CN114835826A - Zwitterionic cellulose and preparation method and application thereof - Google Patents
Zwitterionic cellulose and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses zwitterionic cellulose and a preparation method and application thereof. The preparation method comprises the following steps: s1, carrying out Michael addition reaction on the mercapto acid compound and the sulfamic acid inner salt containing the carbon-carbon double bond to obtain a zwitterionic intermediate; s2, grafting the zwitterionic intermediate prepared in the previous operation on cellulose in a homogeneous system to obtain the zwitterionic cellulose. The invention grafts the zwitterion on the cellulose in homogeneous phase to prepare the zwitterion cellulose, and has the characteristic of good grafting effect.
Description
Technical Field
The invention belongs to the technical field of zwitterionic materials, and particularly relates to zwitterionic cellulose and a preparation method and application thereof.
Background
Cellulose is a renewable resource with the widest distribution and the largest yield in nature, and has the characteristics of biodegradability, biocompatibility, derivatization and the like. However, the high crystallinity of cellulose macromolecules causes the cellulose macromolecules to be difficult to dissolve and infusible, and the development and the utilization of the cellulose macromolecules as basic raw materials are restricted. Therefore, the water solubility and the oil solubility of the cellulose are improved through the derivatization of the cellulose, and abundant cellulose resources can be better developed. Wherein, the zwitterion cellulose is a derivative of cellulose, and the zwitterion can be connected with hydroxyl on the cellulose through chemical reaction. The zwitterion cellulose has the same number of positive and negative charges while keeping the original excellent properties of the cellulose, the whole body is electrically neutral, and a large number of water molecules are strongly adsorbed around the positive and negative ions to form a hydration layer. The hydration layer can prevent the adsorption of protein, bacteria and the like on the surface of the hydration layer, so that the zwitterionic cellulose has superior biocompatibility than natural cellulose. However, most of the existing methods for preparing zwitterionic cellulose are surface-modified cellulose grafted with zwitterions, and the grafting effect is poor.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the invention provides a preparation method of zwitterionic cellulose, which is characterized in that zwitterions are grafted on cellulose in a homogeneous phase to prepare the zwitterionic cellulose and the grafting effect is good.
The invention also provides a preparation method of the zwitterionic cellulose.
The invention also provides the zwitterionic cellulose prepared by the preparation method.
The invention also provides a cellulose gel.
The invention also provides a biological material.
The invention also provides application of the zwitterionic cellulose.
In a first aspect of the present invention, a method for preparing zwitterionic cellulose is provided, which comprises the following steps:
s1, carrying out Michael addition reaction on the mercapto acid compound and the sulfamic acid inner salt containing the carbon-carbon double bond to obtain a zwitterionic intermediate;
s2, grafting the zwitterionic intermediate prepared in the previous operation on cellulose in a homogeneous system to obtain the zwitterionic cellulose.
The preparation method of the zwitterionic cellulose provided by the embodiment of the invention has at least the following beneficial effects: the prepared zwitterion cellulose is prepared by grafting zwitterion intermediates onto cellulose in a homogeneous system, which is different from the conventional zwitterion cellulose prepared by grafting zwitterions on the surface of cellulose through modification.
The invention adopts simple and efficient two-step reaction, has high reaction activity, simple reaction condition and low cost, wherein, the reaction of sulfydryl and carbon-carbon double bond belongs to the Michael addition reaction type in click reaction, and has the characteristics of high efficiency, atom economy and mild condition. In addition, the method grafts the cellulose in a homogeneous phase, the selected solvent system is matched with a cellulose dissolving system, the reaction phenomenon is obvious, the obtained zwitterion cellulose is precipitated and separated out, and the reaction condition can be judged without a complicated detection means. The prepared zwitterionic cellulose has more various application modes than surface modification, not only can be used as an anti-adhesion coating, but also can be compounded with other natural biomedical materials to prepare cellulose gel.
In some embodiments of the present invention, the raw material is dehydrated and then used in the preparation method.
In some embodiments of the invention, the homogeneous system comprises a solvent system comprising dimethylacetamide or an ionic liquid system.
Dimethylacetamide, abbreviated DMAc.
In some preferred embodiments of the invention, the ionic liquid comprises BMIMCl, BMIMBr or BMIM-BF 4 At least one of (1).
BMIMCl: 1-butyl-3-methylimidazolium chloride salt; BMIMBr: 1-butyl-3-methylimidazolium bromide; BMIM-BF 4 : 1-butyl-3-methylimidazolium tetrafluoroborateAn acid salt.
In some embodiments of the invention, the zwitterionic cellulose produced has a degree of substitution of from 0.6 to 0.9.
In some embodiments of the invention, the cellulose comprises at least one of lyocell, purified cotton, modal, cuprammonium or viscose.
In some preferred embodiments of the invention, the cellulose comprises lyocell fibers.
With the above embodiment, the cellulose is lyocell. When dissolved, the lyocell solution is more uniform, showing that the solution is clear and transparent; further providing a uniform reaction environment for the next reaction, and the reaction effect is better.
In some embodiments of the present invention, the mercapto acid compound includes at least one of a mercapto fatty acid and a mercapto aromatic acid.
In some preferred embodiments of the present invention, the mercapto acid compound includes at least one of mercaptopropionic acid, mercaptobutyric acid, mercaptopentanoic acid, mercaptohexanoic acid, mercaptobenzoic acid, mercaptophenylacetic acid, or mercaptophenylpropionic acid.
In some more preferred embodiments of the present invention, the mercaptoacid-based compound comprises at least one of mercaptopropionic acid, mercaptobutyric acid, mercaptopentanoic acid, or mercaptohexanoic acid.
In some more preferred embodiments of the present invention, the mercaptoacid based compound comprises at least one of 3-mercaptopropionic acid, 2-mercaptopropionic acid, 4-mercaptobutyric acid, 3-mercaptobutyric acid, or 2-mercaptobutyric acid.
Wherein, 3-mercaptopropionic acid is abbreviated as 3-MPA; o-mercaptobenzoic acid, also known as thiosalicylic acid, abbreviated TSA.
In some embodiments of the invention, the carbon-carbon double bond in the internal salt of sulfamic acid containing carbon-carbon double bonds is located at the end of the internal salt of sulfamic acid.
In some preferred embodiments of the invention, the sulfamate inner salt containing a carbon-carbon double bond further comprises a carbonyl group, the carbon-carbon double bond being conjugated to the carbonyl group.
In some preferred embodiments of the invention, the carbon-carbon double bond in the internal salt of sulfamic acid containing carbon-carbon double bonds is located at the end of the internal salt of sulfamic acid remote from the sulfobetaine group.
In some preferred embodiments of the invention, the sulfonate betaine group comprises
In some preferred embodiments of the present invention, the internal salt of sulfamic acid containing carbon-carbon double bonds comprises at least one of an internal salt of aminopropanesulfonic acid containing carbon-carbon double bonds, an internal salt of sulfamic acid containing carbon-carbon double bonds, or an internal salt of aminopentanesulfonic acid containing carbon-carbon double bonds.
In some preferred embodiments of the invention, the internal salt of aminopropanesulfonic acid containing a carbon-carbon double bond comprises at least one of an internal salt of N, N-dimethyl (methacryloyloxyethyl) aminopropanesulfonic acid or an internal salt of N, N-dimethyl (methacryloyloxypropyl) aminopropanesulfonic acid.
Among them, N, N-dimethyl (methacryloyloxyethyl) aminopropanesulfonic acid inner salt is abbreviated as DMAPS.
In some embodiments of the invention, the molar ratio of the mercapto acid compound to the internal salt of aminopropanesulfonic acid containing carbon-carbon double bonds is 1: (1-1.2).
In some embodiments of the invention, the molar ratio of the cellulose anhydroglucose units to the mercaptoacid-based compound is 1: (3-15).
In some embodiments of the invention, the molar ratio of the cellulose anhydroglucose units to the mercaptoacid compounds is from about 1: 8.
in some embodiments of the present invention, step S1 includes the following steps: DBU is added into mixed liquid of the mercapto acid compound and the sulfamic acid inner salt containing carbon-carbon double bonds, and the mixture is subjected to a dark reaction in a protective atmosphere to obtain a zwitterionic intermediate, wherein the zwitterionic intermediate is a zwitterionic carboxylic acid intermediate.
Abbreviated DBU: 1, 8-diazabicyclo [5.4.0] undec-7-ene.
In some preferred embodiments of the present invention, the molar ratio of the DBU to the mercaptoacid compound is (4-6): 100.
in some preferred embodiments of the present invention, in step S1, the solvent in the mixture solution of the mercapto acid compound and the carbon-carbon double bond-containing sulfamic acid inner salt is prepared to include dimethylacetamide.
Before the use of the dimethylacetamide, the product is dried for at least 12h by using a 4A molecular sieve.
In some more preferred embodiments of the present invention, in step S1, the solvent in the mixture solution of the mercapto acid compound and the internal salt of sulfamic acid containing a carbon-carbon double bond further includes at least one of N, N-dimethylformamide, dimethylsulfoxide, or N-methylpyrrolidone.
N, N-dimethylformamide, abbreviated DMF; dimethyl sulfoxide, abbreviated as DMSO.
In some more preferred embodiments of the present invention, in step S1, DBU is added to the mixture of 3-mercaptopropionic acid and N, N-dimethyl (methacryloyloxyethyl) aminopropanesulfonic acid inner salt, and the mixture is reacted at 40 to 50 ℃ for 24 hours in an inert gas atmosphere under dark conditions to obtain a zwitterionic carboxylic acid intermediate.
In some embodiments of the invention, in step S2, the zwitterionic intermediate is grafted onto the cellulose by an esterification reaction between carboxyl groups on the zwitterionic intermediate and hydroxyl groups on the cellulose.
Wherein the carboxyl is derived from the mercapto acid compound.
In some preferred embodiments of the invention, the zwitterionic intermediate is a zwitterionic carboxylic acid intermediate.
In some more preferred embodiments of the present invention, in step S2, after the zwitterionic carboxylic acid intermediate is subjected to carboxyl group activation treatment, the carboxyl group on the zwitterionic carboxylic acid intermediate undergoes esterification with the hydroxyl group on the cellulose, so that the zwitterionic intermediate is grafted to the cellulose.
In some more preferred embodiments of the present invention, the carboxyl activating agent used in the carboxyl activating treatment comprises N, N' -carbonyldiimidazole.
N, N' -carbonyldiimidazole, abbreviated CDI.
In some more preferred embodiments of the present invention, in step S2, the zwitterionic carboxylic acid intermediate is subjected to carboxyl activation treatment, mixed with a cellulose solution, heated in a protective atmosphere, and reacted to obtain the zwitterionic cellulose.
In some more preferred embodiments of the present invention, in step S2, the zwitterionic carboxylic acid intermediate and the cellulose solution are mixed, heated to 50-60 ℃ in an inert gas atmosphere, reacted for 12-24h, separated and purified to obtain the zwitterionic cellulose.
In some more preferred embodiments of the present invention, in step S2, the separation and purification step includes: after the zwitterionic carboxylic acid intermediate and the cellulose solution are mixed and reacted, the reaction solution is centrifuged, the supernatant is removed to obtain a solid, and the solid is washed by ethanol, dialyzed and freeze-dried.
In some more preferred embodiments of the present invention, the dialysis time is at least 3 days in step S2.
In some more preferred embodiments of the present invention, the cellulose comprises lyocell fibers, and the step of formulating the cellulose solution comprises: heating and soaking a mixture of the lyocell fibers and dimethylacetamide in a protective atmosphere, adding lithium chloride, stirring, cooling, and dissolving the lyocell fibers to obtain a lyocell fiber solution.
Before the lithium chloride is used, the lithium chloride is dried in a vacuum box at 120 ℃ for 2 hours. Before the use of the dimethylacetamide, the product is dried for 12h by using a 4A molecular sieve.
In some more preferred embodiments of the present invention, the step of formulating the cellulose solution comprises: heating a mixture of 0.83-1.75g of lyocell fiber and 80mL of dimethylacetamide to 125 ℃ in an inert gas atmosphere, stirring and soaking for 60-120min, cooling to 110 ℃ of 105 ℃, adding 8g of lithium chloride, stirring for 50-90min, cooling, and dissolving the lyocell fiber to obtain a lyocell fiber solution.
Wherein the obtained lyocell fiber solution is in the form of light yellow transparent liquid.
The lyocell fibre was dried in a vacuum oven at 110 ℃ for 12 h.
In some more preferred embodiments of the present invention, the cellulose in the cellulose solution is 1-2% by mass.
In some more preferred embodiments of the invention, the cellulose in the cellulose solution is 1.5% by mass.
In some embodiments of the invention, the preparation method comprises the following steps:
s1, carrying out Michael addition reaction on a mixed solution I of a mercapto acid compound and an aminosulfonic acid inner salt containing a carbon-carbon double bond, so as to obtain a mixed solution II containing a zwitterion intermediate;
s2-1, mixing the mixed solution II with a carboxyl activating agent, and performing carboxyl activating treatment on the zwitterion intermediate to obtain a mixed solution III;
and S2-2, mixing the mixed solution III with a cellulose solution to obtain a homogeneous system, and grafting the zwitterion intermediate subjected to carboxyl activation treatment on the cellulose in the homogeneous system to obtain the zwitterion cellulose.
In some preferred embodiments of the present invention, in step S2-1, N' -carbonyldiimidazole is added to the mixture ii, and reacted in a protective atmosphere to obtain an activated zwitterionic intermediate, which is a zwitterionic carboxylic acid intermediate.
In some more preferred embodiments of the present invention, in step S2-1, the molar ratio of N, N' -carbonyldiimidazole to the mercaptoacid-based compound is 1: 1.
in some more preferred embodiments of the present invention, in step S2-1, N' -carbonyldiimidazole is added to the mixed solution ii, and reacted at 40-50 ℃ for 1-3 hours in an inert gas atmosphere to obtain an activated zwitterionic carboxylic acid intermediate.
In some preferred embodiments of the present invention, the solvent in the mixed solution i comprises a solvent i, the solvent in the cellulose solution comprises a solvent ii, and the solvent i and the solvent ii both comprise dimethylacetamide.
In some preferred embodiments of the present invention, the solvent i further comprises at least one of N, N-dimethylformamide, dimethylsulfoxide, or N-methylpyrrolidone.
In a second aspect of the invention, a zwitterionic cellulose is provided, which is prepared by the preparation method.
In a third aspect of the present invention, a zwitterionic cellulose is provided, wherein the structural formula of the zwitterionic cellulose is formula (1):
the R is 1 、R 2 And R 3 Independently selected from H,
At least two of them, wherein m is more than or equal to 1, 4 is more than or equal to a and more than or equal to 1, and 4 is more than or equal to b and more than or equal to 1.
In a fourth aspect of the invention, a cellulose gel is provided, and the raw material for preparing the cellulose gel comprises the zwitterionic cellulose.
In a fifth aspect of the present invention, a biomaterial is provided, wherein the raw material for preparing the biomaterial comprises the above zwitterionic cellulose, or the biomaterial comprises the above zwitterionic cellulose.
In a sixth aspect of the invention, the application of the zwitterionic cellulose in the preparation of biological materials or medical products is provided.
In some embodiments of the invention, the medical product comprises at least one of a medical device or a drug.
Drawings
The invention is further described with reference to the following figures and examples, in which:
FIG. 1 is a schematic diagram showing the principle of preparation of zwitterionic cellulose in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of zwitterionic cellulose in example 1 of the present invention;
FIG. 3 is a nuclear magnetic resonance carbon spectrum of zwitterionic cellulose in example 1 of the present invention;
FIG. 4 is a graph showing the results of the cytotoxicity test of zwitterionic cellulose in example 1 of the present invention;
FIG. 5 is a graph showing the results of bovine serum albumin BSA adsorption tests on cellulose hydrogel microspheres in example 1 of the present invention;
FIG. 6 is a photograph of cellulose hydrogel microspheres (mass ratio of sodium alginate to zwitterionic cellulose is 9: 1) in example 1 of the present invention.
Detailed Description
The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention.
Example 1
The embodiment discloses a zwitterionic cellulose, which comprises the following preparation processes:
material pretreatment:
dehydrating the used raw materials: the materials used contained lithium chloride, dimethylacetamide and lyocell. Lithium chloride dehydration is carried out for 2h in a vacuum box at 120 ℃, dimethylacetamide is dried for 12h by using a 4A molecular sieve, and lyocell fiber is dried for 12h at 110 ℃ in the vacuum box;
dissolution of lyocell fibers: taking 1.74g of lyocell fiber, and adding the lyocell fiber into a reaction vessel; weighing 80mL of dimethylacetamide, adding the dimethylacetamide into a reaction vessel, replacing gas in the reaction vessel with inert gas, heating to 120 ℃, and stirring and soaking for 1 h; then cooling to 110 ℃, adding 8g of lithium chloride, and continuing stirring for 1 h; then the heating device is closed, the temperature is naturally reduced to the room temperature, the lyocell is completely dissolved in the process of temperature reduction, and the solution is in a light yellow transparent liquid state;
(II) according to a molar ratio of 1: 1 weighing 0.27g (2.5mmol) of 3-MPA and 0.70g (2.5mmol) of DMAPS, and dissolving the 3-MPA with 3mL of DMAc to obtain a 3-MPA solution; because DMAPS has low solubility in DMAc, 4mL of DMAc and 1mL of DMSO are added to assist the dissolution, and a DMAPS solution is obtained;
(III) transferring the 3-MPA solution and the DMAPS solution prepared in the step (II) into a round-bottom flask in sequence, adding 19mg of DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene), replacing inert gas, and reacting for 24 hours at 45 ℃ in a dark place to obtain an intermediate product;
(IV) impure intermediate product, adding 0.41g CDI (2.5mmol), replacing inert gas, reacting at 45 ℃ for 3 h;
(v) according to cellulose anhydroglucose unit AGU: the molar ratio of 3-MPA is 1: 3, adding 6.75g of 2% W/W cellulose solution, replacing inert gas, heating to 52 ℃, and reacting for 24 hours;
(VI) directly centrifuging the reaction solution obtained in the step (V), pouring out the supernatant to obtain a white solid, and dissolving the precipitate in DMSO (in a test mode, the precipitate can be completely dissolved to show that the lyocell fiber is successfully modified (if the cellulose is not successfully modified, the cellulose cannot be dissolved);
(VII) washing the solid with anhydrous ethanol for 3 times, dissolving with water, dialyzing for 3 days, filtering, and freeze-drying the filtrate to obtain the product with the yield of 53.7%.
The product obtained in this example 1 Spectrum H:
1 HNMR(400MHz,DMSO-d 6 )
δ 4.46(d,2H),3.69(d,2H),3.5(m,2H),3.10(s,6H),2.33(s,1H),2.12(t,2H),2.02(m,2H),1.15(d, 3H); wherein several methyl characteristic peaks of the target product appear in the spectrogram. Thus, the target product with the correct structural formula is successfully prepared by the steps.
The embodiment provides a cellulose gel, specifically a cellulose gel microsphere, the preparation raw material of which includes the zwitterionic cellulose prepared in the embodiment, and the preparation process specifically includes the following steps:
a series of sodium alginate/zwitterionic cellulose mixed solutions are prepared by using the zwitterionic cellulose prepared in the embodiment as a raw material, wherein the sum of the mass fractions of the sodium alginate and the zwitterionic cellulose in the mixed solution is 2%, and a PBS buffer solution (0.01mol/L, pH is 6.0) is used as a solvent.
And slowly dropwise adding the mixed solution into a barium chloride aqueous solution with the mass fraction of 2% by using a 5mL syringe to obtain a series of cellulose hydrogel spheres containing the zwitterionic cellulose.
In the series of cellulose hydrogel spheres, the mass ratio of sodium alginate to zwitterionic cellulose is respectively 9: 1. 8: 2. 6: 4. 5: 5.
this example provides a biomaterial, the raw material for its preparation comprises the zwitterionic cellulose prepared in this example.
This example provides a medicament comprising the zwitterionic cellulose prepared in this example.
Example 2
The embodiment discloses a zwitterionic cellulose, which comprises the following preparation processes:
material pretreatment: the specific steps are the same as example 1;
(II) according to a molar ratio of 1: 1 weighing 0.54g (5mmol) of 3-MPA and 1.40g (5mmol) of DMAPS, and dissolving the 3-MPA with 6mL of DMAc to obtain a 3-MPA solution; DMAPS is dissolved by using 8mL of DMAc and 2mL of DMSO to obtain a DMAPS solution;
(III) transferring the 3-MPA solution and the DMAPS solution prepared in the step (II) into a round-bottom flask in sequence, adding 38mg of DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene), replacing inert gas, and reacting for 24 hours at 45 ℃ in a dark place to obtain an intermediate product;
(IV) impure intermediate product, adding 0.82g CDI (5mmol), replacing inert gas, reacting at 45 ℃ for 3 h;
(v) according to cellulose anhydroglucose unit AGU: the molar ratio of 3-MPA is 1: 6, adding 9.0g of 1.5% W/W cellulose solution, replacing inert gas, heating to 60 ℃, and reacting for 24 hours;
(VI) directly centrifuging the reaction solution obtained in the step (V), pouring out the supernatant to obtain a white solid, and dissolving the precipitate in DMSO (dimethyl sulfoxide) in a test manner to completely dissolve the precipitate;
(VII) washing the solid with anhydrous ethanol for 3 times, dissolving with water, dialyzing for 3 days, filtering, and freeze-drying the filtrate to obtain the product with the yield of 67.3%.
This example provides a cellulose gel, the raw material for preparation of which comprises the zwitterionic cellulose prepared in this example.
This example provides a biomaterial, the raw material for its preparation comprises the zwitterionic cellulose prepared in this example.
This example provides a medicament comprising the zwitterionic cellulose prepared in this example.
Example 3
This example discloses a zwitterionic cellulose, which differs from example 1 in that:
in step (v), the cellulose anhydroglucose unit AGU: the molar ratio of 3-MPA is 1: 8.
the final yield of zwitterionic cellulose in this example was 70.2%.
This example provides a cellulose gel, the raw material for preparation of which comprises the zwitterionic cellulose prepared in this example.
This example provides a biomaterial, the raw material for its preparation comprises the zwitterionic cellulose prepared in this example.
This example provides a medicament comprising the zwitterionic cellulose prepared in this example.
Example 4
This example discloses a zwitterionic cellulose, which differs from example 1 in that:
in step (v), the cellulose anhydroglucose unit AGU: the molar ratio of 3-MPA is 1: 10.
the final zwitterionic cellulose yield of this example was 74.4%.
This example provides a cellulose gel, the raw material for preparation of which comprises the zwitterionic cellulose prepared in this example.
This example provides a biomaterial whose raw material for preparation includes the zwitterionic cellulose prepared in this example.
This example provides a medicament comprising the zwitterionic cellulose prepared in this example.
Example 5
This example discloses a zwitterionic cellulose, which differs from example 1 in that:
in step (v), the cellulose anhydroglucose unit AGU: the molar ratio of 3-MPA is 1: 15.
the final zwitterionic cellulose yield of this example was 75.8%.
This example provides a cellulose gel, the raw material for preparation of which comprises the zwitterionic cellulose prepared in this example.
This example provides a biomaterial, the raw material for its preparation comprises the zwitterionic cellulose prepared in this example.
This example provides a medicament comprising the zwitterionic cellulose prepared in this example.
From examples 1 to 5, it can be seen that, with the cellulose anhydroglucose unit AGU: the yield of the product gradually increased with increasing molar ratio of 3-MPA. Because the yield of the product is increased firstly, quickly and then slowly, the increase benefit is gradually reduced, but the cost is increased; for general consideration, it is most preferred to use AGU: the molar ratio of 3-MPA is 1: 8.
example 6
The embodiment discloses a zwitterionic cellulose, which comprises the following preparation processes:
material pretreatment: the specific steps are the same as example 1;
(II) according to a molar ratio of 1: weighing 0.39g (2.5mmol) of TSA (thiosalicylic acid) and 0.70g (2.5mmol) of DMAPS (dimethyl formamide PS), dissolving TSA with 3mL of DMAc to obtain a TSA solution, dissolving DMAPS in DMAc with 4mL of DMAc and 1mL of DMSO to obtain a DMAPS solution;
(III) transferring the 3-MPA solution and the DMAPS solution prepared in the step (II) into a round-bottom flask in sequence, adding 19mg of DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene), replacing inert gas, and reacting for 24 hours at 45 ℃ in a dark place to obtain an intermediate product;
(IV) impure intermediate product, adding 0.41g CDI (2.5mmol), replacing inert gas, reacting at 45 ℃ for 3 h;
(v) according to cellulose anhydroglucose unit AGU: TSA molar ratio 1: 6, adding 4.5g of 1.5% W/W cellulose solution according to the proportion, replacing inert gas, heating to 60 ℃, and reacting for 24 hours;
(VI) pouring the reaction solution obtained in the step (V) into 100mL of ethanol for precipitation, then centrifuging, and pouring out the supernatant to obtain a light yellow solid;
(VII) washing the solid with absolute ethyl alcohol for 3 times, dissolving the solid with water, dialyzing for 3 days, filtering, and freeze-drying the filtrate to obtain the product with the yield of less than 10%.
Compared with example 1, the mercaptoacids compound adopted in the present example is TSA containing benzene ring, and the final yield of the zwitterionic cellulose is obviously lower than that of examples 1-5 (aliphatic mercaptoacids compound is adopted in examples 1-5). The inventors speculate that the reason is: compared with aliphatic mercapto acid compounds, TSA containing benzene ring may be due to the fact that benzene ring reduces nucleophilicity of mercapto group, and steric hindrance also affects carboxyl esterification reaction.
Comparative example 1
The comparative example discloses a zwitterionic cellulose, which is prepared by the following steps:
material pretreatment: the specific steps are the same as example 1;
(II) weighing 0.54g (5mmol) of 3-MPA0, dissolving with 6mL of DMAc, and transferring to a reaction container; then weighing 0.82g (5mmol) of CDI, dissolving the CDI with 4mL of DMAc, transferring the solution into a reaction container, replacing nitrogen, and reacting for 3 hours at 45 ℃;
(III) weighing 18.0g of 1.5% W/W cellulose solution, dropwise adding the solution into a reaction container, and then heating to 60 ℃ to continue reacting for 12-24 h;
the comparative example was prepared by reacting cellulose with 3-mercaptopropionic acid followed by DMAPS.
Sampling after reaction for 12H, adding ethanol to precipitate, centrifuging, removing supernatant, and precipitating with DMSO, DMAc, DMF, and H as solvent 2 O, detecting the solubility, and obtaining a result that the materials cannot be dissolved; the reaction was then continued for 24h, at which point a gummy mass was produced in the reaction vessel and was no longer available for further reaction.
The reason is presumed to be: when the reaction time is short, the degree of substitution of OH on the cellulose is too low, the hydrogen bond action of the cellulose is stronger, and the product cannot be dissolved in a common solvent; while the reaction time is prolonged, although the substitution degree of OH can be theoretically improved, side reactions occur between thiol groups on the substituents to generate disulfide bonds, and a certain degree of crosslinking is generated, thereby generating insoluble colloidal substances.
In example 1, the thiol group reacts with the carbon-carbon double bond first, and the thiol group is reacted first, thereby avoiding the above-mentioned situation. Then the carboxyl groups are reacted with the cellulose, the reaction yield can be increased by prolonging the time and increasing the charge ratio.
Test examples
In this test example, the zwitterionic cellulose obtained in the example was tested for performance, specifically:
(1) the test of the degree of substitution of the zwitterionic cellulose is shown in table 1 according to the test results of organic element analysis, wherein the instrument model of the organic element analyzer is as follows: elemantar, Vario EL cube; and (3) a test mode: CHNS mode.
TABLE 1 zwitterionic cellulose substitution test results Table
| Element(s) | N(％) | C(％) | H(％) | S(％) | O(％) |
| Example 1 | 2.42 | 44.13 | 7.19 | 11.04 | / |
Degree of substitution
The degree of substitution is about 0.76.
The authors of document Polym. ball. (2014)71:2559-2569 used a cellulose surface modification scheme, specifically, a sulfabetaine side chain was introduced by a click reaction of azido cellulose and a terminal alkyne, and the content of N% was 4.1% by elemental analysis, but since each substituent contained 4 nitrogen atoms, the number of substituents was 1/4, i.e., 1% of the nitrogen content. The zwitterionic cellulose prepared by the method has obviously higher degree of substitution.
(2) In vitro cytotoxicity test:
the MTT testing step comprises the following steps:
1) log phase L929 mouse cells were collected, cell suspension concentration was adjusted, 100 μ L was added per well, and plated to test cell density 10000/well (96 well flat bottom plate, marginal wells filled with sterile PBS).
2) Transferring to carbon dioxide cell incubator with 5% CO 2 And incubating at 37 ℃, culturing for 18-24h until cell monolayers are paved on the bottom of the hole, and adding the medicine (the zwitterionic cellulose prepared in example 1) after the cells are attached to the wall. Set up 3 concentration gradients (zwitterions)In the mixed solution of cellulose and PBS buffer solution, the mass fraction of the zwitterionic cellulose is respectively 0.5%, 1.0% and 2.0%, each hole is 100uL, 5 multiple holes are arranged, and a positive control group (1mol/L NaOH + culture medium) and a negative control group (without adding medicine, adding an equal amount of fresh culture medium) are arranged at the same time.
3) Then continuing to 5% CO in a carbon dioxide cell incubator 2 Incubated at 37 ℃ for 24 hours.
4) The test sample was removed from the well plate, the wells were washed 2 times with PBS solution, 50uL of MTT solution was added to each well, incubated in an incubator for 4 hours, and then the MTT solution in the wells was discarded.
5) Add 200. mu.L DMSO to each well and shake on a shaker for 10min at low speed to dissolve the crystals sufficiently. Then incubating in an incubator for 4-6 hours; after the incubation is finished, the dissolved solution is sucked out and added into a new 96-well plate, the plate is placed into an enzyme-labeling instrument, and the absorbance value of each well under the absorption wavelength of 570nm is measured.
The test results are shown in fig. 4, with cytotoxicity rating of 1.
(3) Bovine serum albumin BSA adsorption assay:
BSA adsorption test was performed on the series of cellulose hydrogel microspheres (abbreviated as hydrogel spheres) prepared in example 1, and pure alginic acid gel microspheres containing no zwitterionic cellulose of the present invention were used as a control.
The method comprises the following specific steps:
weighing 20mg of dry hydrogel spheres, and placing the hydrogel microspheres into 10mL of PBS buffer solution (0.01M, pH 6.0) containing 1mg/mL BSA for shaking and soaking at the constant temperature of 25 ℃ for 12 hours; then taking the supernatant, and measuring the absorbance of the supernatant at 277nm by using an ultraviolet spectrophotometer; drawing an ultraviolet absorption standard curve of BSA, wherein the ultraviolet absorption standard curve has better linearity in a concentration range of 0.02-2.0mg/mL, and the regression curve is that y is 0.6137x +0.1044, R 2 0.9991; and calculating the adsorption quantity of the BSA in the hydrogel spheres according to a standard curve.
The calculation method of the adsorption amount comprises the following steps:
in the formula: rho 0 and rho 1 are respectively the mass concentration (mg/mL) of BSA in the solution before and after adsorption, V is the volume of the solution, and m is the mass of the hydrogel spheres.
The test results are shown in fig. 5, and the maximum decrease of the measured adsorption rate is 87.5% compared with the control group.
The traditional surface modification reaction can only occur on the surface of the cellulose cluster, the occurrence sites are also probabilistic, and the interior of the cellulose cluster can not be contacted with reactants generally, so that the grafting is not uniform, the grafting rate is not high, and the substitution degree is low. The invention is used for grafting amphoteric substances on cellulose in homogeneous phase, basically reaches the degree of single molecular chain, and the probability of each AGU unit site is equal on the contact with reactants, so the grafting is uniform, and the substitution degree is high.
The zwitterionic celluloses prepared in examples 2-6 were all characterized by nuclear magnetism, and the results indicated that the target compound was prepared with a degree of substitution of 0.6-0.9. The zwitterionic celluloses prepared in examples 2-6 were comparable in performance to the zwitterionic cellulose prepared in example 1.
The invention adopts simple and efficient two-step reaction, has high reaction activity, simple reaction condition and convenient operation. The reaction of sulfydryl and carbon-carbon double bonds belongs to the Michael addition reaction type in click reaction, and is characterized by high efficiency, atom economy and mild conditions; the activating agent CDI adopted in the esterification reaction of carboxyl and hydroxyl is a high-efficiency acylation reagent and carboxylic acid activating reagent, and has higher application value compared with DCC, EDC and the like.
The invention carries out zwitterion modification on cellulose under homogeneous phase conditions, and one of the technical difficulties is as follows: whether the dissolving system of the cellulose is compatible with the subsequent modification reaction system or not, and any reaction system incompatible with the cellulose solution system can cause the instability of the cellulose solution to be separated out, so that the next modification reaction can not be carried out smoothly. The reaction reagents selected by the invention are skillfully selected after creative work, can be compatible with the cellulose solution and hardly affect the stability of the cellulose solution. The final target product can be directly separated out in the system, and the post-treatment is very convenient.
It is to be noted that "room temperature" herein is about 25 ℃ unless otherwise specified; reference herein to a numerical value of "about" means 2% error.
The embodiments of the present invention have been described in detail with reference to the drawings, but the present invention is not limited to the embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the gist of the present invention. Furthermore, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.
Claims (10)
1. A preparation method of zwitterionic cellulose is characterized by comprising the following steps:
s1, carrying out Michael addition reaction on the mercapto acid compound and the sulfamic acid inner salt containing the carbon-carbon double bond to obtain a zwitterionic intermediate;
s2, grafting the zwitterionic intermediate prepared in the previous operation on cellulose in a homogeneous system to obtain the zwitterionic cellulose.
2. The method of claim 1, wherein the homogeneous system comprises a solvent system comprising dimethylacetamide or an ionic liquid system; preferably, the cellulose comprises at least one of lyocell, purified cotton, modal, cuprammonium or viscose.
3. The method according to claim 1, wherein the mercapto acid compound comprises at least one of a mercapto fatty acid and a mercapto aromatic acid; preferably, the mercapto acid compound comprises at least one of mercaptopropionic acid, mercaptobutyric acid, mercaptopentanoic acid, mercaptohexanoic acid, mercaptobenzoic acid, mercaptophenylacetic acid, or mercaptophenylpropionic acid; preferably, the mercapto acid compound includes at least one of mercaptopropionic acid, mercaptobutyric acid, mercaptopentanoic acid, or mercaptohexanoic acid.
4. The method for preparing zwitterionic cellulose according to claim 1, wherein in the internal sulfamate containing carbon-carbon double bonds, the carbon-carbon double bonds are located at the end of the internal sulfamate; preferably, in the internal salt of sulfamic acid containing a carbon-carbon double bond, the carbon-carbon double bond is located at the end of the internal salt of sulfamic acid away from the betaine group of the sulfonic acid; preferably, the internal sulfamate containing carbon-carbon double bonds comprises at least one of an internal sulfamate containing carbon-carbon double bonds, an internal sulfamate containing carbon-carbon double bonds or an internal sulfamate containing carbon-carbon double bonds.
5. The method of claim 1, wherein in step S2, the zwitterionic intermediate is grafted to the cellulose by esterification between carboxyl groups on the zwitterionic intermediate and hydroxyl groups on the cellulose;
preferably, the preparation method comprises the following steps:
s1, carrying out Michael addition reaction on a mixed solution I of a mercapto acid compound and an aminosulfonic acid inner salt containing a carbon-carbon double bond, so as to obtain a mixed solution II containing a zwitterion intermediate;
s2-1, mixing the mixed solution II with a carboxyl activating agent, and performing carboxyl activating treatment on the zwitterion intermediate to obtain a mixed solution III;
s2-2, mixing the mixed solution III with a cellulose solution to obtain a homogeneous system, and grafting a zwitterion intermediate subjected to carboxyl activation treatment onto cellulose in the homogeneous system to obtain the zwitterion cellulose;
preferably, the solvent in the mixed solution I comprises a solvent I, the solvent in the cellulose solution comprises a solvent II, and the solvent I and the solvent II both comprise dimethylacetamide.
6. Zwitterionic cellulose prepared by the process according to any one of claims 1 to 5.
7. A zwitterionic cellulose, characterized in that the zwitterionic cellulose has the formula (1):
the R is 1 、R 2 And R 3 Independently selected from H,
At least two of them, wherein m is more than or equal to 1, 4 is more than or equal to a and more than or equal to 1, and 4 is more than or equal to b and more than or equal to 1.
8. Cellulose gel, characterized in that the starting material for the preparation of said cellulose gel comprises zwitterionic cellulose according to any one of claims 1 to 5 or zwitterionic cellulose according to any one of claims 6 to 7.
9. A biomaterial, wherein the starting material for its production comprises zwitterionic cellulose produced according to the method of any one of claims 1 to 5 or zwitterionic cellulose according to any one of claims 6 to 7, or wherein the biomaterial comprises said zwitterionic cellulose.
10. Use of a zwitterionic cellulose prepared according to the process of any one of claims 1 to 5 or a zwitterionic cellulose according to any one of claims 6 to 7 in the preparation of a biomaterial or medical product.
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