CN102247817B - Endotoxin adsorbent using molecular cluster as functional group and preparation method thereof - Google Patents
Endotoxin adsorbent using molecular cluster as functional group and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an endotoxin adsorbent using a molecular cluster as a functional group and a preparation method thereof, and belongs to the fields of bioseparation and biomedical engineering. By taking agarose gel as a vector, the endotoxin adsorbent is subjected to epoxy activation to be directly coupled with a molecular sieve frame epsilon-polylysine or polyaspartic acid, then the coupled mixture is ingrafted with micromolecular lysine or lycine by virtue of a condensation reaction to prepare the adsorbent. The adsorbent prepared by the method has higher removal rate to endotoxin in serum of a human, but adsorbs less serum protein. Meanwhile, the preparation process of the adsorbent has the advantages of mild conditions, fewer synthesis steps and relatively low material cost.
Description
Technical field
The invention belongs to bio-separation and biomedical engineering field, specially refer to that a kind of what be used for endotoxemia treatment is endotoxin absorbent of functional group and preparation method thereof with the molecular cluster.
Background technology
Endotoxin claims that again (Lipopolysaccharides LPS), is the part of Gram-negative bacteria epicyte to lipopolysaccharides.In the normal human, thereby a certain amount of endotoxin can be made the endotoxin content in the blood remain on reduced levels by hepatic clearance.If liver function is badly damaged or endotoxic content has surpassed the detoxification ability of liver, just can get into body-internal-circulation through the endotoxin of intestinal absorption through liver, the formation endotoxemia, and then cause multiple organ failure even death.It is reported that the U.S. has at least the hundreds of thousands people to suffer from endotoxemia every year, its fatal rate can reach 40%-90%, and the number that Japan dies from endotoxemia every year is 3-5 ten thousand people.Therefore, develop the excessive endotoxic method in the patient blood of efficiently to remove, major and immediate significance will be arranged the life of saving the endotoxemia patient.
Up to now, to endotoxic removal, various research reports have been arranged.Direct treatment removal that mainly concentrates on the antiendotoxin medicine and the blood perfusion in the blood purification therapy that research at present is more are removed.
The antiendotoxin drug main will comprise: lipoid A antagonist, PB, antiendotoxin albumen and polypeptide and endotoxin antibody etc.Lipoid A is toxicity and the biological active center of LPS, and Loppbow etc. discover, the toxic reaction that its biosynthesis precursor substance and nontoxic lipoid A derivative all can antagonism LPS.PB has very strong binding ability as a kind of antibiotic to endotoxin, but it is to central nervous system and the toxic effect of kidney, can not direct drug injection.(JD Renet al.Int Immunopharmacol.2008 Jun such as Jian-Dong Ren; 8 (6): (CRKPTFRRLKWKIKFKFKC CLP-19), realizes electronegative endotoxic removal by positive charge amino acid and circulus 775-81.Epub 2008 Feb 25.) to have synthesized a kind of cyclic peptide.Mouse experiment shows that the mouse survival rate of endotoxemia is 60-80%.US6395717B1 discloses a kind of sialic acid and polymer thereof the result of treatment to the mouse endotoxemia; The mouse survival rate is more than 80%, and this medicine compares with traditional antibiotic therapy, and body can not develop immunity to drugs; Security is higher, but itself and the endotoxic mechanism of action are still indeterminate.
In addition, research shows that phosphatide complexes, lipid A analogue, algae lipopolysaccharides etc. all have neutralization in various degree to endotoxin.More than these all are to the hydrophobicity of the elecrtonegativity of phosphate in the endotoxin molecule or aliphatic chain and designed molecules, but since these molecule synthesis expensive therefore also have for a long time from clinical practice.
Endotoxin antibody comprises that mainly the monoclonal antibody of antiendotoxic polyclonal antibody, antilipoid A, antiendotoxin combine protein antibodies, antiendotoxin acceptor CD14 etc.But these antibody face equally preparation difficulty, cost high, have the bacterium species specificity, cause allergic reaction and problem such as may be in the immune system of patient's damage ineffective easily.
The blood purification therapy has unique curative effect for some great difficult and complicated illness, and hemoperfusion wherein is owing to its lower expense receives researcher's extensive concern.This therapy mainly is based on the specific function base molecule of adsorbent and the physical chemistry of toxicity molecule interacts, and removes the poisonous or morbid substance in the blood through absorption, and then reaches the purpose that purifies the blood and treat disease.Traditional activated carbon, macroreticular resin class adsorbent do not have adsorptive selectivity to the blood endotoxin, and blood compatibility is relatively poor, and removal effect is not obvious.Therefore, the development of new and effective endotoxin absorbent and clinical practice are extremely urgent.
PB is because its good anti-microbial property receives researcher's concern always.In order to solve neurotoxicity and the Toxicity of Kidney problem that direct drug injection exists, a lot of scholars consider to be fixed in to process different types of sorbing material on the various carriers.Aoki in 1994 etc. are fixed on PB first and are used for treating endotoxemia on the fiber carrier.Japan Toray Industried Inc has been fixed to PB and has processed absorption carrier-PB fibre columns on the fiber, and has realized commercialization production (PMX-F, trade name Toraymyxin).
It is carrier with the agarose that Nankai University (Chinese patent CN1493368A) discloses a kind of; Coupling PB, α-polylysine (Mr=10 behind epoxy activation, amination, glutaraldehyde cross-linking; 000-40; 000Da) wait aglucon to make a series of adsorbents that plasma endotoxin is removed that are used for, blood compatibility is good, and removal effect is better.But this adsorbent synthesis step is more, and PB aglucon price is more expensive, will cause potential danger to patient's nerve and kidney in case come off.In addition, there is research (D.Petsch, F.B.Anspach:Journal of Biotechnology 76 (2000) 97-119) to show that PB also has the absorption about 20% to BSA.Comparatively speaking, though α-polylysine is less to BSA absorption, it is expensive (7,000RMB/g).More than these deficiencies limited the adsorbent extensive use clinically of PB and α-polylysine as aglucon.
In addition; In order to improve adsorbent to endotoxic selectivity; It is carrier with Ago-Gel etc. that U.S. Pat 2005/0238641A1 discloses a kind of, and the epoxychloropropane activation connects the adsorbent of branch's aglucon (three (2-amino-ethyl) amine) gained; Higher to the endotoxin clearance in containing endotoxic HSA solution, and to the adsorbance of HSA seldom.But the removal effect in the actual endotoxin blood plasma is not appeared in the newspapers, and the adsorbent that only in actual plasma (or serum), has a good clearance just has potential clinical value.
Therefore, in order to solve preparation difficulties such as (1) antiendotoxin medicine of existing in the research of present endotoxin removal and α-polylysine, cost an arm and a leg; (2) the potential toxicity hidden danger of PB; Defective such as (3) traditional blood perfusion adsorbent blood compatibility is poor, selectivity is not high and removal effect is undesirable the invention provides a kind of cheapness, endotoxin absorbent and preparation method thereof efficiently, is expected to be used for the clinical treatment of endotoxemia.
Summary of the invention
The invention provides a kind of is the endotoxin absorbent and preparation method thereof of functional group with the molecular cluster.Design of the present invention is: with blood compatibility preferably Ago-Gel be matrix; Through direct after the epoxy activation and nontoxic, inexpensive epsilon-polylysine or poly-aspartate coupling; Molecular cluster effect by macromolecule polyalcohol; The grafting little molecule lysine or the betaine that can mainly combine with the endotoxin molecule again through electrostatic interaction; The adsorbent of density through the control loop oxygen activation and the synthetic difference in functionality base density of the addition of molecular cluster functional group is to reach endotoxic selective removal effect in the serum.
Technical scheme of the present invention is following:
A kind of is the endotoxin absorbent of functional group with the molecular cluster; By solid-phase matrix Ago-Gel and functional group molecular composition; This adsorbent by epsilon-polylysine or poly-aspartate as the functional group molecule of the skeleton, through forming the molecular cluster functional group of endotoxin absorbent with the coupling of lysine or betaine.The molecular weight of described epsilon-polylysine is 3600-4300Da, and the molecular weight of poly-aspartate is 1000-5000Da.
Preparing above-mentioned endotoxin absorbent comprises the steps:
(1) epoxychloropropane activated agarose gel: the epoxychloropropane addition is the 0.01-0.04ml/ml gel, and system NaOH concentration is 0.4M, 40 ℃ of 170rpm oscillating reactions 1-2h;
(2) coupling of molecular cluster skeleton: epsilon-polylysine or poly-aspartate addition 0.06-0.4g/ml gel, pH 9-11,50-60 ℃ of 300rpm stirring reaction 3-4h;
(3) epsilon-polylysine coupling lysine or betaine: lysine or betaine addition 0.01-0.02g/ml gel, pH4.5-7.5,37 ℃ of 170rpm oscillating reactions 3-4h;
(4) poly-aspartate coupling lysine or betaine: poly-aspartate is that the addition of ethylenediamine is the 0.1-0.2ml/ml gel through connecing arm reactive grafting ethylenediamine spacerarm, connecing the arm condition earlier, pH4.5-7.5,37 ℃ of 170rpm oscillating reactions 3-4h; Coupling lysine or betaine again, coupling condition is lysine or betaine 0.01-0.02g/ml gel, pH4.5-7.5,37 ℃ of 170rpm oscillating reactions 3-4h.
Described Ago-Gel is a 1-10 μ mol/ml gel through the density of epoxychloropropane activation, and the coupling density of lysine or betaine is 10-100 μ mol/ml gel.
Described endotoxin absorbent after the former processing of reducing phlegm and internal heat, with contain the endotoxic human serum of 1-5EU/ml mix by a certain percentage (1: 5-1: 10), Static Adsorption 2-3h, the endotoxin removal rate is 35%-65%, the haemocyanin adsorption rate is within 20%.
The invention has the beneficial effects as follows:
1, adopt blood compatibility good, the Ago-Gel Sepharose CL-6B that physicochemical property is stable is a matrix, connects micromolecular method again through direct coupling molecule bunch skeleton after the epoxy activation and prepares endotoxin absorbent.The present invention has overcome the toxicity and the unstability of cyanogen bromide method; Thereby the ester bond that the carbonyl dimidazoles method forms may rupture in acid, alkali treatment and cause the risk that aglucon comes off; The shortcoming that the relative step of glutaraldehyde bonding method is more.Preparation process organic solvent uses less, has increased the security of preparation, and reaction condition is gentle, and step is simple.
2, on the Ago-Gel Sepharose CL-6B but a large amount of activated groups is arranged, through the addition of control epoxychloropropane can the control loop oxygen activation density; Addition and reaction temperature through control epsilon-polylysine and poly-aspartate can obtain the endotoxin absorbent of the terminal functional group of coupling different densities, thereby optionally remove the endotoxin in the serum.
3, the epsilon-polylysine or the poly-aspartate that have the molecular cluster effect; Rely on the lower problem of material coupling density after the carboxyl of amino or the aspartic acid of a plurality of lysine residues in its each molecule can solve the epoxy activation, and the molecular cluster effect that forms of a plurality of amino or carboxyl can be through multiple spot effect and the firm relatively effect of the big molecule generation of endotoxin after connecting little molecule lysine or betaine.
4, used epsilon-polylysine, poly-aspartate, lysine and the betaine molecule of this endotoxin absorbent compared cheap and easy to get with PB with α-polylysine.Epsilon-polylysine wherein and poly-aspartate are nontoxic, degradable environmentally friendly macromolecular compound, and heat endurance is high.
The specific embodiment
Be described in detail specific embodiment of the present invention below in conjunction with technical scheme.
Embodiment 1: epsilon-polylysine coupling lysine is as the adsorbent preparation of molecular cluster functional group
(1) epoxychloropropane activated agarose gel
Get the Sepharose CL-6B gel after 10ml cleans, joining 10ml epoxychloropropane concentration is that 1% (v/v), NaOH concentration are in the aqueous solution of 0.4M, 40 ℃ of shaking table 170rpm oscillating reactions 2h, and reaction finishes with till washed with de-ionized water gel to the neutrality;
(2) coupling of epsilon-polylysine
Preparation 10ml concentration is that 6% (w/v), pH are 11 the epsilon-polylysine aqueous solution, the gel in the adding after the intact cleaning of single step reaction, and 50 ℃ of outstanding oar stirring reaction 3-4h of 300rpm, the gel after having reacted fully cleans with deionized water;
(3) terminal functional group lysine is fixing
At 10ml pH is the lysine that adds certain mass in 4.8 the MES buffer solution; Making its concentration is 1% (w/v), and the gel that will go up then after single step reaction finishes adds wherein, regulates pH to 4.8; Add 0.2g 1-ethyl-3-(3-dimethylaminopropyl)-phosphinylidyne diimine (EDC) condensing agent again; 37 ℃, 170rpm oscillating reactions 4h, reaction finishes the back fully cleans with deionized water, promptly obtains final endotoxin absorbent 1.
Embodiment 2: epsilon-polylysine coupling betaine is as the adsorbent preparation of molecular cluster functional group
The epsilon-polylysine end meets the preparation method of endotoxin absorbent 2 of betaine with embodiment 1, only needs change the lysine in the step (3) into betaine, and all the other Step By Conditions are all constant.
Embodiment 3: poly-aspartate coupling lysine is as the adsorbent preparation of molecular cluster functional group
Poly-aspartate coupling lysine comprises four steps as the preparation method of the adsorbent 3 of molecular cluster functional group; Preceding two steps are with (1) among the embodiment 1 and (2); Only need change the epsilon-polylysine in (2) into poly-aspartate, all the other conditions are all constant, step (3) and (4) as follows:
(3) connection of spacerarm
At 10ml pH is the ethylenediamine that adds certain volume in 4.8 the MES buffer solution; Making its concentration is 10% (v/v); The gel that to go up then after single step reaction finishes adds wherein, regulates pH to 4.8, adds 0.2g EDC condensing agent again; 37 ℃, 170rpm oscillating reactions 4h, reaction finishes the back and fully cleans with deionized water;
(4) terminal functional group lysine is fixing
At 10ml pH is the lysine that adds certain mass in 4.8 the MES buffer solution, and making its concentration is 1% (w/v), will go up the gel of single step reaction after intact then and add wherein, regulates pH to 4.8, adds the 0.2gEDC condensing agent again, 37 ℃, 170rpm oscillating reactions 4h.Reaction finishes the back fully cleans with deionized water, promptly obtains final endotoxin absorbent 3.
Embodiment 4: poly-aspartate coupling betaine is as the adsorbent preparation of molecular cluster functional group
The poly-aspartate end meets the preparation method of endotoxin absorbent 4 of betaine with embodiment 3, only needs change the lysine in the step (4) into betaine, and all the other Step By Conditions are all constant.
Embodiment 5: the former processing of reducing phlegm and internal heat of sorbing material and experiment utensil
Used all material and the utensil former processing of all need reducing phlegm and internal heat in the experiment: teat glass cleans up repeatedly and is placed on 250 ℃ of baking ovens and does more than the roasting 2h; Plastic centrifuge tube spends the night through 30% hydrogen peroxide dipping, then with repeatedly back oven dry of apirogen water flushing; Adsorbent earlier with physiological saline drip washing repeatedly passes through 0.2M NaOH (containing 20% ethanol), 1.5M NaOH drip washing then successively, washes till the neutrality with physiological saline, apirogen water at last.
Embodiment 6: endotoxic Static Adsorption is removed in the human serum
Terminal functional group density after removing pyrogen and handling is the adsorbent 1-4 of 10 μ mol/ml, and contains the endotoxic human serum of 1.95EU/ml and mixes in 1: 5 by volume, places the shaking table Static Adsorption 3h of 37 ℃ of 200rpm.The centrifuging and taking supernatant is surveyed residue endotoxin concns and protein concentration, calculates the adsorption rate of four kinds of adsorbents to endotoxic clearance and albumen respectively.
Table 1 is that terminal functional group density is the adsorption rate of the endotoxin absorbent of 10 μ mol/ml to endotoxic clearance and main protein in the human serum.It is 1.95EU/ml that the result is illustrated in the endotoxin initial concentration; Total serum protein and albumin concentration are respectively under the condition of 60.23g/L and 41.67g/L; Between 48%-53%, and the adsorption rate of haemocyanin is within 15% to endotoxic clearance for four kinds of endotoxin absorbents.
Table 1: the adsorption effect of endotoxin and albumen in the human serum
Embodiment 7: the adsorbent of difference in functionality base density (5-14) is to endotoxic static removal effect in the human serum
Synthesize lysine (adsorbent 5-9) and the betaine adsorbent (adsorbent 10-14) that terminal coupling density is respectively 10 μ mol/ml, 37 μ mol/ml, 52 μ mol/ml, 81 μ mol/ml and 100 μ mol/ml through the addition (1%-4% (v/v)) of control epoxychloropropane and the addition (6%-40% (w/v)) of epsilon-polylysine, method is with embodiment 1 and 2.The gained adsorbent is that the serum of 3.81EU/ml mixed in 1: 5 by volume with the endotoxin initial concentration respectively after the former processing of reducing phlegm and internal heat, and surveys the endotoxin concns in the supernatant after the Static Adsorption, calculates the different densities adsorbent to endotoxic clearance.
The adsorbent (15-24) of embodiment 8 difference in functionality base densities is to endotoxic static removal effect in the human serum
Synthesize lysine (adsorbent 15-19) and the betaine adsorbent (adsorbent 20-24) that terminal coupling density is respectively 10 μ mol/ml, 37 μ mol/ml, 52 μ mol/ml, 81 μ mol/ml and 100 μ mol/ml through the addition (1%-4% (v/v)) of control epoxychloropropane and the addition (6%-40% (w/v)) of poly-aspartate, method is with embodiment 3 and 4.The gained adsorbent is that the serum of 3.81EU/ml mixed in 1: 5 by volume with the endotoxin initial concentration respectively after the former processing of reducing phlegm and internal heat, and surveys the endotoxin concns in the supernatant after the Static Adsorption, calculates the different densities adsorbent to endotoxic clearance.
Various adsorbents were to endotoxic removal effect when table 2 was the difference in functionality base density.The synthetic terminal coupling density of addition through control loop oxygen activation density and epsilon-polylysine or poly-aspartate is respectively lysine or the betaine adsorbent of 10 μ mol/ml, 37 μ mol/ml, 52 μ mol/ml, 81 μ mol/ml and 100 μ mol/ml, in the endotoxin initial concentration is the serum of 3.81EU/ml, investigates the influence of functional group density to the endotoxin removal effect.The result is illustrated under certain endotoxin concns, and along with the raising of functional group density, different adsorbents all increase endotoxic clearance to some extent.
Table 2: the adsorbent of difference in functionality base density is to endotoxic removal effect in the human serum
Claims (3)
1. one kind is the endotoxin absorbent of functional group with the molecular cluster; Form by solid-phase matrix Ago-Gel and molecular cluster functional group; It is characterized in that this adsorbent by epsilon-polylysine or poly-aspartate as the functional group molecule of the skeleton, through forming the molecular cluster functional group of endotoxin absorbent with the coupling of lysine or betaine; The molecular weight of epsilon-polylysine is 3600-4300Da, and the molecular weight of poly-aspartate is 1000-5000Da; Ago-Gel is a 1-10 μ mol/ml gel through the density of epoxychloropropane activation, and the coupling density of lysine or betaine is 10-100 μ mol/ml gel.
2. the preparation method of the said endotoxin absorbent of claim 1 is characterized in that following steps:
(1) epoxychloropropane activated agarose gel: epoxychloropropane is the 0.01-0.04ml/ml gel, and system NaOH concentration is 0.4M, 40 ℃ of 170rpm oscillating reactions 1-2h;
(2) epsilon-polylysine or poly-aspartate and epoxy activated agarose gel: epsilon-polylysine or poly-aspartate addition 0.06-0.4g/ml gel, pH 9-11,50-60 ℃ of 300rpm stirring reaction 3-4h;
(3) fixedly lysine or betaine on the epsilon-polylysine skeleton: lysine or betaine 0.01-0.02g/ml gel, pH4.5-7.5,37 ℃ of 170rpm oscillating reactions 3-4h;
Fixedly lysine or betaine on the poly-aspartate skeleton: poly-aspartate is that ethylenediamine is the 0.1-0.2ml/ml gel through connecing arm reactive grafting ethylenediamine spacerarm, connecing the arm condition earlier, pH4.5-7.5,37 ℃ of 170rpm oscillating reactions 3-4h; Coupling lysine or betaine again, coupling condition is lysine or betaine 0.01-0.02g/ml gel, pH4.5-7.5,37 ℃ of 170rpm oscillating reactions 3-4h.
3. the application of claim 1 or 2 said endotoxin absorbents; It is characterized in that: adsorbent after the former processing of reducing phlegm and internal heat, with contain the endotoxic human serum of 1-5EU/ml in proportion 1:5-1:10 mix Static Adsorption 2-3h; The endotoxin removal rate is 35%-65%, and the haemocyanin adsorption rate is within 20%.
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| CN102580683B (en) * | 2012-02-03 | 2014-07-30 | 珠海健帆生物科技股份有限公司 | Endotoxin synergistic adsorbent and preparation method thereof |
| CN105195114B (en) | 2015-10-29 | 2017-08-25 | 重庆郑博生物科技有限公司 | Sorbing material of a variety of virulence factors of pyemia and its production and use |
| EP3463646A4 (en) | 2016-05-26 | 2020-01-08 | Cytosorbents Corporation | The use of a hemocompatible porous polymer bead sorbent for removal of endotoxemia-inducing molecules |
| CN114200126A (en) * | 2021-12-09 | 2022-03-18 | 牟奕 | Solid phase matrix for detecting N-type penicillin and cephalosporin antibiotic antibodies and preparation method thereof |
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Effective date of registration: 20171026 Address after: 116000 Liaoning city of Dalian province Qixianling torch hi tech Park Road 43, two floor room 212 Patentee after: Kang Yuan medical science and Technology (Dalian) Co., Ltd. Address before: 116100 No. 2 Ling Road, Ganjingzi District, Liaoning, Dalian Patentee before: Dalian University of Technology |