CN115433349A - Polylactic acid zwitterionic compound, synthetic method and application - Google Patents
Polylactic acid zwitterionic compound, synthetic method and application Download PDFInfo
- Publication number
- CN115433349A CN115433349A CN202110621940.2A CN202110621940A CN115433349A CN 115433349 A CN115433349 A CN 115433349A CN 202110621940 A CN202110621940 A CN 202110621940A CN 115433349 A CN115433349 A CN 115433349A
- Authority
- CN
- China
- Prior art keywords
- polylactic acid
- compound
- zwitterionic
- zwitterionic compound
- lactide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 claims abstract description 37
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Abstract
The disclosure provides a polylactic acid zwitterionic compound, a synthesis method and application, wherein the synthesis method of the polylactic acid zwitterionic compound comprises the following steps: (1) Mixing a zwitterionic compound with L-lactide, and heating to melt the L-lactide; (2) Adding a catalyst into the mixture obtained in the step (1), and stirring for reaction to obtain the polylactic acid zwitterion compound; wherein the zwitterionic compound comprises one of glycerophosphorylcholine or glycerophosphorylcholine modification; the glycerophosphorylcholine modification comprises formula (I) or formula (II) as follows:
Description
Technical Field
The disclosure relates to the field of beauty, in particular to a polylactic acid zwitterionic compound, a synthesis method and application.
Background
Human aging is a spontaneous inevitable process, and common manifestations include morphological changes and physiological function decline; morphological changes such as cell loss, metabolism slowing, and skin flabbiness and collapse.
poly-L-lactic acid (PLLA), a degradable synthetic polymer, is widely used in the fields of medical use, packaging, etc., and is certified by the FDA in the united states as a biomedical material that can be used in human body. At present, the levorotatory polylactic acid is often adopted as an injection filling product in the medical beauty industry. After the levorotatory polylactic acid is injected, the filling effect can be achieved, and the skin collapse is improved; in the degradation process, the lactic acid is degraded into the levolactic acid through enzymatic decomposition in vivo, has a promotion effect on metabolism of epidermal cells of the skin, can achieve the effects of adjusting microenvironment, enabling the epidermal cells to divide smoothly and tightening and tendering the skin; in addition, the human body contains lactic acid, all living bodies on the earth are composed of L-amino acid, and the L-amino acid has very good compatibility with L-compounds. Therefore, the immune system of the human body can recognize the L-PLA as harmless substances, and macrophages can not phagocytose the L-PLA.
Although the immune system of the human body does not phagocytose the L-polylactic acid, the lactic acid is a "waste material" in the human body, which is a product of incomplete decomposition of muscles during the combustion of carbohydrates, and is restored into sugar by the hydrolysis of fructosidase, so that heat is stored again. However, skin cells cannot utilize the energy, fibroblasts are stimulated to generate a large amount of collagen, invading foreign bodies are wrapped up, polylactic acid is difficult to degrade, and rejection reaction is stimulated. For example, sometimes after injection, there are obvious nodules and hard masses that require months or even longer to relieve themselves.
Disclosure of Invention
Technical problem to be solved
In view of the above technical problems, the present disclosure provides a polylactic acid zwitterionic compound, a synthesis method and an application thereof, in order to at least partially solve at least one of the above technical problems.
(II) technical scheme
In order to solve the technical problem, the technical scheme of the disclosure is as follows:
as an aspect of the present disclosure, there is provided a method for synthesizing a zwitterionic compound of polylactic acid, including:
(1) Mixing a zwitterionic compound with L-lactide, and heating to melt the L-lactide;
(2) Adding a catalyst into the mixture obtained in the step (1), and stirring for reaction to obtain the polylactic acid zwitterionic compound;
wherein the zwitterionic compound comprises one of glycerophosphorylcholine or glycerophosphorylcholine modification;
the glycerophosphorylcholine modification comprises formula (I) or formula (II) as follows:
in one embodiment, the step (1) further comprises a biodegradable material, wherein the biodegradable material comprises one or two of L-glycolide and epsilon-caprolactone;
wherein the molar ratio of the L-glycolide to the L-lactide is (0-100) to 1;
the molar ratio of the epsilon-caprolactone to the L-lactide is (0-100) to 1.
In one embodiment the molar ratio of the zwitterionic compound to the L-lactide is 1: (10-100000);
the mol ratio of the catalyst to the L-lactide is (0.00001-0.1) to 1.
In one embodiment, the molar ratio of the zwitterionic compound to the L-lactide is 1: (50-250);
the mol ratio of the catalyst to the L-lactide is (0.002-0.1) to 1.
In one embodiment, the catalyst comprises one or more of the following: a coordination compound formed by coordinating beta-diketone with zinc ions, magnesium ions and calcium ions respectively; coordination compounds formed by coordination of ketimine with zinc ions, magnesium ions and calcium ions respectively; the amino phenol is respectively coordinated with zinc ions, magnesium ions and calcium ions to form a coordination compound; a coordination compound formed by coordinating beta-diimine with zinc ions, magnesium ions and calcium ions respectively; a coordination compound formed by coordination of Schiff base with zinc ions, magnesium ions and calcium ions respectively; and zinc lactate, zinc acetate, zinc chloride, calcium oxide, magnesium chloride, magnesium oxide, dibutyl magnesium, iron oxide, iron acetate, iron chloride, ferrocene, iron carboxylates, iron acetylacetonate, iron porphyrin, and aluminum chloride.
In one embodiment, after the step (2), the method further comprises:
(3) Purification of polylactic acid zwitterionic compound: adding the polylactic acid zwitterionic compound obtained in the step (2) into an organic solvent for dissolving the polylactic acid zwitterionic compound to dissolve the polylactic acid zwitterionic compound to obtain a polymer solution; then, the polymer solution is dripped into the organic solvent for precipitating the polylactic acid zwitterion compound to precipitate, and the precipitate is dried.
In one embodiment, the organic solvent used for dissolving the polylactic acid zwitterionic compound comprises one or more of chloroform, dichloromethane, acetone and ethyl acetate;
the organic solvent for separating out the polylactic acid zwitterion compound comprises one or more of diethyl ether, methanol and ethanol.
In one embodiment, in the step (1), the reaction conditions are anhydrous and anaerobic, and the reaction temperature is 100-250 ℃; in the step (2), the reaction temperature is 100-250 ℃, and the reaction time is 2-24h.
As another aspect of the present disclosure, there is provided a polylactic acid zwitterionic compound prepared by the above method.
As a third aspect of the present disclosure, there is provided a use of the polylactic acid zwitterionic compound in a cosmetic injection filling.
(III) advantageous effects
1. The method comprises the step of grafting a zwitterionic compound (glycerophosphorylcholine or glycerophosphorylcholine modifier) on polylactic acid by adopting a high-molecular activity polymerization method to form the polylactic acid zwitterionic compound, wherein a product obtained by completely hydrolyzing two fatty acyl groups on a phosphatidylcholine molecule is a water-soluble zwitterionic substance normally existing in a human body. Therefore, the polylactic acid zwitterionic compound not only maintains the degradability of the polylactic acid, but also can prevent the polylactic acid from being adhered to proteins in skin tissues due to the zwitterionic characteristics of the glycerophosphocholine or the modified substances thereof, so that the anti-protein adhesion characteristic is improved, the stability of the polylactic acid in the skin tissues is improved, lumps are prevented from being formed, and the side effects are reduced. Meanwhile, the degraded choline glycerophosphate micromolecules and lactic acid micromolecules generate synergistic effect, so that the metabolism level is improved, the cell growth is stimulated, and the elasticity and the smoothness of the skin are recovered. In addition, the degraded products of the polylactic acid zwitterionic compound, namely glycerophosphorylcholine and lactic acid, are substances existing in vivo, so that the polylactic acid zwitterionic compound has high safety.
2. The glycerophosphorylcholine produced by degradation of the polylactic acid zwitterionic compound provided by the present disclosure is decomposed into choline and glycerophosphate under the action of enzymes in the body. Choline is used for participating in the biosynthesis of acetylcholine in vivo, acetylcholine is one of nerve trigger transmitters, and the pathogenesis of senile dementia is closely related to the deficiency of the neurotransmitter acetylcholine, so that glycerophosphorylcholine generated by degrading polylactic acid zwitterionic compounds provided by the disclosure also has the remarkable effects of strengthening brain, preventing senile dementia and the like; glycerophosphate is a precursor of lecithin and is involved in the synthesis of lecithin. Meanwhile, the glycerophosphorylcholine is used as a skin conditioner, and can improve the activity of lipase, prevent fat accumulation, improve the metabolism of fat and muscle and improve the skin state.
3. The polymerization method adopted by the method can obtain the target compound in one step, the preparation steps are simple, the preparation process is green and nontoxic, the experimental condition requirement is low, and the method is suitable for industrial preparation.
4. The polymer yields obtained using the polymerization processes provided by the present disclosure range from 89 to 93.5%.
Drawings
FIG. 1 is a nuclear magnetic spectrum of a polylactic acid zwitterionic compound of the present disclosure;
FIG. 2 is a graph showing the protein adhesion resistance test of the zwitterionic polylactic acid compound of the present disclosure;
FIG. 3 is a graph showing the test of the hydrolytic performance of the zwitterionic compounds of polylactic acid according to the present disclosure;
fig. 4 is a graph showing the safety test of the polylactic acid zwitterionic compound of the present disclosure.
Detailed Description
For the purpose of promoting a better understanding of the objects, aspects and advantages of the present disclosure, reference is made to the following detailed description taken in conjunction with the accompanying drawings.
The present disclosure also provides a method for synthesizing a polylactic acid zwitterionic compound, comprising:
(1) Mixing a zwitterionic compound with L-lactide, and heating to melt the L-lactide;
(2) Adding a catalyst into the mixture obtained in the step (1), and stirring for reaction to obtain the polylactic acid zwitterion compound;
wherein the zwitterionic compound comprises one of glycerophosphorylcholine or glycerophosphorylcholine modification;
the glycerophosphorylcholine modification comprises the following formula (I) or formula (II):
the method comprises the step of grafting a zwitterionic compound (glycerophosphorylcholine or glycerophosphorylcholine modified substance) on polylactic acid by a high-molecular active polymerization method to form the polylactic acid zwitterionic compound, wherein a product obtained by completely hydrolyzing two fatty acyl groups on a phosphatidylcholine molecule is a water-soluble zwitterionic substance normally existing in a human body. Therefore, the polylactic acid zwitterionic compound in the disclosure not only maintains the degradability of polylactic acid, but also the zwitterionic characteristics of glycerophosphocholine or a modifier thereof can prevent the adhesion of protein and the like in skin tissues of polylactic acid, improve the anti-protein adhesion characteristics, improve the stability of polylactic acid in skin tissues, prevent the formation of lumps and reduce side effects. Meanwhile, the degraded choline glycerophosphate micromolecules and lactic acid micromolecules generate synergistic effect, so that the metabolism level is improved, the cell growth is stimulated, and the elasticity and the smoothness of the skin are recovered. In addition, the degraded products of the polylactic acid zwitterionic compound, namely glycerophosphorylcholine and lactic acid, are substances existing in vivo, so that the polylactic acid zwitterionic compound has high safety.
In addition, the degraded product of the polylactic acid zwitterionic compound provided by the disclosure is decomposed into choline and glycerophosphate under the action of enzymes in the body. Choline is used for participating in the biosynthesis of acetylcholine in vivo, acetylcholine is one of nerve trigger transmitters, and the pathogenesis of senile dementia is closely related to the deficiency of the neurotransmitter acetylcholine, so that glycerophosphorylcholine generated by degrading polylactic acid zwitterionic compounds provided by the disclosure also has the remarkable effects of strengthening brain, preventing senile dementia and the like; glycerophosphate is a precursor of lecithin and is involved in the synthesis of lecithin. Meanwhile, the glycerophosphorylcholine is used as a skin conditioner, and can improve the activity of lipase, prevent fat accumulation, improve the metabolism of fat and muscle and improve the skin state.
In addition, the target compound can be obtained by one step of the polymerization method, the preparation steps are simple, the preparation process is green and non-toxic, the experimental condition requirement is low, and the method is suitable for industrial preparation.
According to an embodiment of the present disclosure, a method for synthesizing glycerophosphorylcholine modification compound formula (I) comprises:
(1) dissolving glycerophosphorylcholine in anhydrous pyridine to prepare a solution with the mass concentration of 0.1-10%, and adding triphenylchloromethane to obtain a reaction solution, wherein the molar ratio of the triphenylchloromethane to the glycerophosphorylcholine is (1-2) to 1.
(2) Reacting the reaction solution in the step (1) at 30-70 ℃ for 1-12h, extracting with ethyl acetate to obtain an organic solution, and concentrating the organic solution to obtain a residue.
(3) Dissolving the residue obtained in the step (2) with anhydrous N, N-dimethylformamide at 0 ℃ to prepare a solution with the mass concentration of 0.1-10%, slowly adding 1-10% of sodium hydride into the solution, stirring the solution at 0 ℃ for 30 minutes, adding benzyl bromide, wherein the molar ratio of the benzyl bromide to the glycerophosphorylcholine is (1-4) to 1, heating the mixture to room temperature, and stirring the mixture overnight.
(4) Adding saturated NH into the mixture obtained in the step (3) 4 The reaction was stopped with Cl solution and extracted with ethyl acetate and the organic layer was concentrated to give the benzylated product.
(5) Dissolving the benzylation product obtained in the step (4) in a mixed solvent of dichloromethane and methanol (V/V = 1: 1) to prepare a solution with the mass concentration of 0.1-10%, adding p-toluenesulfonic acid into the solution, and stirring for 4 hours to obtain a reaction mixture, wherein the mass concentration of the p-toluenesulfonic acid in the solution is 1-10%; and finally, neutralizing the reaction mixture by using a saturated sodium bicarbonate solution, extracting by using ethyl acetate to obtain an organic liquid, and concentrating the organic liquid to obtain the glycerophosphorylcholine modifier shown in the formula (I).
The synthesis route of glycerophosphorylcholine modification formula (I) is as follows:
according to an embodiment of the present disclosure, a method for synthesizing glycerophosphorylcholine modification compound formula (II) comprises:
(1) dissolving glycerophosphorylcholine in anhydrous pyridine to prepare a solution with the mass concentration of 0.1-10%, and adding triphenylchloromethane to obtain a reaction solution, wherein the molar ratio of the triphenylchloromethane to the glycerophosphorylcholine is (1-2) to 1.
(2) And (2) reacting the reaction solution obtained in the step (1) at 30-70 ℃ for 1-12h, extracting with ethyl acetate, and concentrating an organic layer to obtain the glycerophosphorylcholine modification compound shown in the formula (II).
The synthesis route of glycerophosphorylcholine modification compound formula (II) is as follows:
according to the embodiment of the present disclosure, after the step (2), the method further comprises:
step (3), purifying the polylactic acid zwitterionic compound: adding the polylactic acid zwitterionic compound obtained in the step (2) into an organic solvent for dissolving the polylactic acid zwitterionic compound to dissolve the polylactic acid zwitterionic compound to obtain a polymer solution; then, the polymer solution is dripped into the organic solvent for precipitating the polylactic acid zwitterion compound to precipitate, and the precipitate is dried.
According to embodiments of the present disclosure, the organic solvent used to dissolve the polylactic acid zwitterionic compound includes one or more of chloroform, dichloromethane, acetone, ethyl acetate.
According to embodiments of the present disclosure, the organic solvent used to dissolve the polylactic acid zwitterionic compound may be methylene chloride.
According to the embodiment of the disclosure, the organic solvent for precipitating the polylactic acid zwitterionic compound comprises one or more of diethyl ether, methanol and ethanol.
According to an embodiment of the present disclosure, the organic solvent used to precipitate the polylactic acid zwitterionic compound may be diethyl ether.
According to embodiments of the present disclosure, the molar ratio of zwitterionic compound to L-lactide is 1: (10-100000); the molar ratio of the catalyst to the L-lactide is (0.00001-0.1) to 1.
According to embodiments of the present disclosure, the molar ratio of zwitterionic compound to L-lactide is 1: (50-250); the mol ratio of the catalyst to the L-lactide is (0.002-0.1) to 1.
According to embodiments of the present disclosure, for example, the molar ratio of glycerophosphorylcholine to L-lactide may be 1: 50, 1: 100, 1: 200, the molar ratio of catalyst to L-lactide may be 0.002: 1, 0.01: 1, 0.1: 1, and so forth.
According to embodiments of the present disclosure, the catalyst comprises one or more of: a coordination compound formed by coordinating beta-diketone with zinc ions, magnesium ions and calcium ions respectively; a coordination compound formed by coordination of ketimine with zinc ions, magnesium ions and calcium ions respectively; the amino phenol is respectively coordinated with zinc ions, magnesium ions and calcium ions to form a coordination compound; a coordination compound formed by coordination of beta-diimine with zinc ions, magnesium ions and calcium ions respectively; a coordination compound formed by coordination of the Schiff base with zinc ions, magnesium ions and calcium ions respectively; and zinc lactate, zinc acetate, zinc chloride, calcium oxide, magnesium chloride, magnesium oxide, dibutyl magnesium, iron oxide, iron acetate, iron chloride, ferrocene, iron carboxylates, iron acetylacetonate, iron porphyrin, and aluminum chloride.
According to embodiments of the present disclosure, the catalyst may be, for example, zinc acetate.
According to the embodiment of the present disclosure, in the step (1), the reaction conditions are anhydrous and oxygen-free, and the reaction temperature is 100-250 ℃.
According to an embodiment of the present disclosure, for example, the reaction temperature in step (1) may be 120 ℃, 150 ℃, 200 ℃, and the like.
According to the embodiment of the disclosure, in the step (2), the reaction temperature is 100-250 ℃ and the reaction time is 2-24h.
According to embodiments of the present disclosure, for example, the reaction temperature in step (2) may be 120 ℃, 150 ℃, 200 ℃; the reaction time may be 10h, 16h, 24h, etc.
According to an embodiment of the present disclosure, a biodegradable material is further included in step (1), wherein the biodegradable material comprises one or both of L-glycolide and epsilon-caprolactone.
According to an embodiment of the present disclosure, in step (1), the molar ratio of L-glycolide to the L-lactide is (0-100): 1; the mole ratio of the epsilon-caprolactone to the L-lactide is (0-100): 1.
the present disclosure also provides polylactic acid zwitterionic compounds synthesized using the above method, for example, formula (i), formula (ii), formula (iii), formula (iv), with specific structures as follows:
wherein n and x are integers of 1 or more, and y and z are integers of 0 or more.
The disclosure also provides an application of the polylactic acid zwitterion compound in the aspect of cosmetic injection filling.
The following embodiments (i.e., specific examples) are provided to further illustrate the technical solutions of the present disclosure.
Case 1
A polylactic acid zwitterionic compound synthesized by a method comprising:
(1) Taking a 50mL Schlenk bottle, and performing vacuum pumping-nitrogen circulation for three times under a heating condition to ensure that the Schlenk bottle is anhydrous and anaerobic; then, 0.5mmol of glycerophosphorylcholine and 25mmol of L-lactide are added into a Schlenk bottle, and the mixture is heated and stirred under the condition of an oil bath at the temperature of 120 ℃ to completely melt the L-lactide;
(2) After choline glycerophosphate and L-lactide are uniformly mixed, adding 0.05mmol of zinc acetate into a Schlenk bottle, and stirring and reacting at 120 ℃ for 24 hours to generate a polylactic acid zwitterionic compound;
(3) Purification of polylactic acid zwitterionic compound: after the reaction is finished, taking out a Schlenk bottle, cooling to room temperature, and then adding dichloromethane into the Schlenk bottle to dissolve the generated polylactic acid zwitterionic compound to obtain a polymer solution; then, dropwise adding the polymer solution into 50mL of diethyl ether for precipitation and suction filtration to complete primary purification; after repeating the dissolving, precipitating and filtering for three times, the polylactic acid zwitterionic compound is obtained after drying under the vacuum condition, and the yield is 89.5%.
Wherein, the synthetic route of the polylactic acid zwitterionic compound is as follows:
the nuclear magnetic diagram of the zwitterionic compound of polylactic acid prepared in this example is shown in fig. 1, wherein the peak at 3.35ppm (a in fig. 1) is the hydrogen peak of the methyl group attached to the nitrogen, and the peaks at 1.45-1.68ppm (b in fig. 1) and 5.15-5.23ppm (c in fig. 1) are two hydrogen peaks in lactic acid, respectively, which illustrates that the target product is prepared by the synthesis method of this example.
Case 2
(1) Taking a 50mL Schlenk bottle, and performing vacuum pumping-nitrogen circulation for three times under a heating condition to ensure that the Schlenk bottle is anhydrous and anaerobic; then, 0.5mmol of glycerophosphorylcholine and 50mmol of L-lactide are added into a Schlenk bottle, and the mixture is heated and stirred under the condition of an oil bath at the temperature of 120 ℃ to completely melt the L-lactide;
(2) After choline glycerophosphate and L-lactide are uniformly mixed, adding 0.1mmol of zinc acetate into a Schlenk bottle, and stirring and reacting at 120 ℃ for 24 hours to generate a polylactic acid zwitterionic compound;
(3) Purification of polylactic acid zwitterionic compound: after the reaction is finished, taking out a Schlenk bottle, cooling to room temperature, and then adding dichloromethane into the Schlenk bottle to dissolve the generated polylactic acid zwitterionic compound to obtain a polymer solution; then, dropwise adding the polymer solution into 50mL of diethyl ether for precipitation and suction filtration to complete primary purification; after repeating the dissolving, precipitating and filtering for three times, the polylactic acid zwitterionic compound is obtained after drying under the vacuum condition, and the yield is 93.5%.
Case 3
(1) Taking a 50mL Schlenk bottle, and performing vacuum pumping-nitrogen circulation for three times under a heating condition to ensure that the Schlenk bottle is anhydrous and anaerobic; then, 0.5mmol of glycerophosphorylcholine and 100mmol of L-lactide are added into a Schlenk bottle, and the mixture is heated and stirred under the condition of an oil bath at the temperature of 120 ℃ to completely melt the L-lactide;
(2) After choline glycerophosphate and L-lactide are uniformly mixed, adding 0.2mmol of zinc acetate into a Schlenk bottle, and stirring and reacting at 120 ℃ for 24 hours to generate a polylactic acid zwitterion compound;
(3) Purification of polylactic acid zwitterionic compound: after the reaction is finished, taking out the Schlenk bottle, cooling to room temperature, and then adding dichloromethane into the Schlenk bottle to dissolve the generated polylactic acid zwitter-ion compound to obtain a polymer solution; then, dropwise adding the polymer solution into 50mL of diethyl ether for precipitation and suction filtration to complete primary purification; after repeating the dissolving, precipitating and filtering for three times, the polylactic acid zwitterionic compound is obtained after drying under the vacuum condition, and the yield is 91.3%.
As can be seen from cases 1-3, the polymerization method provided by the present disclosure can be used to obtain the polylactic acid zwitterionic compound, and the yield can reach 89-93.5%.
The polylactic acid zwitterionic compounds obtained in examples 1 to 3 were tested for protein adhesion resistance, hydrolysis resistance and safety, respectively, as follows:
(1) Anti-protein adhesion Properties
(1) The polylactic acid zwitterionic compounds prepared in cases 1 to 3 were respectively used to prepare the nano ionic solutions, and the preparation methods were as follows:
putting a certain amount of polylactic acid zwitterionic compound into a sample bottle, adding 5mL of acetone solution, and performing ultrasonic treatment until the polylactic acid zwitterionic compound is completely dissolved; then, adding 95mL of ultrapure water into a clean beaker, and stirring by adopting magnetic force; then, slowly dropwise adding the acetone solution into water under the stirring state, and continuing magnetic stirring for 4 hours until the acetone is completely volatilized to form the nanoparticle solution.
The particle sizes of the nano-ionic solutions obtained in cases 1-3 are listed in table 1.
TABLE 1
| Sample (I) | Particle size |
| Case 1 | 94-3±4.3nm |
| Case 2 | 115.2±7.5nm |
| Case 3 | 123.6±5.2nm |
(2) Separately, the prepared nanoparticle solutions were subjected to an anti-protein adhesion test
An appropriate amount of the nanoparticle solution was weighed, added to a phosphate buffer solution containing 10% bovine serum albumin with pH =7.4, and kept at 37 ℃ for every 10min, and the particle size of the nanoparticles was measured by dynamic light scattering. The test results are shown in fig. 2.
As can be seen from fig. 2, the particle size of the nanoparticle solution does not change much with time, indicating that the nanoparticles of the present disclosure have good resistance to protein adhesion, maintain good stability in a protein environment, and have good in vivo circulation stability.
(2) Hydrolysis Performance test
Hydrolysis experiments were carried out using the zwitterionic compounds of polylactic acid prepared in cases 1-3, respectively, and the specific experimental methods were as follows:
weighing a proper amount of polylactic acid zwitterion compound, and recording the mass W 0 Then added to a phosphate buffer pH =7.4 to give a polymer suspension, which is stirred constantly at 37 ℃ and, after every 24h, filtered, rinsed 3 times with ultrapure water and dried in vacuo at 40 ℃ to constant weight, the mass W is recorded t Then, the mass loss rate W% is calculated as follows:
W％＝(W t -W 0 )/W 0 ×100％。
the results of the above experiments on hydrolysis of the zwitterionic compound of polylactic acid in examples 1 to 3 are shown in FIG. 3. As can be seen from fig. 3, the mass loss rate of the polylactic acid zwitterionic compound gradually increases with the increase of time, which indicates that the polylactic acid zwitterionic compound provided by the present disclosure is degraded in a phosphate buffer, and indicates that the polylactic acid zwitterionic compound provided by the present disclosure has good degradation performance.
(3) Safety test
Toxicity experiments were performed on the polylactic acid zwitterionic compounds of cases 1-3, respectively, by the following specific methods:
inoculating hela cells in a 96-well plate, and culturing overnight by adopting a DMEM nutrient solution to ensure that the cells are completely attached to the wall; then changing the nutrient solution into DMEM nutrient solution containing 200ug/ml of the polylactic acid zwitterionic compound in the disclosure, and continuing culturing for 24h; then washing with fresh DMEM nutrient solution for 3 times, adding DMEM nutrient solution containing 10% of CCK-8, and continuing culturing for 4h; and finally, testing the absorbance of the cells in the 96-well plate at 450nm by using a microplate reader, and comparing the absorbance with a blank control group to obtain the survival rate data of the cells treated by the polylactic acid zwitter-ion compound. The blank control group was cells that were not treated with the polyactic zwitterionic compound, and the specific results are shown in FIG. 4.
Of these, CCK-8 reagent is redox by NAD + to a water-soluble yellow formazan product in the presence of an electron coupling reagent (i.e., when the cell is in a viable state). The more surviving cells produced formazan, the darker the color and the higher the absorbance, and it was considered that the absorbance was higher or lower in proportion to the number of surviving cells.
As can be seen from fig. 4, the cell survival data of the cells treated by the polyactic acid zwitterionic compound is not much different from the cell survival data of the control group, and the cell survival rates are all close to 100%, which indicates that the polyactic acid zwitterionic compounds prepared in cases 1-3 are not cytotoxic, have good biocompatibility and have application prospects in vivo.
The above-mentioned embodiments are intended to illustrate the objects, aspects and advantages of the present disclosure in further detail, and it should be understood that the above-mentioned embodiments are only illustrative of the present disclosure and are not intended to limit the present disclosure, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present disclosure should be included in the scope of the present disclosure.
Claims (10)
1. A method for synthesizing polylactic acid zwitterionic compound comprises the following steps:
(1) Mixing a zwitterionic compound with L-lactide, and heating to melt the L-lactide;
(2) Adding a catalyst into the mixture obtained in the step (1), and stirring for reaction to obtain the polylactic acid zwitterion compound;
wherein the zwitterionic compound comprises one of glycerophosphorylcholine, or a modified glycerophosphorylcholine;
the glycerophosphorylcholine modification comprises the following formula (I) or formula (II):
2. the method for synthesizing a zwitterionic compound of polylactic acid according to claim 1,
the step (1) also comprises a biodegradable material, wherein the biodegradable material comprises one or two of L-glycolide and epsilon-caprolactone;
wherein the molar ratio of the L-glycolide to the L-lactide is (0-100) to 1;
the molar ratio of the epsilon-caprolactone to the L-lactide is (0-100) to 1.
3. The method for synthesizing a zwitterionic polylactic acid compound according to claim 1,
the molar ratio of the zwitterionic compound to the L-lactide is 1: 10-100000;
the molar ratio of the catalyst to the L-lactide is (0.00001-0.1) to 1.
4. The method for synthesizing a zwitterionic compound of polylactic acid according to claim 3,
the molar ratio of the zwitterionic compound to the L-lactide is 1: 50-250;
the molar ratio of the catalyst to the L-lactide is (0.002-0.1) to 1.
5. The method for synthesizing a zwitterionic polylactic acid compound according to claim 1,
the catalyst comprises one or more of the following: a coordination compound formed by coordinating beta-diketone with zinc ions, magnesium ions and calcium ions respectively; coordination compounds formed by coordination of ketimine with zinc ions, magnesium ions and calcium ions respectively; the amino phenol is respectively coordinated with zinc ions, magnesium ions and calcium ions to form a coordination compound; a coordination compound formed by coordination of beta-diimine with zinc ions, magnesium ions and calcium ions respectively; a coordination compound formed by coordination of the Schiff base with zinc ions, magnesium ions and calcium ions respectively; and zinc lactate, zinc acetate, zinc chloride, calcium oxide, magnesium chloride, magnesium oxide, dibutyl magnesium, iron oxide, iron acetate, iron chloride, ferrocene, iron carboxylates, iron acetylacetonate, iron porphyrin, and aluminum chloride.
6. The method for synthesizing a zwitterionic polylactic acid compound according to claim 1,
after the step (2), the method further comprises the following steps:
(3) Purification of polylactic acid zwitterionic compound: adding the polylactic acid zwitterionic compound obtained in the step (2) into an organic solvent for dissolving the polylactic acid zwitterionic compound to dissolve the polylactic acid zwitterionic compound to obtain a polymer solution; then, the polymer solution is dripped into the organic solvent for precipitating the polylactic acid zwitterion compound to precipitate, and the precipitate is dried.
7. The method for synthesizing a zwitterionic compound of polylactic acid according to claim 6,
the organic solvent used for dissolving the polylactic acid zwitterion compound comprises one or more of chloroform, dichloromethane, acetone and ethyl acetate;
the organic solvent for separating out the polylactic acid zwitterion compound comprises one or more of diethyl ether, methanol and ethanol.
8. The method for synthesizing a zwitterionic compound of polylactic acid according to claim 1,
in the step (1), the reaction conditions are anhydrous and anaerobic, and the reaction temperature is 100-250 ℃;
in the step (2), the reaction temperature is 100-250 ℃, and the reaction time is 2-24h.
9. A polylactic acid zwitterionic compound prepared by the method of any one of claims 1 to 8.
10. Use of the polylactic acid zwitterionic compound of claim 9 in cosmetic injectable filling.
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| CN100424112C (en) * | 2007-01-05 | 2008-10-08 | 华南师范大学 | Method for preparing amino acid and lactic acid copolymer |
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