CN107629212B - Rosinyl phosphate surfactant with pH response and application thereof - Google Patents
Rosinyl phosphate surfactant with pH response and application thereof Download PDFInfo
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Abstract
The invention provides a rosinyl phosphate surfactant with pH response and application thereof. The rosin-based phosphate ester surfactant comprises a rosin-based functional group, a phosphate ester functional group and a P-O-C chemical bond. The surfactant provided by the invention combines the advantages of rosin and phosphate, has excellent pH intelligent responsiveness, excellent biocompatibility and biodegradability and lower cytotoxicity, can be used as a drug carrier to load hydrophobic cancer treatment drugs, realizes targeted release of the drugs, and is applied to the field of biomedicine.
Description
Technical Field
The invention relates to the technical field of fine chemical engineering, and particularly relates to a rosinyl phosphate surfactant with pH response and application thereof.
Background
Phospholipids are lipid molecules and are a major component of all cell membranes. Phospholipids are amphiphilic and therefore can form lipid bilayers. Phospholipid molecules are composed of two hydrophobic fatty acid "tails" forming a hydrophilic phosphate "head" that is composed of alcohol or glycerol molecules linked together. Phospholipid compounds have received wide attention due to their high pharmaceutical safety, good biocompatibility, high therapeutic efficiency, high pharmaceutical activity, and the like. In addition, phospholipids have high hydrophobicity and super-hydrophilicity, so that they can be used as cores of drug carriers and are widely used as drug carriers.
Phosphate ester is a kind of phosphoric acid ester compound with a phospholipid-like structure, and is widely used as a surfactant in many fields such as textiles, leather, paint and the like due to excellent emulsifiability, electric resistance, biodegradability and dispersibility. Different hydrophobic and hydrophilic groups are introduced to endow the phosphate with different surface properties, so that the application of the phospholipid is expanded.
Resinic acids (abietic acid, dehydroabietic acid, pimaric acid, etc.) are the main components of rosin obtained from pine and bark exudates, are small molecule biomasses rich in hydrocarbons, with characteristic bulky hydrophenanthrene ring structures, making them unique from other natural biomasses. Because the rosin structure contains unsaturated double bonds, different functional groups can be connected through addition reaction to endow different properties, and the reactivity of the rosin can be enhanced through the acyl chlorination of carboxyl in the rosin. Rosin-based surfactants have been extensively studied.
Disclosure of Invention
The first purpose of the invention is to provide a rosin-based phosphate ester surfactant, which comprises a rosin-based functional group, a phosphate ester functional group and a P-O-C chemical bond.
The structural formula of the rosin-based phosphate surfactant comprises a rosin-based functional group, a phosphate functional group and a P-O-C chemical bond, so that a novel rosin phosphate surfactant is obtained, the rosin phosphate surfactant changes the space structure of a lipophilic group compared with lecithin due to the introduction of a rosin ternary rigid skeleton structure, and in the self-assembly process, the three-membered ring has more excellent assembly performance and stability due to the rigid structure and strong lipophilic performance, so that various structural assemblies can be formed, and the surfactant has intelligent responsiveness to the pH value and different self-assembly forms under different pH values. Because the introduced rosin group is a natural product, the rosin modified polyvinyl acetal has good biocompatibility and lower cytotoxicity, and has excellent self-assembly performance, compared with other surfactants, the rosin modified polyvinyl acetal can be used as a drug carrier and realizes the targeted release of drugs.
The rosin-based phosphate surfactant is prepared by esterification reaction of polyphosphoric acid, phosphorus oxychloride or spiral phospholipid and a compound containing rosin base.
Wherein the compound containing rosin group is rosin acyl chloride or rosin amine ester modified by triethanolamine.
The rosin acyl chloride is preferably prepared by using chloroform as a solvent and reacting rosin with phosphorus trichloride.
Wherein the molar ratio of the rosin to the phosphorus trichloride is preferably 1 (2-3); the reaction temperature is preferably 50-55 ℃, the reaction time is 3-4h, phosphorus trichloride is slowly dripped into rosin, and the mixture is steamed in a rotary manner after the reaction is finished, so that the phosphorus trichloride-containing rosin is obtained.
In a preferred embodiment of the present invention, the rosin-based phosphate surfactant is selected from one of four structural compounds of the following formula I, formula II, formula III, and formula IV:
wherein n and m are positive integers.
Wherein, the compound of the formula I is obtained by modifying rosin acyl chloride with soybean lecithin, and the reaction process is as follows:
and (2) reacting soybean lecithin with rosin acyl chloride in the presence of triethylamine to obtain the compound shown in the formula 1.
Among them, the solvent in the reaction may be a solvent commonly used in the art, and is preferably methylene dioxide.
The reaction steps are as follows: adding triethylamine in a preset amount into a soybean lecithin solution of dichloromethane as a catalyst and an acid-binding agent, dropwise adding a dichloromethane solution of rosin acyl chloride by using a constant-pressure dropping funnel when the material temperature reaches 40-90 ℃, controlling the temperature to be 40-90 ℃, cooling to room temperature after the reaction is finished, and removing dichloromethane to obtain the rosin acyl chloride. Among them, the temperature is preferably 60 ℃.
Wherein the molar ratio of triethylamine to rosin acyl chloride is 1-3:1, and the molar ratio of soybean lecithin to rosin acyl oxide is 1: 1-3.
In the above step, the product may be washed with 10% sodium hydroxide solution after the reaction is finished and cooled to room temperature to remove impurities. After washing with a sodium hydroxide solution, diethyl ether was added thereto, and the mixture was separated with a separatory funnel, and the aqueous phase was discarded, and anhydrous magnesium sulfate was added to the resulting oil phase to remove the remaining water.
In a preferred embodiment of the invention, the compound of formula II is prepared by esterification of rosin acyl chloride with triethanolamine to form II-a, then with polyphosphoric acid to form II-b, and finally quaternization with dimethyl sulfate.
Preferably: triethanolamine
With acid chlorides
Esterification reaction is carried out to obtain an intermediate product II-a
Then reacting with polyphosphoric acid to generate a compound shown as a formula II-b
Quaternization with dimethyl sulfate to obtain the compound of formula II
The preparation method of II-a can be as follows: adding triethanolamine slowly into xylene solution of rosin acyl chloride under the condition of vacuumizing and stirring at a constant speed, heating to 140 ℃ and 150 ℃, reacting for 2-6h, and removing impurities to obtain the rosin acyl chloride.
Wherein, the molar ratio of the rosin acyl chloride to the triethanolamine can be 1-3:1, and is preferably 1.8: 1.
Wherein, the impurity removing step can be as follows: using 10% sodium hydroxide solution lotion to saponify the synthesized triethanolamine rosin ester, wherein the rosin acyl chloride is insoluble in water; and then mixing the saturated sodium chloride aqueous solution and the rosin triethanolamine ester according to the volume ratio of 2: 8 add saturated sodium chloride solution. And finally, separating by using a separating funnel, discarding the water phase, adding anhydrous magnesium sulfate into the obtained oil phase, and removing the residual water to obtain the purified product, namely the rosin amine ester II-a.
The preparation method of II-b can be as follows: mixing rosin amine ester II-a and polyphosphoric acid in a ratio of 4:1, reacting in xylene as a solvent, heating a reaction system to 150 ℃ for reaction, until substantially no gas is discharged, and regarding the reaction as the reaction is substantially finished for about 5-8h, and removing impurities to obtain the rosin amine ester II-a.
Wherein, the impurity removing step can be specifically as follows: after the reaction is finished, washing with 10% sodium hydroxide sodium solution to remove polyphosphoric acid, extracting with diethyl ether, retaining oil phase, and removing diethyl ether by rotary evaporation.
The preparation method of formula II may be: under the condition of isopropanol as a solvent, heating the rosin phospholipid II-b to be completely molten, and slowly dripping dimethyl sulfate to carry out quaternization reaction under the condition of stirring and refluxing. After the dropwise addition, the reaction mixture is heated to the reaction temperature and reacted for 8 hours under the reflux condition. After the reaction was completed and cooled, the solvent was removed by rotary evaporation.
The reaction sequence of the preparation method of the compound of the formula II is specifically as follows:
in a preferred embodiment of the present invention, the compound of formula III can be prepared by reacting rosin acid chloride with triethanolamine and phosphorus oxychloride.
The reaction process can be specifically as follows:
preferably, triethanolamine may be used
Esterification reaction is carried out on the rosin acyl chloride to obtain an intermediate product III-a rosin amine ester
Then reacting with phosphorus oxychlorideTo obtain the product III phosphate
In a preferred embodiment, the preparation of III-a may be: slowly adding the rosin acyl chloride xylene solution into the triethanolamine xylene solution under the condition of vacuumizing and uniform stirring, controlling the molar ratio to be 1-3:1, heating to 110-. Among them, it is preferable to control the molar ratio of 2: 0.95, heating to 150 ℃, reacting for 6h, and removing impurities to obtain the product.
The step of removing impurities may be: using a proper amount of about 10% sodium hydroxide sodium chloride solution lotion to saponify the synthesized triethanolamine rosin ester, wherein the rosin acyl chloride is insoluble in water; and then mixing the saturated sodium chloride aqueous solution and the rosin triethanolamine ester according to the volume ratio of 2: 8 add saturated sodium chloride solution. Finally, the mixture was separated by a separatory funnel, the aqueous phase was discarded, and anhydrous magnesium sulfate was added to the obtained oil phase to remove the remaining water.
In a preferred embodiment, the preparation method of III may be: mixing rosin amine ester III-a and phosphorus oxychloride in a ratio of 3:2, adding xylene as a solvent, adding triethylamine as a catalyst, and absorbing gas generated by reaction by using a solution. Heating the system to 150 ℃ under mechanical stirring, reacting for 5-8h, washing with cold water after the reaction is finished, and removing phosphorus oxychloride to obtain the phosphorus oxychloride.
In a preferred embodiment, the compound of formula IV can be prepared by reacting rosin acid chloride with triethanolamine and then with the esterification product of phosphorus oxychloride with pentaerythritol.
The reaction sequence of the process for the preparation of the compound of formula IV may be:
the compound of formula IV takes phosphorus oxychloride as raw material and acetonitrile as solvent to perform esterification reaction with pentaerythritol to generate intermediate product IV-a
And then reacting with III-a to obtain the compound.
In a preferred embodiment, the preparation of IV-a may be: mixing and stirring acetonitrile, pentaerythritol and phosphorus oxychloride according to the proportion, slowly heating to 50-90 ℃, reacting for 1-3h, adding AlCl3When white precipitate is generated in the reaction system, adding AlCl every half an hour3Stirring for 5-7 hours at the temperature of 60-90 ℃ gradually and constantly, and removing impurities to obtain the product.
Wherein, the impurity removal can be as follows: after the reaction is finished, rotary evaporation is carried out, and after the system is cooled, the product is sequentially subjected to cold water, anhydrous ether and dichloromethane washing and suction filtration to be dried. A white sandy solid was obtained.
In a preferred embodiment, the preparation of IV may be: mixing rosin amine ester III-a and spiral phospholipid in a ratio of 1:1, taking dimethylbenzene as a solvent, heating the system to 150 ℃ under mechanical stirring for reaction until no gas is discharged basically, and washing with cold water after the reaction is finished to remove phosphorus oxychloride.
The second object of the invention also provides a preparation method of the surfactant, which comprises the step of carrying out esterification reaction on a compound containing rosin groups as a raw material and polyphosphoric acid, phosphorus oxychloride or spiral phospholipid.
The invention also provides the application of the surfactant in preparing a drug solubilizer or a drug carrier.
The rosin-based phosphate surfactant provided by the invention contains phosphate, amino hydrophilic groups and rosin ternary rigid skeleton lipophilic groups, in the self-assembly process, the rigid structure and strong lipophilicity of a three-membered ring are realized, and the phosphate and amino hydrophilic groups enable the rosin-based phosphate surfactant to have more excellent assembly performance and stability, can form various structural assemblies, has intelligent responsiveness to pH values, and has different self-assembly forms at different pH values. The space structure and the hydrophilic and lipophilic properties of the provided compound are similar, the compound has similar self-assembly performance, integrates the advantages of rosin and phospholipid, has better biocompatibility, biodegradability and lower cytotoxicity, can be used as a drug carrier for loading hydrophobic cancer treatment drugs, has a targeted drug loading effect, and can be applied to the field of biomedicine.
Drawings
FIG. 1 is an infrared spectrum of a compound of formula I in accordance with the present invention;
FIG. 2 is a surface tension diagram of compound I in an example according to the present invention;
FIG. 3 is a graph of the cellular activity of compound I (PC-R) according to the invention in example I;
FIG. 4 is a cell culture micrograph of Compound I (PC-R) according to the present invention example;
FIG. 5 is a transmission electron micrograph at a concentration of 2CMC of Compound I according to example of the present invention;
FIG. 6 is a transmission electron micrograph at 5CMC of the concentration of compound I in the example according to the invention;
FIG. 7 is a transmission electron micrograph of compound I at a concentration of 10CMC in accordance with this invention;
fig. 8 is a transmission electron micrograph of compound I at 40CMC, pH 3, 6, 9, 12 according to an example of the present invention;
FIG. 9 is a graph of the drug release profile at two pH conditions for a concentration of 40CMC of compound I in accordance with an example of the present invention;
FIG. 10 is an IR spectrum of a compound of III-a according to example of the present invention;
FIG. 11 is an IR spectrum of a compound of IV-a in accordance with the present invention.
Detailed Description
The following describes embodiments of the present invention in further detail with reference to the examples and the accompanying drawings. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products available from regular distributors, not indicated by the manufacturer.
The modified rosin acid chlorides referred to in the examples were prepared as follows: taking 100g of dehydrogenated rosin (obtained by carrying out heavy knotting on first-grade disproportionated rosin by adopting ethanol)Crystallized 3-5 times), dissolved in 150ml chloroform, and PCl3Adding into four-mouth bottle, and mixing with modified rosin and PCl3Slowly dropwise adding a chloroform solution of the modified rosin in a molar ratio of 1 (2-3), controlling the reaction temperature at 55 ℃, continuing to react for 3 hours after dropwise adding, transferring the reaction mixture into a round-bottom flask, and carrying out rotary evaporation to obtain an orange viscous product, namely rosin acyl chloride.
EXAMPLE 1 preparation of the Compound of formula I
Firstly, dissolving 10g of soybean lecithin in 30mL of dichloromethane, pouring the soybean lecithin solution into a three-neck flask, adding 3mL of triethylamine as a catalyst, dropwise adding 30mL of dichloromethane solution containing 4.8g of rosin acyl chloride by using a constant-pressure dropping funnel when the material temperature reaches 60 ℃, controlling the temperature at 60 ℃, reacting for 5 hours, cooling to room temperature after the reaction is finished, and saponifying the obtained product into salt by using 10% sodium hydroxide solution to wash the product insoluble in water; and finally adding ether, separating by using a separating funnel, discarding the water phase, adding anhydrous magnesium sulfate into the obtained oil phase, and removing the residual water to obtain the purified product. Rotary evaporation to obtain the compound of formula I in a yellow viscous state.
EXAMPLE 2 preparation of Compounds of formula II-a
Dissolving 10g of rosin acyl chloride in 140ml of dimethylbenzene, adding the mixture into a four-neck flask, slowly adding triethanolamine under the conditions of vacuumizing and uniform stirring, and controlling the molar ratio to be 1.8:1, heating to 150 ℃ and reacting for 6 h. Using a proper amount of 10% sodium hydroxide sodium chloride solution lotion to saponify the synthesized triethanolamine rosin ester, wherein the rosin acyl chloride is insoluble in water; and then mixing the saturated sodium chloride aqueous solution and the rosin triethanolamine ester according to the volume ratio of 2: 8 add saturated sodium chloride solution. And finally, separating by using a separating funnel, discarding the water phase, adding anhydrous magnesium sulfate into the obtained oil phase, and removing the residual water to obtain the purified product, namely the rosin amine ester compound II-a.
EXAMPLE 3 preparation of the Compound of formula II
Putting II-a and polyphosphoric acid into a four-mouth bottle with a mechanical stirrer, a reflux condenser tube and a thermometer in a ratio of 4:1, adding xylene as a solvent, and absorbing gas generated by the reaction by using the solution. Heating the system to 150 ℃ under mechanical stirring for reaction until no gas is discharged basically, and taking the reaction as the reaction basically finishes for about 5-8h, and washing with a proper amount of 10% sodium hydroxide sodium chloride solution to saponify the rosin acyl chloride which is insoluble in water; and then mixing the saturated sodium chloride aqueous solution and the rosin triethanolamine ester according to the volume ratio of 2: 8 add saturated sodium chloride solution. And finally, separating by using a separating funnel, discarding the water phase, adding anhydrous magnesium sulfate into the obtained oil phase, and removing the residual water to obtain a purified product II-b.
10g (exactly to 0.001g) of esteramine II-b is added into a 250ml three-neck flask, 1g (10 percent of the total mass ratio) of isopropanol is added as a solvent, the mixture is heated to 75 ℃ until the mixture is completely melted, and 1.715g (1: 2.97) of dimethyl sulfate in a molar ratio n (esteramine) n (dimethyl sulfate) is slowly added dropwise under the condition of stirring and refluxing for quaternization. After the dropwise addition, the reaction mixture is heated to the reaction temperature and reacted for 8 hours under the reflux condition. And after the reaction is finished and cooled, removing the solvent by rotary evaporation to obtain the product, namely the ester quaternary ammonium salt III.
EXAMPLE 4 preparation of the Compound of formula III-a
Adding 8.2ml of triethanolamine into a four-neck flask, slowly adding 10g of rosin acyl chloride xylene solution under the conditions of vacuumizing and uniform stirring, and controlling the molar ratio to be 0.95: 2, heating to 150 ℃ and reacting for 6 h. Using a proper amount of 10% sodium hydroxide sodium chloride solution lotion to saponify the synthesized triethanolamine rosin ester, wherein the rosin acyl chloride is insoluble in water; and then mixing the saturated sodium chloride aqueous solution and the rosin triethanolamine ester according to the volume ratio of 2: 8 add saturated sodium chloride solution. And finally, separating by using a separating funnel, discarding the water phase, adding anhydrous magnesium sulfate into the obtained oil phase, and removing the residual water to obtain the purified product III-a.
EXAMPLE 5 preparation of the Compound of formula III
Putting the rosin amine ester III-a and phosphorus oxychloride into a four-mouth bottle with a mechanical stirrer, a reflux condenser tube and a thermometer in a ratio of 3:2, adding xylene as a solvent, and absorbing gas generated by the reaction by using the solution. Heating the system to 150 ℃ under mechanical stirring for reaction until no gas is discharged basically, and taking the reaction as the reaction basically finishes for about 5-8h, and washing with a proper amount of 10% sodium hydroxide sodium chloride solution to saponify the rosin acyl chloride which is insoluble in water; and then mixing the saturated sodium chloride aqueous solution and the rosin triethanolamine ester according to the volume ratio of 2: 8 add saturated sodium chloride solution. And finally, separating by using a separating funnel, discarding the water phase, adding anhydrous magnesium sulfate into the obtained oil phase, and removing the residual water to obtain a purified product III.
EXAMPLE 6 preparation of Compounds of formula IV-a
In a 500mL four-necked flask equipped with a condenser and a thermometer, 370mL of acetonitrile, 20g of pentaerythritol, and 34mL of phosphorus oxychloride were added all at once. Stirring and heating slowly, when the temperature rises to 50 ℃, HCl begins to be generated, when the temperature rises to 76 ℃, the system is thoroughly clarified, reacting for 1-2h, and adding about 0.125g AlCl3Gradually generating white precipitate, and then adding 0.125g AlCl every half hour3Adding the mixture for 8 times, keeping the temperature at 82 ℃ gradually as the reaction proceeds, stirring for 5-7 hours to allow the mixture to react fully, performing rotary evaporation after the reaction is completed, cooling the system, sequentially performing cold water, anhydrous ether, dichloromethane and lotion on the product, and performing suction filtration to dry the product as far as possible. A white sandy solid was obtained.
EXAMPLE 7 preparation of the Compound of formula IV
In a 500ml four-necked flask equipped with a condenser and a thermometer, 148ml of acetonitrile, 8g of pentaerythritol and 13.6ml of phosphorus oxychloride were charged in one portion. Stirring and heating slowly, when the temperature is raised to 50 deg.C, HCl is generated, when the temperature is raised to 76 deg.C, the system is thoroughly clarified, reacting for 1-2h, adding about 0.04g AlCl3Gradually generating white precipitate, and then adding 0.04g AlCl every half hour3Adding the mixture for 8 times, keeping the temperature at 82 ℃ gradually as the reaction proceeds, stirring for 5-7 hours to allow the mixture to react fully, performing rotary evaporation after the reaction is completed, cooling the system, sequentially performing cold water, anhydrous ether, dichloromethane and lotion on the product, and performing suction filtration to dry the product as far as possible. White sandy solid rosin amine ester is obtained.
Putting the rosin amine ester and the spiral phospholipid obtained in the step into a four-mouth bottle with a mechanical stirrer, a reflux condenser tube and a thermometer according to the proportion of 1:1, adding 150ml of xylene as a solvent, and absorbing gas generated by reaction by using NaOH solution. Heating the system to 150 ℃ under mechanical stirring for reaction until no gas is discharged basically, and washing with cold water to remove phosphorus oxychloride after the reaction is finished for about 5-8 hours.
Test example characterization and testing
JEM-1010TEM tested the self-assembled state of the compound in solution, operating at 120 kV.
The prepared sample is recorded in an infrared spectrum through Fourier transform infrared (Thermo Nicolet 380FTIR) spectrum, and the wave number range is 500-4000cm-1。
The leaching solution of the material was subjected to hela cytotoxicity test structural characterization by MTS method.
Drug loading performance was tested as follows: dissolving 0.25mg/mL adriamycin hydrochloride in deionized water, performing ultrasonic treatment to completely dissolve the adriamycin hydrochloride, then dropwise adding the adriamycin hydrochloride into a compound micelle aqueous dispersion with a certain concentration, wherein the volume of the solution is 4mL in total, performing ultrasonic stirring at room temperature in a dark place for 0.5h, and finally filtering the obtained micelle solution by a 0.15-micrometer filter to remove residual substances such as adriamycin and the like. And (3) measuring the absorbance of the obtained filtrate at 485nm by using an ultraviolet spectrophotometer, then calculating the content of the adriamycin which is not loaded on the micelle according to an adriamycin standard curve, and finally calculating the content of the adriamycin loaded on the micelle. The Encapsulation Efficiency (EE) and drug Loading (LC) of doxorubicin were calculated as follows:
in vitro release of doxorubicin (phosphate buffered solution) release of appropriate concentration:
in vitro release studies were performed on the target prodrug using phosphate buffered solutions at pH 7.4 and pH 5. 5mL of DOX-loaded micelles were dialyzed in 95mL of buffer solution enclosed in dialysis bags (3500Da) while maintaining the system temperature at 37 ℃ and the rotation speed at 100rpm, and then 2mL of buffer solution was taken out of 95mL at predetermined time intervals (0.5, 1, 1.5, 2, 3, 4,5, 6, 8, 12h) for doxorubicin content determination, while 2mL of fresh buffer solution was added. The content of released adriamycin in the obtained buffer solution is determined by measuring the absorbance at 485nm by using an ultraviolet spectrophotometer. This was repeated three times. Wherein the content of the first and second substances,
wherein, Er: cumulative release of the drug; ve: displacement volume of PBS; ci: the concentration of the released liquid during the ith replacement sampling; v0: total volume of release medium; n: the number of times PBS was replaced; m isdrug: the total mass of the drug carried by the nano particles.
Wherein, Ci: the concentration of the released liquid during the ith replacement sampling; v: release medium ensembleAccumulating; n: the number of times PBS was replaced; m isdrug: total mass of drug carried by the nanoparticles
A compound of formula I
The IR spectrum is shown in FIG. 1, and 1738cm compared with soybean lecithin-1Is the C ═ O stretching vibration peak of ester, 1051cm-1、1063cm-1Is P-O-C stretching vibration peak, 1230cm-1P ═ O stretching vibration peak. 1804cm-1The point is the bending vibration peak of O-P-O-C-O, which indicates the successful synthesis of the compound I.
Surface Property test
FIG. 2 is a surface tension chart of compound I (PC-R), soybean lecithin is a natural surfactant, and the critical surface tension is 54.45 mN/m. The surface tension of the modified rosin acyl chloride is shown in FIG. 2. CMC is 0.4mmol/L, and the surface tension at the critical micelle concentration is 41.98 mN/m. The surface property after modification is better.
Cytotoxicity test
The cytotoxicity of the test compound was tested by using a cell viability assay. Briefly, Hela cells (ATCC, USA) were expanded and maintained in Dulbecco's Modified Eagle medium (HyClone, Logan, UT, USA) supplemented with 10% fetal bovine serum (Invitrogen, Carlsbad, Calif., USA) and 100U/ml penicillin and 100mg/ml streptomycin at 37 deg.C, 5% CO2Cells were harvested at log phase of growth and final concentration 3 × 103Individual cells/well were seeded onto 96-well plates. After 24 hours of culture, the cell cultures were treated with 200mM concentration of the drug. After culturing the cells in [3- (4, 5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2 (4-sulfophenyl) -2H-tetrazole/phenazine methosulfate (MTS/PMS; Promega, Madison, Wis., USA) for 72H, 20. mu.L of them were taken out and added to each well, and the absorbance at 490nm was measured. A control group treated with 5% ethanol was also performed.
FIGS. 3 and 4 are a graph showing the cell viability of Compound I (PC-R) and a microscopic graph showing that the cell viability reached 90% or more after 72 hours at concentrations of 3525 and 70510ug/ml, respectively, when compound I (PC-R) was cultured at a concentration of 70510ug/ml, indicating that Compound I has low cytotoxicity and excellent biocompatibility, while the uniform and ordered arrangement of hella cells in FIG. 4 also demonstrates that the cell viability is high, which is consistent with the results in FIG. 3.
Self-assembly capability at different concentrations
FIGS. 5 to 7 are transmission electron micrographs of Compound I at 2, 5 and 10CMC, respectively. At a surfactant concentration of 2CMC, the micelles are spherical in shape with a diameter below 100nm, at an increase in concentration to 5CMC, they are elliptical in shape and within 10nm in size, and at a concentration of 10MC, a vesicular structure appears. The compound I is shown to have excellent self-assembly performance.
pH-value responsiveness of Compound I
Fig. 8 is a transmission electron micrograph of compound i at 40CMC pH 3, 6, 9, 12, respectively; as can be seen from an electron microscope image, the compound I is self-assembled into a sheet shape, a fusiform shape, a vesicle and a fiber tube structure in an aqueous solution at 40CMC respectively, and the pH sensitivity and the excellent pH response performance are shown.
Drug loading and targeting
When the pH value of the compound I is 7.4 at 40CMC, the Encapsulation Efficiency (EE) and the drug loading rate (LC) can reach 82.5 percent and 20 percent, which shows that the compound I has excellent drug loading performance.
As can be seen from the release curve of fig. 9, the drug-loaded release is greatly different under two different pH conditions, indicating that a targeted release effect on pH can be achieved.
Compounds of formula III-a
The IR spectrum is shown in FIG. 10 and 1724cm-1Is the C ═ O stretching vibration peak of ester, 1642cm-1The peak is C ═ O stretching vibration peak, and the C ═ C stretching vibration peak in abietic acid skeleton is 1462cm-1 and 1380cm-1And 1170cm-1Appeared at 3405cm-1Is an-OH stretching vibration peak, which indicates the successful synthesis of the compound III-a.
IR spectrum of compound of formula IV-a
The IR spectrum is shown in FIG. 11, 1308cm-1Is the P ═ O stretching vibration peak of ester, 1020cm-1Is P-O-C stretching vibration peak, 922cm-1、850cm-1、782cm-1And 688cm-1Is the spiral vibration peak, 550cm-1Is a P-Cl stretching vibration peak, which indicates the successful synthesis of the compound IV-a.
Finally, the method of the present invention is only a preferred embodiment and is not intended to limit the scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (13)
1. A rosin-based phosphate ester surfactant comprises a rosin-based functional group, a phosphate functional group and a P-O-C chemical bond, wherein the rosin-based phosphate ester surfactant is a compound shown as the following formula I:
2. the rosin-based phosphate surfactant according to claim 1, wherein the compound of formula I is obtained by modifying rosin acyl chloride with soybean lecithin, and the reaction process is specifically as follows:
and (2) reacting soybean lecithin with rosin acyl chloride in the presence of triethylamine to obtain the compound shown in the formula I.
3. A rosin-based phosphate surfactant comprising a rosin-based functional group and a phosphate functional group and a P-O-C chemical bond, the rosin-based phosphate surfactant being one of a compound of formula II, a compound of formula III and a compound of formula IV:
wherein n and m are positive integers.
4. The rosin-based phosphate surfactant according to claim 3, wherein the rosin-based phosphate surfactant is prepared by esterification of polyphosphoric acid, phosphorus oxychloride or spirophospholipid with a compound containing a rosin group.
5. The rosin-based phosphate ester surfactant according to claim 4, wherein the rosin-based compound is rosin acid chloride or a triethanolamine-modified rosin amine ester.
6. The rosin-based phosphate surfactant according to claim 5, wherein the rosin acyl chloride is prepared by reacting rosin with phosphorus trichloride in chloroform as a solvent.
7. The rosin-based phosphate ester surfactant according to claim 3, wherein the reaction sequence of the preparation method of the compound of formula II is as follows:
the compound of formula II is prepared by esterification reaction of rosin acyl chloride raw material and triethanolamine to generate II-a, then reaction with polyphosphoric acid to generate II-b, and finally quaternization with dimethyl sulfate.
8. The rosin-based phosphate surfactant according to claim 3, wherein the compound of formula III is prepared by reacting rosin acyl chloride with triethanolamine and phosphorus oxychloride; the reaction process is as follows:
9. the rosin-based phosphate ester surfactant according to claim 3, wherein the reaction sequence of the preparation method of the compound of formula IV is as follows:
the compound shown in the formula IV is prepared by reacting rosin acyl chloride with triethanolamine and then reacting with an esterification reaction product of phosphorus oxychloride and pentaerythritol.
10. The rosin-based phosphate surfactant according to any one of claims 1 to 9, wherein the rosin-based phosphate surfactant has pH responsiveness.
11. The method for producing a rosin-based phosphate surfactant according to claim 1 or 2, which comprises the step of reacting soybean lecithin with rosin acyl chloride in the presence of triethylamine.
12. The method for producing the rosin-based phosphate surfactant according to any one of claims 3 to 9, which comprises the step of subjecting a rosin-based compound as a starting material to an esterification reaction with polyphosphoric acid, phosphorus oxychloride or spirophospholipid.
13. Use of a rosin-based phosphate ester surfactant according to any one of claims 1 to 10 for the preparation of a drug solubilizer or a drug carrier or a targeted drug release carrier.
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| CN106823984A (en) * | 2016-12-22 | 2017-06-13 | 北京林业大学 | A kind of abietyl tertiary amine class surfactant and its preparation method and application |
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