CN110317335B - PH responsive compound and preparation method and application thereof - Google Patents
PH responsive compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a pH responsive compound and a preparation method and application thereof, wherein a substance A and vinyl diglycol ether are used as raw materials, wherein the substance A is castor oil or ricinoleic acid, and the castor oil and the ricinoleic acid can be extracted by castor oil and belong to renewable resources; the whole reaction is carried out in a reaction system taking dichloromethane as a solvent, the method only has one step of reaction, has few reaction steps and is suitable for industrial production; meanwhile, the reaction temperature is between 15 and 25 ℃, the reaction condition is very mild, and the influence on human bodies is avoided. The pH responsive compound prepared by the invention is an amphiphilic compound and can be self-assembled into a nano micelle in water; the nano micelle has good biocompatibility and no toxicity, does not influence the health of a human body, and cannot be rejected by the human body; meanwhile, the compound can be degraded under the acidic condition of weak acid or medium-strong acid, is used as a drug carrier, and is particularly suitable to be used as a targeting carrier of some anticancer drugs.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a pH responsive compound and a preparation method and application thereof.
Background
The drug carrier is a system which can change the mode of entering the human body and the distribution of the drug in the human body, control the release speed of the drug and deliver the drug to a target organ; the drug carrier material plays a very important role in the research of controlled release preparations and is beneficial to improving the treatment effect of the drug; the pH responsive nano micelle has stronger targeting property, so that the medicine can quickly act on the diseased part, thereby improving the medicine effect and quickening the recovery time of the patient, and the pH responsive nano micelle is greatly concerned by scientists.
However, the existing pH responsive substances have poor biocompatibility, are easily rejected by human bodies, have certain toxicity, can cause harm to the human bodies, and greatly limit the practical application of the pH responsive substances to drug carriers.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a pH responsive compound, a preparation method and application thereof, wherein the compound is non-toxic, has good biocompatibility and can be used as a drug carrier. In order to achieve the purpose, the invention provides the following technical scheme: a pH-responsive compound comprises the following substances in parts by weight:
substance A: 1 part;
ethylene glycol vinyl ether: 2-6 parts;
the substance A is castor oil or ricinoleic acid.
As a further improvement of the invention, when the substance A is castor oil, the pH-responsive compound has the formula
The number average molecular weight thereof was 1500-12000.
As a further improvement of the invention, when the substance A is ricinoleic acid, the structural formula of the pH-responsive compound is
The number average molecular weight thereof is 500-4500.
As a further improvement of the present invention, a process for the preparation of a pH-responsive compound, comprising the steps of: the method comprises the following steps: preparing raw materials according to the set weight part, adding the substance A and the accelerant into a reaction vessel filled with a solvent, stirring and mixing, and forming a first mixed solution after uniformly mixing;
step two: adding the vinyl diglycol ether into a reaction container filled with a solvent, stirring and mixing, and forming a second mixed solution after uniformly mixing;
step three: adding the second mixed solution into the first mixed solution, stirring and mixing, and then reacting; and after the reaction is finished, filtering and purifying to obtain the pH responsive compound.
As a further improvement of the invention, the promoter is a mixture of p-toluenesulfonic acid and zinc acetate, and the mass ratio of the p-toluenesulfonic acid to the zinc acetate is 2: 1.
As a further improvement of the invention, the solvent in step one and step two is dichloromethane.
As a further improvement of the invention, the step three of adding the second mixed solution into the first mixed solution for stirring and mixing refers to dropwise adding the second mixed solution into the first mixed solution by using a dropper at a dropping speed of one drop for two seconds under the condition that the rotating speed is 200-400 r/min.
As a further improvement of the invention, the reaction in the third step is carried out at a rotation speed of 200-400r/min and a temperature of 15-25 ℃, and the reaction time is 3-5 h.
As a further improvement of the invention, the pH-responsive compound is used as a pharmaceutical carrier.
The invention has the beneficial effects that: the material A and the vinyl diglycol ether are used as raw materials, wherein the material A is castor oil or ricinoleic acid, and the castor oil and the ricinoleic acid can be extracted by castor oil and belong to renewable resources; the raw materials used in the invention have wide sources, and are nontoxic and harmless; meanwhile, the raw materials are low in price; the whole reaction is carried out in a reaction system taking dichloromethane as a solvent, the method only has one step of reaction, has few reaction steps and is suitable for industrial production; meanwhile, the reaction temperature is between 15 and 25 ℃, the whole reaction is carried out under normal pressure, the reaction condition is very mild, no influence is caused on human bodies, no toxic or harmful substance is generated in the reaction process, and the safety of workers is ensured, and the method is green and environment-friendly.
During the reaction, the substance A is firstly mixed with dichloromethane to form a first mixed solution, and simultaneously the vinyl diglycol ether is also mixed with dichloromethane to form a second mixed solution; then adding the second mixed solution into the first mixed solution for mixing reaction; the purpose of doing so is to make substance A and ethylene glycol vinyl ether disperse more evenly in solvent dichloromethane, react more fully; when the second mixed solution is added into the first mixed solution, the invention adopts a dropping method, and the dropping speed is one drop in two seconds; the purpose of this operation is to prevent the reaction from being too violent and producing more by-products; the reaction is milder by adopting dropwise addition, and an ideal product is finally prepared easily; as one of creativity of the invention, the solution is also added with an accelerant which is a mixture of p-toluenesulfonic acid and zinc acetate, and under the combined action of the two substances, the reaction rate of reactants can be greatly accelerated, and the reaction time is shortened; and the polymerization degree of the product can be greatly improved, the product with higher molecular weight is easily generated, and the practical application value of the product is improved.
The pH responsive compound prepared by the invention is an amphiphilic compound and can be self-assembled into a nano micelle in water; the nano micelle has good biocompatibility and no toxicity, does not influence the health of a human body, and cannot be rejected by the human body; meanwhile, the compound can be degraded under the acidic condition of weak acid or medium-strong acid, is used as a drug carrier, and is particularly suitable to be used as a targeting carrier of some anticancer drugs.
Drawings
FIG. 1 is a Gel Permeation Chromatography (GPC) spectrum of the pH-responsive compound obtained in example 1
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of the pH-responsive compound prepared in example 1;
FIG. 3 is an infrared spectrum of a pH-responsive compound prepared in example 1;
FIG. 4 is a DLS particle size distribution diagram of the pH-responsive compound nanomicelle prepared in example 1 under acidic conditions;
FIG. 5 is a NMR chart of a pH-responsive compound obtained in example 7;
FIG. 6 is an infrared spectrum of a pH-responsive compound prepared in example 7;
FIG. 7 is a DLS particle size distribution diagram of the pH-responsive compound nanomicelle prepared in example 7 under acidic conditions;
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and examples.
Example 1
A method of preparing a pH-responsive compound comprising the steps of:
the method comprises the following steps: adding 5g of castor oil and 15mg of accelerator into a reaction vessel filled with 20ml of dichloromethane, stirring and mixing, stirring for 10min under the condition that the rotating speed is 400r/min, and uniformly mixing to form a first mixed solution; wherein the accelerator is a mixture of p-toluenesulfonic acid and zinc acetate, and the mass ratio of the accelerator to the zinc acetate is 2: 1;
step two: adding 15g of vinyl diglycol ether into a reaction container of 30ml of dichloromethane, stirring and mixing, stirring for 20min under the condition that the rotating speed is 400r/min, and uniformly mixing to form a second mixed solution;
step three: under the condition that the rotating speed is 300r/min, a dropper is used for dripping the second mixed solution into the first mixed solution at the dripping speed of one drop in two seconds, and the second mixed solution is stirred and mixed; then, the reaction is carried out under the conditions that the rotating speed is 300r/min and the temperature is 20 ℃, and the reaction time is 4 hours; after the reaction is finished, the reaction is completed, saturated sodium bicarbonate is used for stopping the reaction, dichloromethane is used for washing for three times, an organic phase is collected and dried for 10min at the temperature of 35 ℃ and the pressure of 0.09Mpa, and a crude product is obtained; the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1 as developing solvent) to give 16.8g of a pH-responsive compound in 84% yield. The pH-responsive compound had Mn 6781, Mw 8205, and PDI 1.21 by GPC.
Example 2
The addition amount of the vinyldiglycol ether in the second step of example 1 was changed to 10g, and the other conditions were not changed, thereby obtaining 12.3g of the pH-responsive compound with a yield of 82%. The pH-responsive compound had Mn 2705, Mw 3219, and PDI 1.19 as measured by GPC.
Example 3
The addition amount of the vinyl diglycol ether in the second step of example 1 was changed to 20g, and the other conditions were not changed, thereby obtaining 20.7g of the pH-responsive compound with a yield of 82.8%. The pH-responsive compound had Mn 8456, Mw 10316, and PDI 1.22, as measured by GPC.
Example 4
The amount of the ethylene diglycol ether added in the second step of example 1 was changed to 25g, and the remaining conditions were unchanged, whereby 24.3g of the pH-responsive compound was obtained in a yield of 81%. The pH-responsive compound had Mn 7037, Mw 8233, and PDI 1.17, as measured by GPC.
Example 5
The amount of the ethylene glycol divinyl ether added in the second step of example 1 was changed to 30g, and the remaining conditions were not changed, so that 28.4g of the pH-responsive compound was obtained with a yield of 81%. The pH-responsive compound had Mn 6708, Mw 7781, and PDI 1.16 by GPC.
Example 6
The accelerator in step one of example 1 was changed to p-toluenesulfonic acid under otherwise unchanged conditions to finally obtain 9.4g of a pH-responsive compound with a yield of 47%. The pH-responsive compound had Mn of 2569, Mw of 3160, and PDI of 1.23, as measured by GPC.
Example 7
A method of preparing a pH-responsive compound comprising the steps of:
the method comprises the following steps: adding 5g of ricinoleic acid and 15mg of accelerator into a reaction container filled with 20ml of dichloromethane, stirring and mixing, stirring for 10min under the condition that the rotating speed is 400r/min, and uniformly mixing to form a first mixed solution; wherein the accelerator is a mixture of p-toluenesulfonic acid and zinc acetate, and the mass ratio of the accelerator to the zinc acetate is 2: 1;
step two: adding 15g of vinyl diglycol ether into a reaction container of 30ml of dichloromethane, stirring and mixing, stirring for 20min under the condition that the rotating speed is 400r/min, and uniformly mixing to form a second mixed solution;
step three: under the condition that the rotating speed is 300r/min, a dropper is used for dripping the second mixed solution into the first mixed solution at the dripping speed of one drop in two seconds, and the second mixed solution is stirred and mixed; then, the reaction is carried out under the conditions that the rotating speed is 300r/min and the temperature is 20 ℃, and the reaction time is 4 hours; after the reaction is finished, the reaction is completed, saturated sodium bicarbonate is used for stopping the reaction, dichloromethane is used for washing for three times, an organic phase is collected and dried for 10min at the temperature of 35 ℃ and the pressure of 0.09Mpa, and a crude product is obtained; the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1 as developing solvent) to give 17.6g of a pH-responsive compound in 88% yield. The pH-responsive compound had Mn 2231, Mw 2432, and PDI 1.09 as measured by GPC.
Example 8
The addition amount of the ethylene diglycol ether in the second step of example 1 was changed to 20g, and the other conditions were not changed, whereby 20.9g of the pH-responsive compound was obtained with a yield of 83.6%. The pH-responsive compound had Mn 2782, Mw 3255, and PDI 1.17 by GPC.
Example 9
The addition amount of the vinyl diglycol ether in the second step of example 1 was changed to 25g, and the other conditions were not changed, thereby obtaining 25.7g of the pH-responsive compound with a yield of 85.7%. The pH-responsive compound had Mn 3363, Mw 4338, and PDI 1.29 by GPC.
Example 10
The accelerator in the first step of example 7 was changed to p-toluenesulfonic acid, and the remaining conditions were unchanged to finally obtain 9.2g of a pH-responsive compound with a yield of 46%. The pH-responsive compound had Mn 1078, Mw 1272, and PDI 1.18 by GPC.
The experimental equations of examples 1 to 6 are all
The experimental equations of examples 7 to 10 are all
The pH-responsive compound obtained in example 1 was examined by NMR spectroscopy, and an image thereof was obtained as shown in FIG. 2.
Example 1 nuclear magnetic resonance hydrogen spectrum of pH-responsive compound:1H NMR(500MHz,CDCl3)δ5.61–5.07(dt,6H),δ4.39–4.03(d,4H),δ3.62(t, J ═ 49.5,4.4Hz,272H), delta 1.65-1.16 (d,257H), delta 0.78(t, J ═ 35.7Hz, 9H.) from the nuclear magnetic hydrogen spectrum analysis of the target product, there is a group of multiple peaks at chemical shifts delta 5.61-5.07, the peak type splits into dt peaks, which are then seen as the positions of the hydrogens on the carbon-carbon double bonds on the carbon chain of the target product; a group of d peaks are arranged at the positions with chemical shifts delta 4.39-4.03, and are methylene groups of a glycerol structure in the castor oil; a group of t peaks are arranged at the position of chemical shift delta 3.62, which is the position of methylene connected with a carbon-oxygen bond at the position 6, and the t peaks are formed under the coupling action of hydrogen on the connected carbon; the d peak appearing at the position of chemical shift delta 1.65-1.16 is methyl which reacts to generate acetal bond, which indicates that reactants are subjected to electrophilic addition and react according to the design direction; the t peak appearing at the position of chemical shift δ 0.78 is a methyl peak at the end of the carbon chain, which is chemically equivalent due to the same chemical environment, and is integrated into nine hydrogens.
Referring to FIG. 3: an infrared spectrum of the pH-responsive compound prepared in example 1; from the IR spectrum, it can be seen that the peak intensity is 1740cm-1An absorption peak is near, and the absorption peak is judged as an ester group absorption peak of the main chain; in the range of 1150-1060 cm-1An absorption peak is a characteristic peak of the fatty ether; at 3500cm-1The hydroxyl group of the polymer branch was judged to be present in a diahere state by the presence of an absorption peak.
Fig. 2 and 3 simultaneously demonstrate the success of the synthesis of the product obtained in example 1, whose formula is:
the pH responsive compound prepared in example 1 is prepared into nano-micelle, and the preparation method comprises the following steps:
s1: 20mg of the pH-responsive compound (prepared in example 1) was dissolved in 2ml of tetrahydrofuran to form a solution;
s2, adding the solution prepared in the step 20ulS1 into 2ml of deionized water, and mixing and stirring to prepare the nano micelle. And (3) testing the biological compatibility:
resuscitating the HEPG2 cells and HK-2 cells, after culturing to a logarithmic growth phase, digesting with 0.25% trypsin for use; inoculating cells in a 96-well culture plate, culturing for 24h, removing culture solution, adding 100ul of pH-responsive compound nano-micelle, setting 6 multiple wells for each dose, setting 6 dose groups in total, setting the final mass concentration to be 0, 10, 25, 50, 100 and 250ug/mL respectively, and setting a positive control group. After continuing to culture for 24 hours, carrying out WST-1 detection, and detecting the percentage content of active cells in each dosage group;
| mass concentration ug/ml | HEPG2 cell viability/%) | HK-2 cell viability/%) |
| 0 | 94 | 92 |
| 10 | 94 | 92 |
| 25 | 94 | 92 |
| 50 | 94 | 92 |
| 100 | 93 | 91 |
| 250 | 90 | 90 |
As can be seen from the above table, after the pH-responsive compound nano-micelles with different concentrations are added, the survival rates of the HEPG2 cells and the HK-2 cells are basically unchanged, so that the pH-responsive compound nano-micelles have no influence on the growth and reproduction of the cells, can be regarded as non-cytotoxicity, and have good biocompatibility.
Dividing ICR mice into 3 groups, wherein each group comprises 50 mice, namely a control group, a low-dose experimental group (50mg/kg) and a high-dose experimental group (100 mg/kg); under the condition of normal feeding of an ICR mouse, tail vein injection is carried out on the ICR mouse to obtain pH responsive compound nano-micelles with corresponding concentrations; once a week for 4 weeks; after 4 weeks, the survival rate is counted;
| group of | Survival rate/%) |
| Control group | 90 |
| Low dose test group | 90 |
| High dose test group | 90 |
From the above table, the survival rate of the mouse is not changed after the pH responsive compound nano-micelle is added, which indicates that the pH responsive compound nano-micelle is nontoxic and has no influence on the survival of the mouse; further indicates that the pH responsive compound nano micelle has good biocompatibility and can not cause harm to human bodies.
Acid degradation experiment
Preparing a buffer solution with the pH value of 4.6 by using citric acid and trisodium citrate; placing 0.1g of pH responsive compound nano micelle into the buffer solution, standing for a period of time, and measuring the DLS particle size by using a particle size tester to obtain a graph shown in FIG. 4;
as can be seen from fig. 4, after the nano-micelle is placed under an acidic condition for 24 hours, the particle size of the nano-micelle is obviously changed, so that the nano-micelle is proved to be degraded under the acidic condition, that is, the compound can be degraded under the acidic condition and has pH responsiveness; under the condition of weak acid or medium-strong acid (pH is less than 6.5), acetal bonds in the pH-responsive compound prepared by the invention are broken to generate corresponding aldehyde and alcohol, namely, various small molecular substances are changed into water and carbon dioxide through further decomposition.
Load nile red experiment:
dissolving 0.1g of the pH-responsive compound prepared in example 1 in 10ml of tetrahydrofuran to form a solution A, mixing 0.5ml of the solution A with 5ml of deionized water, adding 0.05g of Nile Red, and stirring at 100rad/min for 10min to form a mixed solution; then carrying out ultraviolet test on the mixed solution;
the experimental results are as follows: as the Nile red is insoluble in water, when only the Nile red exists, no absorption peak exists in an ultraviolet spectrogram; when Nile red is loaded by the compound nano-micelle of the invention, the Nile red is found in 487cm in the ultraviolet spectrum-1Has an absorption peak, so that the feasibility of encapsulating the medicament by the prepared pH-responsive compound can be proved, namely the prepared pH-responsive compound can be used as a medicament carrier.
The pH-responsive compound obtained in example 7 was examined by NMR spectroscopy, and an image thereof was obtained as shown in FIG. 5.
EXAMPLE 7 NMR of pH-responsive CompoundsSpectrum:1H NMR(500MHz,CDCl3) δ 5.46(dt, J ═ 28.2,23.6,8.7Hz,2H), δ 4.94-4.59 (q,7H), δ 4.07-3.06 (t,97H), δ 0.91-0.83 (t,3H), from nuclear magnetic hydrogen spectrum analysis of the target product, there is a set of multiple peaks at chemical shift δ 5.46, the peak type splits into dt peaks, from which it can be seen the position of hydrogen on the carbon-carbon double bond on the carbon chain of the target product; a group of q peaks appear at delta 4.94-4.59 positions and are acetal bonds generated by hydrogen bond addition reaction; a group of t peaks are arranged at the position with the chemical shift delta 4.07-3.06, which is the position of methylene connected with a carbon-oxygen bond on the original reactant of the ethylene diglycol ether, and the t peaks are formed under the coupling action of hydrogen on the connected carbon, and the reaction can be carried out according to the design direction according to the quantity of the t peaks; the t peak appearing at the position of chemical shift δ 0.91 to 0.83 is a methyl peak at the end of the carbon chain of the proricinoleic acid, and the integral is 3 hydrogens.
Referring to FIG. 6: an infrared spectrum of the pH-responsive compound prepared in example 7; the infrared spectrum shows that the intensity is 3200-2500 cm-1The peak has a wide and scattered peak shape, and several continuous small peaks appear at 955-915 cm-1A broad and weak absorption peak exists, and the main chain carboxyl OH is judged to be in a diaassociated state; in the range of 1150-1060 cm-1An absorption peak is a characteristic peak of the fatty ether; at 3500cm-1The hydroxyl group of the polymer branch was judged to be present in a diahere state by the presence of an absorption peak.
FIGS. 5 and 6 simultaneously demonstrate the success of the synthesis of the product obtained in example 7, having the formula:
the pH-responsive compound prepared in example 7 was prepared as a nano-micelle by the method comprising:
s1: 20mg of the pH-responsive compound (prepared in example 7) was dissolved in 2ml of tetrahydrofuran to form a solution;
s2, adding the solution prepared in the step 20ulS1 into 2ml of deionized water, and mixing and stirring to prepare the nano micelle. And (3) testing the biological compatibility:
resuscitating the HEPG2 cells and HK-2 cells, after culturing to a logarithmic growth phase, digesting with 0.25% trypsin for use; inoculating cells in a 96-well culture plate, culturing for 24h, removing culture solution, adding 100ul of pH-responsive compound nano-micelle, setting 6 multiple wells for each dose, setting 6 dose groups in total, setting the final mass concentration to be 0, 10, 25, 50, 100 and 250ug/mL respectively, and setting a positive control group. After continuing to culture for 24 hours, carrying out WST-1 detection, and detecting the percentage content of active cells in each dosage group;
| mass concentration ug/ml | HEPG2 cell viability/%) | HK-2 cell viability/%) |
| 0 | 91 | 93 |
| 10 | 91 | 93 |
| 25 | 91 | 93 |
| 50 | 91 | 93 |
| 100 | 90 | 91 |
| 250 | 87 | 89 |
As can be seen from the above table, after the pH-responsive compound nano-micelles with different concentrations are added, the survival rates of the HEPG2 cells and the HK-2 cells are basically unchanged, so that the pH-responsive compound nano-micelles have no influence on the growth and reproduction of the cells, can be regarded as non-cytotoxicity, and have good biocompatibility.
Dividing ICR mice into 3 groups, wherein each group comprises 50 mice, namely a control group, a low-dose experimental group (50mg/kg) and a high-dose experimental group (100 mg/kg); under the condition of normal feeding of an ICR mouse, tail vein injection is carried out on the ICR mouse to obtain pH responsive compound nano-micelles with corresponding concentrations; once a week for 4 weeks; after 4 weeks, the survival rate is counted;
| group of | Survival rate/%) |
| Control group | 94 |
| Low dose test group | 94 |
| High dose test group | 92 |
From the above table, the survival rate of the mouse is not substantially changed after the pH responsive compound nano-micelle is added, which indicates that the pH responsive compound nano-micelle is substantially nontoxic and has no influence on the survival of the mouse; further indicates that the pH responsive compound nano micelle has good biocompatibility and can not cause harm to human bodies.
Acid degradation experiment
Preparing a buffer solution with the pH value of 4.6 by using citric acid and trisodium citrate; placing 0.1g of pH responsive compound nano micelle in the buffer solution, standing for a period of time, and measuring the DLS particle size by using a particle size tester to obtain a graph shown in FIG. 7;
as can be seen from fig. 7, after the nano-micelle is placed under an acidic condition for 24 hours, the particle size of the nano-micelle is obviously changed, so that the nano-micelle is proved to be degraded under the acidic condition, that is, the compound can be degraded under the acidic condition and has pH responsiveness; under the condition of weak acid or medium-strong acid (pH is less than 6.5), acetal bonds in the pH-responsive compound prepared by the invention are broken to generate corresponding aldehyde and alcohol, namely, various small molecular substances are changed into water and carbon dioxide through further decomposition.
Load nile red experiment:
dissolving 0.1g of the pH-responsive compound prepared in example 7 in 10ml of tetrahydrofuran to form a solution A, mixing 0.5ml of the solution A with 5ml of deionized water, adding 0.05g of Nile Red, and stirring at 100rad/min for 10min to form a mixed solution; then carrying out ultraviolet test on the mixed solution;
the experimental results are as follows: as the Nile red is insoluble in water, when only the Nile red exists, no absorption peak exists in an ultraviolet spectrogram; when Nile red is loaded by the compound nano-micelle of the invention, the Nile red is found to be 490cm in the ultraviolet spectrum-1Has an absorption peak, so that the feasibility of encapsulating the medicament by the prepared pH-responsive compound can be proved, namely the prepared pH-responsive compound can be used as a medicament carrier.
The pH responsive compound is prepared from a substance A and vinyl diglycol ether as raw materials, wherein the substance A is castor oil or ricinoleic acid, and the castor oil and the ricinoleic acid can be extracted through castor oil and belong to renewable resources; the raw materials used in the invention have wide sources, and are nontoxic and harmless; meanwhile, the raw materials are low in price; the whole reaction is carried out in a reaction system taking dichloromethane as a solvent, the method only has one step of reaction, has few reaction steps and is suitable for industrial production; meanwhile, the reaction temperature is between 15 and 25 ℃, the whole reaction is carried out under normal pressure, the reaction condition is very mild, no influence is caused on human bodies, no toxic or harmful substance is generated in the reaction process, and the safety of workers is ensured, and the method is green and environment-friendly.
During the reaction, the substance A is firstly mixed with dichloromethane to form a first mixed solution, and simultaneously the vinyl diglycol ether is also mixed with dichloromethane to form a second mixed solution; then adding the second mixed solution into the first mixed solution for mixing reaction; the purpose of doing so is to make substance A and ethylene glycol vinyl ether disperse more evenly in solvent dichloromethane, react more fully; when the second mixed solution is added into the first mixed solution, the invention adopts a dropping method, and the dropping speed is one drop in two seconds; the purpose of this operation is to prevent the reaction from being too violent and producing more by-products; the reaction is milder by adopting dropwise addition, and an ideal product is finally prepared easily; as one of creativity of the invention, the solution is also added with an accelerant which is a mixture of p-toluenesulfonic acid and zinc acetate, and under the combined action of the two substances, the reaction rate of reactants can be greatly accelerated, and the reaction time is shortened; and the polymerization degree of the product can be greatly improved, the product with higher molecular weight is easily generated, and the practical application value of the product is improved.
The pH responsive compound prepared by the invention is an amphiphilic compound and can be self-assembled into a nano micelle in water; the nano micelle has good biocompatibility and no toxicity, does not influence the health of a human body, and cannot be rejected by the human body; meanwhile, the compound can be degraded under the acidic condition of weak acid or medium-strong acid, is used as a drug carrier, and is particularly suitable to be used as a targeting carrier of some anticancer drugs.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.
Claims (9)
1. A pH-responsive compound characterized by: the material is prepared by the following reaction of the following materials in parts by weight:
substance A: 1 part;
ethylene glycol vinyl ether: 2-6 parts;
the substance A is castor oil or ricinoleic acid.
2. A pH-responsive compound according to claim 1, wherein: when the substance A is castor oil, the structural formula of the pH-responsive compound is shown in the specification
The number average molecular weight thereof was 1500-12000.
3. A pH-responsive compound according to claim 1, wherein: when the substance A is ricinoleic acid, the structural formula of the pH-responsive compound is
The number average molecular weight thereof is 500-4500.
4. A method of preparing a pH-responsive compound as claimed in any one of claims 1 to 3, wherein: the method comprises the following steps:
the method comprises the following steps: preparing raw materials according to the set weight part, adding the substance A and the accelerant into a reaction vessel filled with a solvent, stirring and mixing, and forming a first mixed solution after uniformly mixing;
step two: adding the vinyl diglycol ether into a reaction container filled with a solvent, stirring and mixing, and forming a second mixed solution after uniformly mixing;
step three: adding the second mixed solution into the first mixed solution, stirring and mixing, and then reacting; and after the reaction is finished, filtering and purifying to obtain the pH responsive compound.
5. The method of claim 4 for preparing a pH-responsive compound, wherein: the accelerant is a mixture of p-toluenesulfonic acid and zinc acetate, and the mass ratio of the accelerant to the zinc acetate is 2: 1.
6. The method of claim 5 for preparing a pH-responsive compound, wherein: the solvent in the first step and the second step is dichloromethane.
7. The method of claim 6, wherein the pH-responsive compound is prepared by: the step three of adding the second mixed solution into the first mixed solution and stirring and mixing means that the second mixed solution is dropwise added into the first mixed solution by a dropper at a dropping speed of one drop in two seconds under the condition that the rotating speed is 200-400 r/min.
8. The method of claim 7, wherein the pH-responsive compound is prepared by: the reaction in the third step is carried out at the rotation speed of 200-400r/min and the temperature of 15-25 ℃, and the reaction time is 3-5 h.
9. Use of a pH-responsive compound according to claim 8, wherein: the pH-responsive compound is used as a pharmaceutical carrier.
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| CN108102006A (en) * | 2018-02-12 | 2018-06-01 | 中国药科大学 | Crosslinkable amphipathic natural polysaccharide and its application |
| CN109575303A (en) * | 2018-12-03 | 2019-04-05 | 温州大学 | A kind of amphiphilic polymer and preparation method thereof |
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| CN108102006A (en) * | 2018-02-12 | 2018-06-01 | 中国药科大学 | Crosslinkable amphipathic natural polysaccharide and its application |
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