is 20 to 60° C., and the time is 12 to 48 hours.

[0041] Preferably, in step S2, the molar ratio of the methionine unit in the methionine polymer to the halogen group in the halogen-containing compound is 1:(0.5-3);

[0042] In step K2, the molar ratio of the methionine unit in the methionine polymer to the functional group in the compound containing the functional group is 1:(1-3).

[0043] Preferably, in step S2, the temperature of the cross-linking reaction is 15 to 50° C., and the time is 4 to 48 hours;

[0044] In step K2, the reaction temperature is 20 to 60° C. and the reaction time is 12 to 36 hours;

[0045] In step K3, the mass ratio of the methionine polymer modified substance to the substrate is 1:(0.1-1);

[0046] In step K3, the reaction temperature is 30-60° C. and the reaction time is 8-48 hours.

[0047] Preferably, in step S1, the ring-opening polymerization reaction is carried out in a solvent; wherein the solvent is selected from at least one of tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile and dichloromethane;

[0048] In step S2, the cross-linking reaction is carried out in a solvent; wherein the solvent is selected from at least one of water, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and tetrahydrofuran;

[0049] In step K1, the ring-opening polymerization reaction is carried out in a solvent; wherein the solvent is selected from at least one of tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile and dichloromethane.

[0050] The present invention also provides a sulfonium salt cation adsorbent prepared by the preparation method described in the above technical scheme.

[0051] The present invention also provides an application of the sulfonium salt cationic adsorbent described in the above technical solution in the preparation of a material for rapid adsorption of bacteria in blood.

[0052] The preparation method of the sulfonium salt cationic adsorbent of the present invention is to first perform a ring-opening polymerization reaction on a methionine monomer to form a methionine polymer; and further prepare a bacterial adsorbent based on the methionine polymer with bacterial selectivity. Route one is to perform a cross-linking reaction on the above-mentioned methionine polymer base with a halogen-containing compound to form a cross-linked sulfonium salt structure; Route two is to first modify the above-mentioned methionine polymer base with a compound containing a functional group, so that its side chain introduces an active functional group that can further react, and then the modified methionine polymer is cross-linked with a cross-linkable compound to form a cross-linked sulfonium salt structure, or the modified methionine polymer is mixed with a loadable matrix to react so that the surface of the matrix is ​​covered with a layer of sulfonium salt polymer. The above-mentioned preparation methods of the present invention all first prepare a methionine polymer with bacterial selectivity, and then use it as a basis to further prepare a bacterial adsorbent with a sulfonium salt structure. The sulfonium salt adsorption material prepared by the present invention can realize efficient selection of bacteria and blood cells in the blood, and can realize efficient adsorption of bacteria in the blood; it also has excellent blood compatibility, and does not cause coagulation and hemolysis risks while efficiently adsorbing bacteria; in addition, it has bactericidal properties while having bacterial adsorption capacity; in addition, the preparation method of the present invention is simple, the yield is high, and the reaction conditions are mild and controllable, which is convenient for large-scale production.

[0053] The test results show that the bacterial removal rate of the sulfonium salt cationic adsorbent of the present invention at a concentration of 8 mg / mL reaches more than 90%, showing an excellent bacterial adsorption rate. After the sulfonium salt cationic adsorbent of the present invention is mixed with whole blood for 1 hour, there is no obvious adsorption of blood cells and platelets on the surface, and no changes in the components of whole blood are caused, showing excellent blood compatibility and will not cause thrombosis and coagulation. The sulfonium salt cationic adsorbent of the present invention treats whole blood containing bacteria, and the bacterial adsorption rate in the blood reaches more than 85% after 20 minutes of treatment, proving that the sulfonium salt cationic adsorbent of the present invention can achieve the purification of bacteria in blood infection and the bacterial adsorption rate is fast and the efficiency is high; after 1 hour of treatment, the bacteria on the surface of the adsorbent die, proving that the sulfonium salt cationic adsorbent of the present invention has a bactericidal effect while having bacterial adsorption capacity. After the sulfonium salt cationic adsorbent of the present invention is soaked in PBS buffer for 24 hours, the polymer dissolution rate is below 0.25%, and the dissolution rate is extremely low, proving that the sulfonium salt adsorbent has good stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0055] Figure 1This is a diagram showing the bacterial removal rate of the sulfonium salt cationic adsorbent obtained in Example 1;

[0056] Figure 2 This is a diagram showing the effect of the sulfonium salt cation adsorbent obtained in Example 1 on the changes in blood components after whole blood is treated;

[0057] Figure 3 This is a diagram showing the effect of the sulfonium salt cationic adsorbent obtained in Example 1 on the change in the number of bacteria in the blood after the whole blood containing bacteria is treated; wherein, Figure 3 (a) is a schematic diagram of the sample after the sulfonium salt cation adsorbent is mixed with whole blood containing bacteria. Figure 3 (b) is a schematic diagram of a test sample being placed in a tester for testing; Figure 3 (c) is the test effect diagram;

[0058] Figure 4 This is a diagram showing the bacterial status on the surface of the sulfonium salt cationic adsorbent after the sulfonium salt cationic adsorbent obtained in Example 1 treated the whole blood containing bacteria for 1 hour; wherein, Figure 4 (a)-4(b) are the effect pictures at different magnifications;

[0059] Figure 5 This is a diagram showing the stability test results of the sulfonium salt cationic adsorbent obtained in Example 1. DETAILED DESCRIPTION

[0060] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0061] In this article, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0062] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0063] Herein, when it comes to numerical ranges, unless otherwise specified, the numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0064] In this article, when referring to the unit of a data range, if there is a unit only after the right endpoint, it means that the units of the left and right endpoints are the same. For example, 4~48h means that the units of the left endpoint "4" and the right endpoint "48" are both h.

[0065] The present invention provides a method for preparing a sulfonium salt cationic adsorbent, comprising the following steps:

[0066] S1: Under the action of the initiator, the methionine monomer undergoes a ring-opening polymerization reaction to form a methionine polymer;

[0067] in,

[0068] The methionine monomer is at least one of D,L-methionine, D-methionine and L-methionine;

[0069] The methionine polymer is at least one of formula (1-1), formula (1-2) and formula (1-3):

[0070]

[0071] S2: cross-linking the methionine polymer with a halogen-containing compound to obtain a sulfonium salt cationic adsorbent;

[0072] in,

[0073] The halogen-containing compound is selected from at least one of formulas a1 to a13:

[0074]

[0075] In the above formulas a1 to a13, the multiple X in each compound are independently selected from: I, Br, Cl or epoxy group, and the multiple X in each compound are not epoxy groups at the same time;

[0076] Or including the following steps:

[0077] K1: Under the action of the initiator, the methionine monomer undergoes a ring-opening polymerization reaction to form a methionine polymer;

[0078] in,

[0079] The methionine monomer is at least one of D,L-methionine, D-methionine and L-methionine;

[0080] The methionine polymer is at least one of formula (1-1), formula (1-2) and formula (1-3):

[0081]

[0082] K2: reacting the methionine polymer with a compound containing a functional group to obtain a methionine polymer modified substance;

[0083] in,

[0084] The compound containing a functional group is selected from at least one of iodoacetic acid, iodoacetylene, 4-(2-bromoethyl)phenylboronic acid, allyl iodide and trifluoromethanesulfonate azide;

[0085] The methionine polymer modified substance is selected from at least one of formula (1-1-1) to formula (1-3-5):

[0086]

[0087] K3: mixing the methionine polymer modified substance with the object to be combined to obtain a sulfonium salt cation adsorbent;

[0088] in,

[0089] The object to be combined is a cross-linkable compound or a loadable matrix;

[0090] The cross-linkable compound is at least one of a polyhydroxy compound, a polyamine compound and a compound containing multiple double bonds;

[0091] The loadable matrix is ​​at least one of polymer microspheres, molecular sieves and magnetic beads.

[0092] The sulfonium salt cationic adsorbent prepared by the present invention is a cationic bacterial adsorbent material containing a sulfonium salt group, and is a cationic adsorbent that efficiently removes bacteria in the blood. The preparation process is simple, and the adsorption efficiency of bacteria is high, and the adsorption efficiency is high, and the adsorption efficiency is fast. The sulfonium salt adsorbent has excellent blood compatibility through structural design, and will not cause thrombosis and coagulation. The adsorbent can achieve early purification of bacteria in blood infection to prevent the subsequent severe inflammatory reaction from causing harm to the human body.

[0093] The above-mentioned preparation method of the present invention includes two technical solutions belonging to the same inventive concept, which are respectively introduced below.

[0094] Regarding the first technical solution:

[0095] A method for preparing a sulfonium salt cationic adsorbent comprises the following steps:

[0096] S1: Under the action of the initiator, the methionine monomer undergoes a ring-opening polymerization reaction to form a methionine polymer;

[0097] in,

[0098] The methionine monomer is at least one of D,L-methionine, D-methionine and L-methionine;

[0099] The methionine polymer is at least one of formula (1-1), formula (1-2) and formula (1-3):

[0100]

[0101] S2: cross-linking the methionine polymer with a halogen-containing compound to obtain a sulfonium salt cationic adsorbent;

[0102] in,

[0103] The halogen-containing compound is selected from at least one of formulas a1 to a13:

[0104]

[0105] In the above formulas a1 to a13, the multiple Xs in each compound are independently selected from: I, Br, Cl or epoxy group, and the multiple Xs in each compound are not epoxy groups at the same time.

[0106] [About step S1]:

[0107] S1: Under the action of the initiator, the methionine monomer undergoes a ring-opening polymerization reaction to form a methionine polymer.

[0108] In the present invention, the methionine monomer is at least one of D,L-methionine, D-methionine and L-methionine. Wherein, D,L-methionine is also called D,L-methionine, or mixed methionine. D-methionine and L-methionine are two isomers of methionine, wherein D-methionine (also called D-methionine) is a right-handed isomer and L-methionine (also called L-methionine) is a left-handed isomer.

[0109] In the present invention, the initiator is preferably at least one of a monoamine-containing compound, a hexamethylsilyl amide-containing lithium compound and a tertiary amine-containing compound; more preferably at least one of n-hexylamine, bis(trimethylsilyl)amide lithium, ethylenediamine, butanediamine, aniline and dendritic polyamide. In the present invention, the molar ratio of the initiator to the methionine monomer is preferably 1:(10-100), specifically 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100.

[0110] In the present invention, the ring-opening polymerization reaction is preferably carried out in a solvent medium. Among them, the solvent is preferably at least one of tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile and dichloromethane. The solvent is preferably an anhydrous solvent, for example, tetrahydrofuran is anhydrous tetrahydrofuran. In the present invention, the amount of the solvent is not particularly limited, and it can be used to fully dissolve and mix the materials.

[0111] In the present invention, the temperature of the ring-opening polymerization reaction is preferably 15 to 60° C., specifically 15° C., 20° C., 25° C., 30° C., 35° C., 40° C., 45° C., 50° C., 55° C., 60° C., and more preferably 20 to 60° C. The time of the ring-opening polymerization reaction is preferably 2 to 48 hours, specifically 8 hours, 24 hours, 36 hours, 48 ​​hours. Through the above ring-opening polymerization reaction, methionine polymers are generated in the system.

[0112] In the present invention, after the ring-opening polymerization reaction, post-treatment is preferably performed. The post-treatment preferably includes: precipitation using a precipitant and then drying. Wherein, the precipitant is preferably diethyl ether. The drying is preferably vacuum drying. The drying temperature is preferably 10 to 40° C., and the drying time is preferably 6 to 36 hours. After drying, a methionine polymer is obtained. The obtained methionine polymer is shown in formula (1-1), formula (1-2), and formula (1-3).

[0113] In the present invention, the structures of methionine monomers and corresponding methionine polymers are shown in Table 1:

[0114] Table 1: Structures of methionine monomers and corresponding methionine polymers

[0115]

[0116] [About step S2]:

[0117] S2: cross-linking the methionine polymer with a halogen-containing compound to obtain a sulfonium salt cationic adsorbent.

[0118] In the present invention, the halogen-containing compound is selected from at least one of formulas a1 to a13:

[0119]

[0120] In the above formulas a1 to a13, the multiple Xs in each compound are independently selected from: I, Br, Cl or epoxy groups, and the multiple Xs in each compound are not epoxy groups at the same time. It can be seen that in formulas a1 to a13, there are multiple Xs in each compound, and the multiple Xs in each compound are independently selected from I, Br, Cl or epoxy groups; taking formula a1 as an example, there are 3 Xs, and these 3 Xs are independently selected from the above groups, that is, these 3 Xs can be the same or different. Moreover, the multiple Xs in each compound are not epoxy groups at the same time, that is, each substituent X in each compound must contain a halogen.

[0121] In the present invention, the halogen-containing compound is preferably at least one of 1,3,5-tribromobenzene, 1,4-bis(bromomethyl)-2,5-diiodobenzene, 1,3,4,6-tetrabromobenzene, 1,3,4,5,6-pentabromobenzene, perbromobenzene, 1,3,5-tri(bromomethyl)benzene, hexaperbromomethylbenzene, 1,4-dibromo-2,5-bis(bromomethyl)benzene, iodoform and tetrabromomethane.

[0122] In the present invention, the molar ratio of the methionine unit in the methionine polymer to the halogen group in the halogen-containing compound is 1:(0.5-3), specifically 1:0.5, 1:1.0, 1:1.5, 1:2.0, 1:2.5, 1:3.0.

[0123] In the present invention, the cross-linking reaction is preferably carried out in a solvent medium. Among them, the solvent is preferably at least one of water, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and tetrahydrofuran. In some embodiments, the solvent is a mixed solvent of N,N-dimethylformamide and water. In the mixed solvent of N,N-dimethylformamide and water, the volume ratio of N,N-dimethylformamide and water is preferably 1: (0.5-4), specifically 1: 0.5, 1: 1.0, 1: 1.5, 1: 2.0, 1: 2.5, 1: 3.0, 1: 3.5, 1: 4.0. In the present invention, there is no special restriction on the amount of the solvent, as long as the material can be fully dissolved and mixed.

[0124] In the present invention, the temperature of the cross-linking reaction is not particularly limited, and it can be carried out at room temperature; the room temperature can be 10 to 40°C, specifically 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C. The time of the cross-linking reaction is preferably 4 to 48 hours, more preferably 24 to 36 hours. After the above cross-linking reaction, a sulfonium salt cationic adsorbent is generated in the system.

[0125] In the present invention, after the cross-linking reaction, post-treatment is preferably performed. The post-treatment preferably includes: washing the precipitate after the reaction. The washing liquid used for the washing is preferably deionized water and ether. After washing, a sulfonium salt cationic adsorbent is obtained.

[0126] The preparation method of the sulfonium salt cationic adsorbent of the present invention first performs a ring-opening polymerization reaction on a methionine monomer to form a methionine polymer; and further prepares a bacterial adsorbent based on the methionine polymer with bacterial selectivity. Specifically, the methionine polymer base is subjected to a cross-linking reaction with a halogen-containing compound to form a cross-linked sulfonium salt structure to obtain a sulfonium salt cationic adsorbent. The sulfonium salt adsorbent material prepared by the present invention can achieve efficient selection of bacteria and blood cells in the blood, and will not cause coagulation and hemolysis risks while efficiently adsorbing bacteria. It is expected to be used for rapid removal of microbial toxicity in the blood in the early stage of trauma and block the generation of subsequent inflammatory storms.

[0127] Regarding the second technical solution:

[0128] A method for preparing a sulfonium salt cationic adsorbent comprises the following steps:

[0129] K1: Under the action of the initiator, the methionine monomer undergoes a ring-opening polymerization reaction to form a methionine polymer;

[0130] in,

[0131] The methionine monomer is at least one of D,L-methionine, D-methionine and L-methionine;

[0132] The methionine polymer is at least one of formula (1-1), formula (1-2) and formula (1-3):

[0133]

[0134] K2: reacting the methionine polymer with a compound containing a functional group to obtain a methionine polymer modified substance;

[0135] in,

[0136] The compound containing a functional group is selected from at least one of iodoacetic acid, iodoacetylene, 4-(2-bromoethyl)phenylboronic acid, allyl iodide and trifluoromethanesulfonate azide;

[0137] The methionine polymer modified substance is selected from at least one of formula (1-1-1) to formula (1-3-5):

[0138]

[0139] K3: mixing the methionine polymer modified substance with the object to be combined to obtain a sulfonium salt cation adsorbent;

[0140] in,

[0141] The object to be combined is a cross-linkable compound or a loadable matrix;

[0142] The cross-linkable compound is at least one of a polyhydroxy compound, a polyamine compound and a compound containing multiple double bonds;

[0143] The loadable matrix is ​​at least one of polymer microspheres, molecular sieves and magnetic beads.

[0144] [About step K1]:

[0145] K1: Under the action of the initiator, methionine monomer undergoes a ring-opening polymerization reaction to form a methionine polymer.

[0146] This step is the same as step S1 in the first technical solution above. The initiator, type and amount of methionine monomer, reaction conditions, obtained product, etc. are all the same as those in step S1 above, and will not be described in detail here.

[0147] [About step K2]:

[0148] K2: reacting the methionine polymer with a compound containing a functional group to obtain a methionine polymer modification product.

[0149] In the present invention, the compound containing functional groups is selected from at least one of iodoacetic acid, iodoacetylene, 4-(2-bromoethyl)phenylboronic acid, allyl iodide and trifluoromethanesulfonate azide. In the present invention, when the methionine units in the methionine polymer are mixed with the compound containing functional groups, it is preferred to control the amount of the compound containing functional groups to be excessive, preferably 1 to 3 times the theoretical amount, specifically 1.5 times, 3 times. The theoretical amount refers to the amount of the compound containing functional groups required for all methionine units in the methionine polymer to completely react with the compound containing functional groups.

[0150] In the present invention, the reaction is preferably carried out in a solvent medium. The solvent is preferably at least one of N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile and dichloromethane. In the present invention, the amount of the solvent is not particularly limited, as long as the materials can be fully dissolved and mixed uniformly.

[0151] In the present invention, the reaction temperature is not particularly limited and can be carried out at room temperature; the room temperature can be 10 to 40°C, specifically 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C. The reaction time is preferably 12 to 24h, specifically 12h, 14h, 16h, 18h, 20h, 22h, 24h. After the above reaction, a methionine polymer modification is generated in the system.

[0152] In the present invention, after the above reaction, post-treatment is preferably performed. The post-treatment preferably includes: dialysis and freeze-drying. Wherein, the molecular weight cutoff of the dialysis bag used for the dialysis is preferably 1000-5000Da, specifically 1000Da, 1500Da, 2000Da, 2500Da, 3000Da, 3500Da, 4000Da. After dialysis, the solution in the dialysis bag is freeze-dried to obtain the methionine polymer modification.

[0153] In the present invention, the methionine polymer modified substance is selected from at least one of formula (1-1-1) to formula (1-3-5):

[0154]

[0155] The above step K2 of the present invention is to modify the methionine polymer base obtained in step K1 by using a compound containing a functional group, so as to introduce an active functional group that can further react into its side chain, thereby obtaining a modified methionine polymer.

[0156] [About step K3]:

[0157] K3: The methionine polymer modification product is mixed with the object to be combined to react, so as to obtain a sulfonium salt cation adsorbent.

[0158] In the present invention, the object to be combined is a cross-linkable compound or a loadable matrix.

[0159] About cross-linkable compounds:

[0160] The cross-linkable compound is preferably at least one of a polyhydroxy compound, a polyamine compound and a multi-double bond compound, and more preferably at least one of a branched polyethyleneimine and polydipentaerythritol hexaacrylate. The methionine polymer modifier is mixed with the cross-linkable compound to undergo a cross-linking reaction to form a cross-linked sulfonium salt structure compound. In the present invention, the mass ratio of the methionine polymer modifier to the cross-linkable compound is preferably 1: (0.1-1), specifically 1: 0.1, 1: 0.5, 1: 0.75, 1: 1.

[0161] In the present invention, the cross-linking reaction is preferably carried out under the action of a catalyst or a photoinitiator. The catalyst is preferably at least one of dihydroxymethyl acetone, photoinitiator 2959 and 2,4,6-trimethylbenzoyl-diphenylphosphine oxide. The amount of the catalyst is preferably 0.1% to 5% of the mass of the methionine polymer modifier, specifically 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%. The photoinitiator is preferably at least one of benzophenone, photoinitiator 2959 and 2,4,6-trimethylbenzoyl-diphenylphosphine oxide. The amount of the photoinitiator is preferably 1% to 5% of the mass of the methionine polymer modifier, specifically 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%. In one embodiment, the crosslinkable compound is branched polyethyleneimine; in this embodiment, the mixing reaction is carried out under the action of a catalyst; the catalyst is dihydroxymethyl acetone. In another embodiment, the crosslinkable compound is polydipentaerythritol hexaacrylate; in this embodiment, the mixing reaction is carried out under the action of a photoinitiator; the photoinitiator is benzophenone.

[0162] About loadable matrix:

[0163] The loadable matrix is ​​preferably at least one of polymer microspheres, molecular sieves and magnetic beads. Among them, the polymer microspheres are preferably at least one of polystyrene microspheres and polyvinyl alcohol microspheres (PVA microspheres). The type of the molecular sieve is not particularly limited, and it can be a known conventional molecular sieve. The magnetic beads are magnetic beads in the field of chemistry, and the full name is superparamagnetic nano-microspheres. They are a material with a magnetic core inside, a wrapping layer on the outside, and many active groups distributed on the surface. The methionine polymer modifier can react with the above-mentioned various loadable matrix materials through chemical grafting, physical action, etc., so that the surface of the matrix material is covered with a layer of sulfonium salt polymer. In the present invention, the mass ratio of the methionine polymer modifier to the loadable matrix material is preferably 1: (1-10), and can be specifically 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, 1: 10.

[0164] In the present invention, when the methionine polymer modified substance and the object to be combined are mixed and reacted, it is preferably carried out in a solvent medium. Among them, the solvent is preferably at least one of tetrahydrofuran, ethanol, dimethyl sulfoxide and water. In the present invention, the amount of the solvent is not particularly limited, as long as it can dissolve or disperse the materials uniformly.

[0165] In the present invention, the temperature of the mixed reaction is not particularly limited and can be carried out at room temperature. The time of the mixed reaction is preferably 0.5 to 24 hours, specifically 0.5 hours, 8 hours, 12 hours, 16 hours, 20 hours, and 24 hours. After the mixed reaction, a sulfonium salt cationic adsorbent is obtained.

[0166] The preparation method of the sulfonium salt cationic adsorbent of the present invention is to first perform a ring-opening polymerization reaction on a methionine monomer to form a methionine polymer; and further prepare a bacterial adsorbent based on the methionine polymer with bacterial selectivity. Specifically, the methionine polymer base is first modified by a compound containing a functional group, so that an active functional group that can further react is introduced into its side chain, and then the modified methionine polymer is cross-linked with a cross-linkable compound to form a cross-linked sulfonium salt structure, or the modified methionine polymer is mixed with a loadable matrix to react so that the surface of the matrix is ​​covered with a layer of sulfonium salt polymer. The sulfonium salt adsorbent material prepared by the present invention can achieve efficient selection of bacteria and blood cells in the blood, and will not cause coagulation and hemolysis risks while efficiently adsorbing bacteria. It is expected to be used for rapid removal of microbial toxicity in the blood in the early stage of trauma and block the generation of subsequent inflammatory storms.

[0167] The present invention also provides a sulfonium salt cation adsorbent prepared by the preparation method described in the above technical scheme.

[0168] The present invention also provides the use of the sulfonium salt cationic adsorbent described in the above technical solution in the preparation of bacteria adsorption materials in blood.

[0169] The preparation method of the sulfonium salt cationic adsorbent of the present invention is to first perform a ring-opening polymerization reaction on a methionine monomer to form a methionine polymer; and further prepare a bacterial adsorbent based on the methionine polymer with bacterial selectivity. Route one is to perform a cross-linking reaction on the above-mentioned methionine polymer base with a halogen-containing compound to form a cross-linked sulfonium salt structure; Route two is to first modify the above-mentioned methionine polymer base with a compound containing a functional group, so that its side chain introduces an active functional group that can further react, and then the modified methionine polymer is cross-linked with a cross-linkable compound to form a cross-linked sulfonium salt structure, or the modified methionine polymer is mixed with a loadable matrix to react so that the surface of the matrix is ​​covered with a layer of sulfonium salt polymer. The above-mentioned preparation methods of the present invention all first prepare a methionine polymer with bacterial selectivity, and then use it as a basis to further prepare a bacterial adsorbent with a sulfonium salt structure. The sulfonium salt adsorption material prepared by the present invention can realize efficient selection of bacteria and blood cells in the blood, and can realize efficient adsorption of bacteria in the blood; it also has excellent blood compatibility, and does not cause coagulation and hemolysis risks while efficiently adsorbing bacteria; in addition, it has bactericidal properties while having bacterial adsorption capacity; in addition, the preparation method of the present invention is simple, the yield is high, and the reaction conditions are mild and controllable, which is convenient for large-scale production.

[0170] The bacterial adsorption material can simply and quickly remove toxic metabolites and harmful impurities from the blood through an extracorporeal circulation system containing an adsorbent, thereby achieving the treatment of bacterial infection in the blood and avoiding the occurrence of severe inflammatory reactions caused by bacterial infection. The sulfonium salt structure adsorbent of the present invention has a higher charge density and lower toxicity than traditional cations such as ammonium salts, and therefore has a higher selectivity for bacteria and cells. Therefore, the sulfonium salt adsorption material of the present invention can achieve efficient adsorption of bacteria in the blood while avoiding the occurrence of phenomena such as coagulation and hemolysis.

[0171] The sulfonium salt adsorbent material of the present invention maintains a stable structure in an aqueous solution without swelling or dissolving. It can be used as a bacterial adsorbent material in blood, having both bacterial adsorption capacity and bactericidal properties; moreover, the sulfonium salt adsorbent can satisfy the requirement of not causing hemolysis and coagulation when purifying bacteria in blood.

[0172] The test results show that the bacterial removal rate of the sulfonium salt cationic adsorbent of the present invention at a concentration of 8 mg / mL reaches more than 90%, showing an excellent bacterial adsorption rate. After the sulfonium salt cationic adsorbent of the present invention is mixed with whole blood for 1 hour, there is no obvious adsorption of blood cells and platelets on the surface, and no changes in the components of whole blood are caused, showing excellent blood compatibility and will not cause thrombosis and coagulation. The sulfonium salt cationic adsorbent of the present invention treats whole blood containing bacteria, and the bacterial adsorption rate in the blood reaches more than 85% after 20 minutes of treatment, proving that the sulfonium salt cationic adsorbent of the present invention can achieve the purification of bacteria in blood infection and the bacterial adsorption rate is fast and the efficiency is high; after 1 hour of treatment, the bacteria on the surface of the adsorbent die, proving that the sulfonium salt cationic adsorbent of the present invention has a bactericidal effect while having bacterial adsorption capacity. After the sulfonium salt cationic adsorbent of the present invention is soaked in PBS buffer for 24 hours, the polymer dissolution rate is below 0.25%, and the dissolution rate is extremely low, proving that the sulfonium salt adsorbent has good stability.

[0173] In order to further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the present invention.

[0174] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. Among them, the branched polyethyleneimine has a Mw of 10,000 and is sourced from Anergy Co., Ltd. The polydipentaerythritol hexaacrylate has a CAS number of 29570-58-9 and is sourced from Anergy Co., Ltd. PVA microspheres are sourced from Aladdin.

[0175] Example 1

[0176] 1. Product preparation

[0177] S1: Ring-opening polymerization of n-hexylamine initiator and D,L-methionine in anhydrous tetrahydrofuran at a molar ratio of 1:30 was carried out at 30°C for 24 hours. Then, the following post-treatment was carried out: ether precipitation was performed three times and vacuum drying was performed to obtain methionine polymer.

[0178] S2: The methionine polymer obtained in step S1 is mixed with the halogen-containing compound 1,3,5-tribromobenzene and a solvent (a mixed solvent of N,N-dimethylformamide and water, with a volume ratio of N,N-dimethylformamide and water of 1:1), wherein the molar ratio of the methionine unit in the methionine polymer to the halogen group in the halogen-containing compound is 1:3.0, and the mixture is reacted at 30°C for 24 hours. The following post-treatment is then performed: the precipitate after the reaction is washed with deionized water and ether in turn, thereby obtaining a sulfonium salt cation adsorbent.

[0179] 2. Product testing:

[0180] (2.1) Bacterial clearance rate

[0181] Different masses of sulfonium salt cationic adsorbents were mixed with PBS buffer solution to prepare adsorbent solutions with concentrations of 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 4 mg / mL, and 8 mg / mL, respectively, and then mixed with 10 8 After 20 min of mixing with 1000 CFU / mL Staphylococcus aureus, the bacterial number in the supernatant was calculated by agar plate counting method to calculate the bacterial clearance rate. Derived from ExThera Mrdical) for control trials.

[0182] The test results are as follows Figure 1 As shown, it can be seen that at the same concentration, the bacterial removal rate of the sulfonium salt cationic adsorbent of the present invention is significantly higher than that of the commercially available adsorbent, wherein the bacterial removal rate of the sulfonium salt cationic adsorbent solution with a concentration of 8 mg / mL reaches 99.9%. The above proves that the sulfonium salt cationic adsorbent of the present invention can effectively improve the bacterial adsorption rate.

[0183] (2.2) Blood compatibility

[0184] After the sulfonium salt cationic adsorbent was mixed with whole blood for 1 hour, the changes in blood components (white blood cells WBC, red blood cells RBC, platelets PLT) were tested. At the same time, the above commercially available adsorbent was used as a control test.

[0185] The test results are as follows Figure 2 As shown, it can be seen that the number of red blood cells, white blood cells and platelets in the blood does not change significantly after being treated with the sulfonium salt adsorbent and the commercially available adsorbent, which proves that the sulfonium salt cationic adsorbent of the present invention has excellent blood compatibility.

[0186] (2.3) Blood Bacteria Purification Test

[0187] After the sulfonium salt cationic adsorbent was mixed with whole blood containing bacteria, the change of bacterial content in the blood was tested. At the same time, the above commercially available adsorbent was used for control test.

[0188] The test results are as follows Figure 3 As shown, Figure 3 (a) is a schematic diagram of the sample after the sulfonium salt cation adsorbent is mixed with whole blood containing bacteria. Figure 3 (b) is a schematic diagram of a test sample being placed in a tester for testing; Figure 3 (c) is the test effect diagram. It can be seen that after 20 minutes of treatment, the commercially available adsorbent reduced the bacterial content in whole blood from the initial amount of 5×10 7 CFU / mL decreased to 3.5×10 7CFU / mL, the bacterial adsorption rate in the blood was only 30%; while the sulfonium salt cationic adsorbent was able to absorb 5×10 7 The CFU / mL dropped to nearly 0 CFU / mL, and the bacterial adsorption rate in the blood was as high as over 99%, with an adsorption efficiency of 0.41×10 8 CFU / mg·min. When the treatment time was extended to 40 min, the bacterial content in the whole blood treated with the commercially available adsorbent was still as high as 2.5×10 7 CFU / mL, the bacterial adsorption rate is only 50%, which is far lower than the effect of the sulfonium salt cationic adsorbent treated for 20 minutes. The above proves that the sulfonium salt cationic adsorbent of the present invention can achieve rapid purification of bacteria in blood infection, and the adsorption efficiency is relatively high, reaching 0.41×10 8 CFU / mg·min.

[0189] After 1 hour of treatment, the sulfonium salt cation adsorbent was taken out and the state of bacteria adsorbed on its surface was observed. The results were as follows: Figure 4 As shown, Figure 4 (a)-4(b) are effect diagrams at different magnifications. It can be seen that the bacteria on the surface of the adsorbent have lost their basic morphology, proving that all the bacteria have died. The above proves that the sulfonium salt cationic adsorbent of the present invention has a bactericidal effect while having the ability to adsorb bacteria.

[0190] (2.4) Stability

[0191] The sulfonium salt cationic adsorbent was stirred in PBS buffer at 37°C for 24 h, and the polymer dissolution was tested using an ultraviolet spectrophotometer.

[0192] Figure 5 The dissolution of the polymer from the sulfonium salt adsorbed microspheres at 12 h and 24 h. From the results, it can be seen that the dissolution rate is 0.023% at 12 h and 0.049% at 24 h. The dissolution rate is extremely low, proving that the sulfonium salt adsorbent has good stability.

[0193] Example 2

[0194] 1. Product preparation

[0195] S1: Ring-opening polymerization of n-hexylamine initiator and D,L-methionine in anhydrous tetrahydrofuran at a molar ratio of 1:50 was carried out at 30°C for 24 hours. Then, the following post-treatment was carried out: precipitated with diethyl ether three times and then dried in vacuum to obtain methionine polymer.

[0196] S2: The methionine polymer obtained in step S1 is mixed with the halogen-containing compound 1,4-bis(bromomethyl)-2,5-diiodobenzene and a solvent (a mixed solvent of N,N-dimethylformamide and water, with a volume ratio of N,N-dimethylformamide and water of 1:1), wherein the molar ratio of the methionine unit in the methionine polymer to the halogen group in the halogen-containing compound is 1:1.5, and the mixture is reacted at 35°C for 24 hours. The following post-treatment is then performed: the precipitate after the reaction is washed with deionized water and ether in turn, thereby obtaining a sulfonium salt cationic adsorbent.

[0197] 2. Product testing

[0198] (2.1) Bacterial clearance rate

[0199] The test was carried out according to the test method in Example 1. The results showed that the bacterial removal rate of the sulfonium salt cationic adsorbent obtained in Example 2 reached 99.5% at a concentration of 8 mg / mL, showing an excellent bacterial adsorption effect.

[0200] (2.2) Blood compatibility

[0201] The test was carried out according to the test method in Example 1. The results showed that the sulfonium salt cationic adsorbent obtained in Example 2 did not cause changes in the whole blood components, proving that the sulfonium salt cationic adsorbent obtained in Example 2 had excellent blood compatibility.

[0202] (2.3) Blood Bacteria Purification Test

[0203] The test was carried out according to the test method in Example 1. The results showed that after 20 minutes of treatment, the adsorption rate of bacteria in the blood by the sulfonium salt cationic adsorbent in Example 2 reached 94%, which can effectively purify bacteria in blood infection.

[0204] After 1 hour of treatment, the sulfonium salt cationic adsorbent was taken out and the state of bacteria adsorbed on its surface was observed. The result was similar to that in Example 1. The bacteria on the surface of the adsorbent had lost their basic morphology, proving that all the bacteria were dead. The above proves that the sulfonium salt cationic adsorbent in Example 2 has both bacterial adsorption capacity and bactericidal performance.

[0205] (2.4) Stability

[0206] The test was carried out according to the test method in Example 1, and the results showed that the 24h dissolution rate was only 0.12%, showing excellent stability.

[0207] Example 3

[0208] 1. Product preparation

[0209] S1: Ring-opening polymerization of ethylenediamine initiator and L-methionine in a molar ratio of 1:30 was carried out in dimethyl sulfoxide at 30°C for 12 hours, followed by post-treatment as follows: precipitating with diethyl ether three times and then vacuum drying to obtain a methionine polymer.

[0210] S2: Mix the methionine polymer obtained in step S1 with the halogen-containing compound tetrabromomethane and the solvent N,N-dimethylformamide, wherein the molar ratio of the methionine unit in the methionine polymer to the halogen group in the halogen-containing compound is 1:0.5, and react at 35°C for 24 hours. Then perform the following post-treatment: wash the precipitate after the reaction with deionized water and ether in turn, thereby obtaining a sulfonium salt cationic adsorbent.

[0211] 2. Product testing

[0212] (2.1) Bacterial clearance rate

[0213] The test was carried out according to the test method in Example 1. The results showed that the bacterial removal rate of the sulfonium salt cationic adsorbent obtained in Example 3 reached 90.2% at a concentration of 8 mg / mL, showing an excellent bacterial adsorption effect.

[0214] (2.2) Blood compatibility

[0215] The test was carried out according to the test method in Example 1. The results showed that the sulfonium salt cationic adsorbent obtained in Example 3 did not cause changes in the whole blood components, proving that the sulfonium salt cationic adsorbent obtained in Example 3 had excellent blood compatibility.

[0216] (2.3) Blood Bacteria Purification Test

[0217] The test was carried out according to the test method in Example 1. The results showed that after 20 minutes of treatment, the adsorption rate of bacteria in the blood by the sulfonium salt cationic adsorbent in Example 3 reached 85%, which can effectively purify bacteria in blood infection.

[0218] After 1 hour of treatment, the sulfonium salt cationic adsorbent was taken out and the state of bacteria adsorbed on its surface was observed. The result was similar to that in Example 1. The bacteria on the surface of the adsorbent had lost their basic morphology, proving that all the bacteria were dead. The above proves that the sulfonium salt cationic adsorbent in Example 3 has both bacterial adsorption capacity and bactericidal performance.

[0219] (2.4) Stability

[0220] The test was carried out according to the test method in Example 1, and the results showed that the 24-hour dissolution rate was only 0.05%, showing excellent stability.

[0221] Example 4

[0222] 1. Product preparation

[0223] S1: n-butylamine initiator and D-methionine were subjected to ring-opening polymerization in tetrahydrofuran at a molar ratio of 1:50, crown ether was added as a catalyst, and the reaction was carried out at 30°C for 12 hours. Then the following post-treatment was performed: ether was used for precipitation three times and vacuum drying was performed to obtain a methionine polymer.

[0224] S2: Mix the methionine polymer obtained in step S1 with the epoxy compound 1,3,5-triglycidyl-S-triazinetrione and the solvent N,N-dimethylformamide, wherein the molar ratio of the methionine unit in the methionine polymer to the halogen group in the halogen-containing compound is 1:0.5, and react at 35°C for 24 hours. Then perform the following post-treatment: wash the precipitate after the reaction with deionized water and ether in turn, thereby obtaining a sulfonium salt cationic adsorbent.

[0225] 2. Product testing

[0226] (2.1) Bacterial clearance rate

[0227] The test was carried out according to the test method in Example 1. The results showed that the bacterial removal rate of the sulfonium salt cationic adsorbent obtained in Example 4 reached 97.7% at a concentration of 8 mg / mL, showing an excellent bacterial adsorption effect.

[0228] (2.2) Blood compatibility

[0229] The test was carried out according to the test method in Example 1. The results showed that the sulfonium salt cationic adsorbent obtained in Example 4 did not cause changes in the whole blood components, proving that the sulfonium salt cationic adsorbent obtained in Example 4 had excellent blood compatibility.

[0230] (2.3) Blood Bacteria Purification Test

[0231] The test was conducted according to the test method in Example 1. The results showed that after 20 minutes of treatment, the adsorption rate of bacteria in the blood by the sulfonium salt cationic adsorbent in Example 4 reached 93%, which can effectively purify bacteria in blood infection.

[0232] After 1 hour of treatment, the sulfonium salt cationic adsorbent was taken out and the state of bacteria adsorbed on its surface was observed. The result was similar to that in Example 1. The bacteria on the surface of the adsorbent had lost their basic morphology, proving that all the bacteria were dead. The above proves that the sulfonium salt cationic adsorbent in Example 4 has both bacterial adsorption capacity and bactericidal performance.

[0233] (2.4) Stability

[0234] The test was carried out according to the test method in Example 1, and the results showed that the 24-hour dissolution rate was only 0.02%, showing excellent stability.

[0235] Example 5

[0236] 1. Product preparation

[0237] S1: Tetrabutylammonium acetate initiator and D,L-methionine were subjected to ring-opening polymerization in tetrahydrofuran at a molar ratio of 1:50, crown ether was added as a catalyst, and the reaction was carried out at 30°C for 12 hours. Then the following post-treatment was performed: ether was used for precipitation three times and then vacuum dried to obtain a methionine polymer.

[0238] S2: Mix the methionine polymer obtained in step S1 with the iodine-containing compound methyl iodide and the solvent dimethyl sulfoxide, wherein the molar ratio of the methionine unit in the methionine polymer to the halogen group in the halogen-containing compound is 1:0.3, and react at 30°C for 24 hours. Then perform the following post-treatment: wash the precipitate after the reaction with deionized water and ether in turn, thereby obtaining a sulfonium salt cationic adsorbent.

[0239] 2. Product testing

[0240] (2.1) Bacterial clearance rate

[0241] The test was carried out according to the test method in Example 1. The results showed that the bacterial removal rate of the sulfonium salt cationic adsorbent obtained in Example 5 at a concentration of 8 mg / mL reached 98.4%, showing an excellent bacterial adsorption effect.

[0242] (2.2) Blood compatibility

[0243] The test was carried out according to the test method in Example 1. The results showed that the sulfonium salt cationic adsorbent obtained in Example 5 did not cause changes in the whole blood components, proving that the sulfonium salt cationic adsorbent obtained in Example 5 had excellent blood compatibility.

[0244] (2.3) Blood Bacteria Purification Test

[0245] The test was carried out according to the test method in Example 1. The results showed that after 20 minutes of treatment, the adsorption rate of bacteria in the blood by the sulfonium salt cationic adsorbent in Example 5 reached 99%, which can effectively purify bacteria in blood infection.

[0246] After 1 hour of treatment, the sulfonium salt cationic adsorbent was taken out and the state of bacteria adsorbed on its surface was observed. The result was similar to that in Example 1. The bacteria on the surface of the adsorbent had lost their basic morphology, proving that all the bacteria were dead. The above proves that the sulfonium salt cationic adsorbent in Example 5 has both bacterial adsorption capacity and bactericidal performance.

[0247] (2.4) Stability

[0248] The test was carried out according to the test method in Example 1. The results showed that the 24-hour dissolution rate was only 0.05%, showing excellent stability.

[0249] Example 6

[0250] 1. Product preparation

[0251] K1: Lithium bis(trimethylsilyl)amide initiator and D,L-methionine were subjected to ring-opening polymerization in anhydrous tetrahydrofuran at a molar ratio of 1:30, and the reaction was carried out at 30°C for 8 hours. The following post-treatment was then performed: precipitated with diethyl ether three times and then dried in vacuum to obtain a methionine polymer.

[0252] K2: Take 1 g of the methionine polymer obtained in step K1 and dissolve it in 50 mL of N,N-dimethylformamide solvent, add 3 times the theoretical amount of iodoacetic acid, and react at 25°C for 24 hours. Then perform the following post-treatment: dialyze the product using a dialysis bag with a molecular weight cutoff of 3500, and freeze-dry to obtain a methionine polymer modification.

[0253] K3: Take 1 g of the methionine polymer modified product obtained in step K2, 0.5 g of branched polyethyleneimine, and catalyst dihydroxymethylacetone (the amount used is 1% of the mass of the methionine polymer modified product), dissolve them in tetrahydrofuran, and react at 30° C. for 12 h. Then, precipitate with diethyl ether to obtain a sulfonium salt cation adsorbent.

[0254] 2. Product testing

[0255] (2.1) Bacterial clearance rate

[0256] The test was carried out according to the test method in Example 1. The results showed that the bacterial removal rate of the sulfonium salt cationic adsorbent obtained in Example 6 reached 97.2% at a concentration of 8 mg / mL, showing an excellent bacterial adsorption effect.

[0257] (2.2) Blood compatibility

[0258] The test was carried out according to the test method in Example 1. The results showed that the sulfonium salt cationic adsorbent obtained in Example 6 did not cause changes in the components of red blood cells, white blood cells and platelets, proving that the sulfonium salt cationic adsorbent obtained in Example 6 had excellent blood compatibility.

[0259] (2.3) Blood Bacteria Purification Test

[0260] The test was carried out according to the test method in Example 1. The results showed that after 20 minutes of treatment, the adsorption rate of bacteria in the blood by the sulfonium salt cationic adsorbent in Example 6 reached 98%, which can effectively purify bacteria in blood infection.

[0261] After 1 hour of treatment, the sulfonium salt cationic adsorbent was taken out and the state of bacteria adsorbed on its surface was observed. The result was similar to that in Example 1. The bacteria on the surface of the adsorbent had lost their basic morphology, proving that all the bacteria were dead. The above proves that the sulfonium salt cationic adsorbent in Example 6 has both bacterial adsorption capacity and bactericidal performance.

[0262] (2.4) Stability

[0263] The test was carried out according to the test method in Example 1, and the results showed that the 24-hour dissolution rate was only 0.05%, showing excellent stability.

[0264] Example 7

[0265] 1. Product preparation

[0266] K1: Lithium bis(trimethylsilyl)amide initiator and D,L-methionine were subjected to ring-opening polymerization in anhydrous tetrahydrofuran at a molar ratio of 1:30, and the reaction was carried out at 30°C for 8 hours. The following post-treatment was then performed: precipitated with diethyl ether three times and then dried in vacuum to obtain a methionine polymer.

[0267] K2: Take 1 g of the methionine polymer obtained in step K1 and dissolve it in 50 mL of N,N-dimethylformamide solvent, add 3 times the theoretical amount of allyl iodide, and react at 30°C for 12 hours. Then perform the following post-treatment: dialyze the product using a dialysis bag with a molecular weight cutoff of 3500, and freeze-dry to obtain a methionine polymer modification.

[0268] K3: Take 1 g of the methionine polymer modified substance obtained in step K2, 0.75 g of polydipentaerythritol hexaacrylate, and a photoinitiator benzophenone (the amount used is 1.5% of the mass of the methionine polymer modified substance), dissolve them in ethanol, and react at 40° C. for 0.5 h. Then, precipitate with diethyl ether to obtain a sulfonium salt cationic adsorbent.

[0269] 2. Product testing

[0270] (2.1) Bacterial clearance rate

[0271] The test was carried out according to the test method in Example 1. The results showed that the bacterial removal rate of the sulfonium salt cationic adsorbent obtained in Example 7 reached 99.9% at a concentration of 8 mg / mL, showing an excellent bacterial adsorption effect.

[0272] (2.2) Blood compatibility

[0273] The test was carried out according to the test method in Example 1. The results showed that the sulfonium salt cationic adsorbent obtained in Example 7 did not cause changes in the main components of whole blood, proving that the sulfonium salt cationic adsorbent obtained in Example 7 has excellent blood compatibility.

[0274] (2.3) Blood Bacteria Purification Test

[0275] The test was carried out according to the test method in Example 1. The results showed that after 20 minutes of treatment, the adsorption rate of bacteria in the blood by the sulfonium salt cationic adsorbent in Example 7 was as high as 95%, which can effectively purify bacteria in blood infection.

[0276] After 1 hour of treatment, the sulfonium salt cationic adsorbent was taken out and the state of bacteria adsorbed on its surface was observed. The result was similar to that in Example 1. The bacteria on the surface of the adsorbent had lost their basic morphology, proving that all the bacteria were dead. The above proves that the sulfonium salt cationic adsorbent in Example 7 has both bacterial adsorption capacity and bactericidal performance.

[0277] (2.4) Stability

[0278] The test was carried out according to the test method in Example 1, and the results showed that the 24-hour dissolution rate was only 0.02%, showing excellent stability.

[0279] Example 8

[0280] 1. Product preparation

[0281] K1: Lithium bis(trimethylsilyl)amide initiator and D,L-methionine were subjected to ring-opening polymerization in anhydrous tetrahydrofuran at a molar ratio of 1:30, and the reaction was carried out at 30°C for 8 hours. The following post-treatment was then performed: precipitated with diethyl ether three times and then dried in vacuum to obtain a methionine polymer.

[0282] K2: Take 1 g of the methionine polymer obtained in step K1 and dissolve it in 50 mL of N,N-dimethylformamide solvent, add 1.5 times the theoretical amount of bromoethylphenylboronic acid, and react at 25°C for 24 hours. Then perform the following post-treatment: dialyze the product using a dialysis bag with a molecular weight cutoff of 3500, and freeze-dry to obtain a methionine polymer modification.

[0283] K3: 1 g of the methionine polymer modified product obtained in step K2 was dissolved in a solvent (a mixed solvent of dimethyl sulfoxide and water, with a volume ratio of dimethyl sulfoxide to water of 1:2), and 2 g of PVA microspheres were added to react at 25°C for 8 h. Then, the microspheres were rinsed with deionized water and ethanol in turn, and dried to obtain a sulfonium salt cation adsorbent.

[0284] 2. Product testing

[0285] (2.1) Bacterial clearance rate

[0286] The test was carried out according to the test method in Example 1. The results showed that the bacterial removal rate of the sulfonium salt cationic adsorbent obtained in Example 8 reached 99.9% at a concentration of 8 mg / mL, showing an excellent bacterial adsorption effect.

[0287] (2.2) Blood compatibility

[0288] The test was carried out according to the test method in Example 1. The results showed that the sulfonium salt cationic adsorbent obtained in Example 8 did not cause changes in the main components of whole blood, proving that the sulfonium salt cationic adsorbent obtained in Example 8 has excellent blood compatibility.

[0289] (2.3) Blood Bacteria Purification Test

[0290] The test was carried out according to the test method in Example 1. The results showed that after 20 minutes of treatment, the adsorption rate of bacteria in the blood by the sulfonium salt cationic adsorbent in Example 8 reached 99%, which can effectively purify bacteria in blood infection.

[0291] After 1 hour of treatment, the sulfonium salt cationic adsorbent was taken out and the state of bacteria adsorbed on its surface was observed. The result was similar to that in Example 1. The bacteria on the surface of the adsorbent had lost their basic morphology, proving that all the bacteria were dead. The above proves that the sulfonium salt cationic adsorbent in Example 8 has both bacterial adsorption capacity and bactericidal performance.

[0292] (2.4) Stability

[0293] The test was carried out according to the test method in Example 1, and the results showed that the 24h dissolution rate was only 0.11%, showing excellent stability.

[0294] Example 9

[0295] 1. Product preparation

[0296] K1: Aniline initiator and D-methionine were subjected to ring-opening polymerization in anhydrous tetrahydrofuran at a molar ratio of 1:25, and the reaction was carried out at 30°C for 8 hours. Then, the following post-treatment was performed: ether was used for precipitation three times and vacuum drying was performed to obtain a methionine polymer.

[0297] K2: Take 1 g of the methionine polymer obtained in step K1 and dissolve it in 50 mL of N,N-dimethylformamide solvent, add 1.5 times the theoretical amount of bromoethylphenylboronic acid, and react at 25°C for 24 hours. Then perform the following post-treatment: dialyze the product using a dialysis bag with a molecular weight cutoff of 3500, and freeze-dry to obtain a methionine polymer modification.

[0298] K3: 1 g of the methionine polymer modified product obtained in step K2 was dissolved in a solvent (a mixed solvent of dimethyl sulfoxide and water, with a volume ratio of dimethyl sulfoxide to water of 1:2), and a 100 mg / mL PVA aqueous solution (the mass ratio of the methionine polymer modified product to the PVA aqueous solution was 1:0.5) was added, and the reaction was carried out at 25°C for 12 hours to form microspheres. Then, the microspheres were rinsed with deionized water and ethanol in turn, and dried to obtain a sulfonium salt cation adsorbent.

[0299] 2. Product testing

[0300] (2.1) Bacterial clearance rate

[0301] The test was carried out according to the test method in Example 1. The results showed that the bacterial removal rate of the sulfonium salt cationic adsorbent obtained in Example 9 at a concentration of 8 mg / mL reached 95.4%, showing an excellent bacterial adsorption effect.

[0302] (2.2) Blood compatibility

[0303] The test was carried out according to the test method in Example 1. The results showed that the sulfonium salt cationic adsorbent obtained in Example 9 did not cause changes in the main components of whole blood, proving that the sulfonium salt cationic adsorbent obtained in Example 9 has excellent blood compatibility.

[0304] (2.3) Blood Bacteria Purification Test

[0305] The test was carried out according to the test method in Example 1. The results showed that after 20 minutes of treatment, the adsorption rate of bacteria in the blood by the sulfonium salt cationic adsorbent in Example 9 reached 95%, which can effectively purify bacteria in blood infection.

[0306] After 1 hour of treatment, the sulfonium salt cationic adsorbent was taken out and the state of bacteria adsorbed on its surface was observed. The result was similar to that in Example 1. The bacteria on the surface of the adsorbent had lost their basic morphology, proving that all the bacteria were dead. The above proves that the sulfonium salt cationic adsorbent in Example 9 has both bacterial adsorption capacity and bactericidal performance.

[0307] (2.4) Stability

[0308] The test was carried out according to the test method in Example 1, and the results showed that the 24-hour dissolution rate was only 0.2%, showing excellent stability.

[0309] Example 10

[0310] 1. Product preparation

[0311] K1: Aniline initiator and D,L-methionine were subjected to ring-opening polymerization in anhydrous tetrahydrofuran at a molar ratio of 1:50 at 30°C for 16 hours, followed by post-treatment as follows: precipitated with ether three times and then dried in vacuum to obtain a methionine polymer.

[0312] K2: Take 1 g of the methionine polymer obtained in step K1 and dissolve it in 50 mL of N,N-dimethylformamide solvent, add 1 times the theoretical amount of 1,3,5-tri(bromomethyl)benzene, and react at 37°C for 24 hours. Then perform the following post-treatment: dialyze the product using a dialysis bag with a molecular weight cutoff of 3500, and freeze-dry to obtain a methionine polymer modification.

[0313] K3: 1 g of the methionine polymer modified product obtained in step K2 was dissolved in a solvent (a mixed solvent of dimethyl sulfoxide and water, with a volume ratio of dimethyl sulfoxide to water of 1:1), and 1 g of polystyrene microspheres (the mass ratio of the methionine polymer modified product to the polystyrene microspheres was 1:1) was added, and the microspheres were formed after reacting at 37°C for 12 hours. Then, the microspheres were rinsed with deionized water and ethanol in turn, and dried to obtain a sulfonium salt cation adsorbent.

[0314] 2. Product testing

[0315] (2.1) Bacterial clearance rate

[0316] The test was carried out according to the test method in Example 1. The results showed that the bacterial removal rate of the sulfonium salt cationic adsorbent obtained in Example 10 at a concentration of 8 mg / mL reached 98%, showing an excellent bacterial adsorption effect.

[0317] (2.2) Blood compatibility

[0318] The test was carried out according to the test method in Example 1. The results showed that the sulfonium salt cationic adsorbent obtained in Example 10 did not cause changes in the main components of whole blood, proving that the sulfonium salt cationic adsorbent obtained in Example 10 has excellent blood compatibility.

[0319] (2.3) Blood Bacteria Purification Test

[0320] The test was carried out according to the test method in Example 1. The results showed that after 20 minutes of treatment, the adsorption rate of bacteria in the blood by the sulfonium salt cationic adsorbent in Example 10 reached more than 95%, which can effectively purify bacteria in blood infection.

[0321] After 1 hour of treatment, the sulfonium salt cationic adsorbent was taken out and the state of bacteria adsorbed on its surface was observed. The result was similar to that in Example 1. The bacteria on the surface of the adsorbent had lost their basic morphology, proving that all the bacteria were dead. The above proves that the sulfonium salt cationic adsorbent in Example 10 has both bacterial adsorption capacity and bactericidal performance.

[0322] (2.4) Stability

[0323] The test was carried out according to the test method in Example 1. The results showed that the 24-hour dissolution rate was only 0.15%, showing excellent stability.

[0324] Embodiment 11

[0325] 1. Product preparation

[0326] K1: PAMAM dendrimer (ethylenediamine core, 2.0 generation) initiator and D,L-methionine were subjected to ring-opening polymerization in anhydrous tetrahydrofuran at a molar ratio of 1:25, and the reaction was carried out at 30°C for 16 hours. Then the following post-treatment was performed: precipitated with diethyl ether three times and then dried in vacuum to obtain methionine polymer.

[0327] K2: Take 1 g of the methionine polymer obtained in step K1 and dissolve it in 50 mL of N,N-dimethylformamide solvent, add 3 times the theoretical amount of bromovinylphenylboronic acid, and react at 37°C for 24 hours. Then perform the following post-treatment: dialyze the product using a dialysis bag with a molecular weight cutoff of 3500, and freeze-dry to obtain a methionine polymer modification.

[0328] K3: 1 g of the methionine polymer modified product obtained in step K2 was dissolved in a solvent (a mixed solvent of dimethyl sulfoxide and water, with a volume ratio of dimethyl sulfoxide to water of 1:1), and 8 g of a PVA aqueous solution (the mass ratio of the methionine polymer modified product to the PVA aqueous solution was 1:8) was added, and the reaction was carried out at 37°C for 24 hours to form microspheres. Then, the microspheres were rinsed with deionized water and ethanol in turn, and dried to obtain a sulfonium salt cation adsorbent.

[0329] 2. Product testing

[0330] (2.1) Bacterial clearance rate

[0331] The test was carried out according to the test method in Example 1. The results showed that the bacterial removal rate of the sulfonium salt cationic adsorbent obtained in Example 11 reached 99% at a concentration of 8 mg / mL, showing an excellent bacterial adsorption effect.

[0332] (2.2) Blood compatibility

[0333] The test was carried out according to the test method in Example 1. The results showed that the sulfonium salt cationic adsorbent obtained in Example 11 did not cause changes in the main components of whole blood, proving that the sulfonium salt cationic adsorbent obtained in Example 11 has excellent blood compatibility.

[0334] (2.3) Blood Bacteria Purification Test

[0335] The test was carried out according to the test method in Example 1. The results showed that after 20 minutes of treatment, the adsorption rate of bacteria in the blood by the sulfonium salt cationic adsorbent in Example 11 reached more than 99%, which can effectively purify bacteria in blood infection.

[0336] After 1 hour of treatment, the sulfonium salt cationic adsorbent was taken out and the state of bacteria adsorbed on its surface was observed. The result was similar to that in Example 1. The bacteria on the surface of the adsorbent had lost their basic morphology, proving that all the bacteria were dead. The above proves that the sulfonium salt cationic adsorbent in Example 11 has both bacterial adsorption capacity and bactericidal performance.

[0337] (2.4) Stability

[0338] The test was carried out according to the test method in Example 1. The results showed that the 24-hour dissolution rate was only 0.25%, showing excellent stability.

[0339] Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the method of the present invention and its core ideas, including the best mode, and also enable any technician in the field to practice the present invention, including making and using any device or system, and implementing any combined method. It should be pointed out that for ordinary technicians in this technical field, without departing from the principle of the present invention, the present invention can also be improved and modified, and these improvements and modifications also fall within the scope of protection of the claims of the present invention. The scope of patent protection of the present invention is defined by the claims and may include other embodiments that can be thought of by those skilled in the art. If these other embodiments have structural elements similar to the literal expression of the claims, or if they include equivalent structural elements that are not substantially different from the literal expression of the claims, then these other embodiments should also be included in the scope of the claims.

Claims

1. A method for preparing a sulfonium salt cationic adsorbent, characterized in that: The following steps are involved: S1: Under the action of the initiator, the methionine monomer undergoes a ring-opening polymerization reaction to form a methionine polymer; in, The methionine monomer is at least one of D,L-methionine, D-methionine and L-methionine; The methionine polymer is at least one of formula (1-1), formula (1-2) and formula (1-3): S2: cross-linking the methionine polymer with a halogen-containing compound to obtain a sulfonium salt cationic adsorbent; in, The halogen-containing compound is selected from at least one of formulas a1 to a13: In the above formulas a1 to a13, the multiple X in each compound are independently selected from: I, Br, Cl or epoxy group, and the multiple X in each compound are not epoxy groups at the same time; Or including the following steps: K1: Under the action of the initiator, the methionine monomer undergoes a ring-opening polymerization reaction to form a methionine polymer; in, The methionine monomer is at least one of D,L-methionine, D-methionine and L-methionine; The methionine polymer is at least one of formula (1-1), formula (1-2) and formula (1-3): K2: reacting the methionine polymer with a compound containing a functional group to obtain a methionine polymer modified substance; in, The compound containing a functional group is selected from at least one of iodoacetic acid, iodoacetylene, 4-(2-bromoethyl)phenylboronic acid, allyl iodide and trifluoromethanesulfonate azide; The methionine polymer modified substance is selected from at least one of formula (1-1-1) to formula (1-3-5): K3: mixing the methionine polymer modified substance with the object to be combined to obtain a sulfonium salt cation adsorbent; in, The object to be combined is a cross-linkable compound or a loadable matrix; The cross-linkable compound is at least one of a polyhydroxy compound, a polyamine compound and a compound containing multiple double bonds; The loadable matrix is ​​at least one of polymer microspheres, molecular sieves and magnetic beads.

2. The preparation method according to claim 1, characterized in that: In step S2, the halogen-containing compound is selected from at least one of 1,3,5-tribromobenzene, 1,4-bis(bromomethyl)-2,5-diiodobenzene, 1,3,4,6-tetrabromobenzene, 1,3,4,5,6-pentabromobenzene, perbromobenzene, 1,3,5-tri(bromomethyl)benzene, hexaperbromomethylbenzene, 1,4-dibromo-2,5-bis(bromomethyl)benzene, iodoform and tetrabromomethane; In step K3, the cross-linkable compound is selected from at least one of branched polyethyleneimine and polydipentaerythritol hexaacrylate; The polymer microspheres are at least one of polystyrene microspheres and polyvinyl alcohol microspheres.

3. The preparation method according to claim 1, characterized in that: In step S1, the initiator is at least one of a monoamine-containing compound, a hexamethylsilylamine-containing lithium compound and a tertiary amine-containing compound; In step K1, the initiator is at least one of a monoamine-containing compound, a hexamethylsilylamine-containing lithium compound and a tertiary amine-containing compound.

4. The preparation method according to claim 1 or 3, characterized in that: In step S1, the initiator is at least one of n-hexylamine, lithium bis(trimethylsilyl)amide, ethylenediamine, butanediamine, aniline and dendritic polyamide; In step K1, the initiator is at least one of n-hexylamine, lithium bis(trimethylsilyl)amide, ethylenediamine, butanediamine, aniline and dendritic polyamide.

5. The preparation method according to claim 1, characterized in that: In step S1, the temperature of the ring-opening polymerization reaction is 15 to 60° C., and the time is 2 to 48 hours; In step K1, the temperature of the ring-opening polymerization reaction is 20 to 60° C., and the time is 12 to 48 hours.

6. The preparation method according to claim 1, characterized in that: In step S2, the molar ratio of the methionine unit in the methionine polymer to the halogen group in the halogen-containing compound is 1:(0.5-3); In step K2, the molar ratio of the methionine unit in the methionine polymer to the functional group in the compound containing the functional group is 1:(1-3).

7. The preparation method according to claim 1, characterized in that: In step S2, the cross-linking reaction temperature is 15 to 50° C. and the time is 4 to 48 hours; In step K2, the reaction temperature is 20 to 60° C. and the reaction time is 12 to 36 hours; In step K3, the mass ratio of the methionine polymer modified substance to the substrate is 1:(0.1-1); In step K3, the reaction temperature is 30-60° C. and the reaction time is 8-48 hours.

8. The preparation method according to claim 1, characterized in that: In step S1, the ring-opening polymerization reaction is carried out in a solvent; wherein the solvent is selected from at least one of tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile and dichloromethane; In step S2, the cross-linking reaction is carried out in a solvent; wherein the solvent is selected from at least one of water, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and tetrahydrofuran; In step K1, the ring-opening polymerization reaction is carried out in a solvent; wherein the solvent is selected from at least one of tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile and dichloromethane.

9. A sulfonium salt cation adsorbent obtained by the preparation method according to any one of claims 1 to 8.

10. Use of the sulfonium salt cationic adsorbent according to claim 9 in preparing a material for rapid adsorption of bacteria in blood.

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