CN109054010B - Imidazole ring modified acid-sensitive polycarbonate material and preparation and application thereof - Google Patents
Imidazole ring modified acid-sensitive polycarbonate material and preparation and application thereof Download PDFInfo
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- CN109054010B CN109054010B CN201810768062.5A CN201810768062A CN109054010B CN 109054010 B CN109054010 B CN 109054010B CN 201810768062 A CN201810768062 A CN 201810768062A CN 109054010 B CN109054010 B CN 109054010B
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- drug
- imidazole ring
- modified acid
- sensitive
- ring modified
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Abstract
The invention belongs to the field of new auxiliary materials and new dosage forms of medicinal preparations, relates to an imidazole ring modified acid-sensitive polycarbonate material, and preparation and application thereof, and particularly relates to an acid-sensitive long-circulating polycarbonate material, preparation thereof, and application thereof as a medicament carrier in medicament delivery. The structure of the imidazole ring modified acid-sensitive amphiphilic polycarbonate material is shown as follows, wherein m and n are described in the claims and the specification.
Description
Technical Field
The invention belongs to the field of new auxiliary materials and new dosage forms of medicinal preparations, relates to an imidazole ring modified acid-sensitive polycarbonate material, and preparation and application thereof, and particularly relates to an acid-sensitive long-circulating polycarbonate material, preparation thereof, and application thereof as a medicament carrier in medicament delivery.
Background
Nowadays, most of antitumor drugs are insoluble drugs, and some auxiliary materials are generally added to improve the water solubility of the antitumor drugs, but some toxic and side effects are increased, so that the problem of the insoluble drugs is solved significantly by means of preparations, and therefore, the design of a better drug delivery carrier is significant.
In recent years, a great deal of experimental results show the advantages of the nano-preparation as a drug carrier, including small particle size, low toxicity and side effects, easy modification of functional groups, and the like. Compared with the stable static structure of the nanoparticles, the nano-micelle has a dynamic structure and has better kinetic and thermodynamic properties. The hydrophobic core of the nanomicelle can solubilize and encapsulate the drug in an aqueous environment. In the nano micelle, the pH sensitive material can ensure that the micelle keeps stable and does not release the drug under the condition of blood neutrality, improve the in vivo circulation time of the drug and release the drug at lower pH after entering the tumor.
Polyester materials are used in the biomedical field in a very wide range of applications, mainly due to their low toxicity, biodegradability and good biocompatibility. Among them, polycarbonate has characteristics of lower glass transition temperature and melting point, easier hydrolysis and higher elasticity, and has been applied to biomedical materials such as surgical sutures, biodegradable elastomers, tissue engineering scaffolds in the form of classical spun fibers, and the like. In addition to the application of bio-mechanical materials, polycarbonate has been tried as a material for injection gels and polymeric micelles for the design of drug carriers.
The imidazole ring is an amphiphilic compound, the aliphatic polycarbonate is connected with the 1- (3-aminopropyl) imidazole, has the effect of changing the hydrophilicity through protonation, is alkaline and hydrophobic, keeps the stability of the medicament in blood, prolongs the half-life period of the medicament, can be changed into hydrophilicity through protonation under the condition that the pKa is less than 6.5, enables the micelle to expand to release the medicament, has good tumor site selective release, and improves the anti-tumor effect of the insoluble medicament.
Disclosure of Invention
The invention aims to provide a pH-sensitive polymer material for injection, which is an imidazole ring modified acid-sensitive polycarbonate material.
The second purpose of the invention is to improve the in vivo blood concentration and half-life period of the insoluble drug by using the imidazole ring modified acid-sensitive polycarbonate material.
The third purpose of the invention is to provide the novel imidazole ring modified acid-sensitive amphiphilic polycarbonate material and the application thereof in a drug delivery system.
The invention realizes the aim through the following technical scheme:
the structure of the imidazole ring modified acid-sensitive amphiphilic polycarbonate material is shown as follows:
wherein,
m is 8-160, preferably 30-40, and more preferably 32;
n is 45 to 227, preferably 91 to 136, more preferably 113.
Further, the invention provides an imidazole ring modified acid-sensitive amphiphilic polycarbonate material, which has the structure as follows:
the invention also provides a preparation method of the imidazole ring modified acid-sensitive amphiphilic polycarbonate material, which comprises the following steps:
(a) monomer synthesis: reacting 2, 2-dimethylolpropionic acid (I) with benzyl chloride to obtain carboxyl protected benzyl 2, 2-dimethylolpropionate (II), and performing ring closure reaction on the II and ethyl chloroformate to obtain a monomer (III), wherein the reaction formula is as follows:
(b) polymerization reaction: white solids (IV) with different polymerization degrees are obtained by controlling the amount of (III) by using mPEG as an initiator and DBU (1, 8-diazabicycloundecen-7-ene) as a catalyst.
(c) And (3) carrying out palladium-carbon reduction reaction on the polymer in the formula (IV), and removing benzyloxy protection to obtain the carboxyl functionalized polymer compound in the formula (V). The reaction formula is as follows:
(d) the compound of formula (V) is reacted with an acid chloride to convert the carboxyl group to an acid chloride, which is then coupled to Im. To obtain the compound of formula (VI). The reaction formula is as follows:
step (d) reacting the carboxyl group with thionyl chloride to form an acid chloride, which is linked to 1- (3-aminopropyl) imidazole.
The final product obtained in the step (d) is mPEG-PCC-Im, and the substitution degree of the imidazole ring is 90-100%.
The acid-sensitive polycarbonate modified by the amphiphilic imidazole ring has the functions of pH sensitivity, solubilization of insoluble drugs and improvement of anti-tumor effect of the drugs.
The amphiphilic imidazole ring modified acid-sensitive polycarbonate can be used as a solubilizing carrier of an insoluble drug to prepare a polymer micelle of the insoluble drug, wherein the insoluble drug can be any one of tacrolimus, adriamycin, taxanes, camptothecin, anthraquinone antitumor drugs or dihydropyridines and non-steroidal anti-inflammatory drugs or derivatives thereof.
In the polymer micelle, the weight ratio of the insoluble drug to the amphiphilic imidazole ring modified acid-sensitive polycarbonate is as follows: 1: 1-1: 4, preferably: 1: 3-1: 4.
the polymer micelle can be prepared by an emulsion solvent volatilization method, and comprises the following steps:
the emulsifying solvent volatilization method is that the acid-sensitive polycarbonate modified by the amphiphilic imidazole ring and the insoluble drug are simultaneously dissolved in an organic solvent (such as dichloromethane, chloroform and the like), added into a water phase, stirred and volatilized after ultrasonic treatment to remove the organic solvent, and then the free drug is removed by high-speed centrifugation to obtain the drug-loaded micelle. The invention has the following beneficial effects: the preparation method of the novel multifunctional amphiphilic polymer polycarbonate has the advantages of mild preparation process of the carrier and easy operation. The prepared drug-loaded polymer micelle is simple and convenient to prepare, small and uniform in particle size, high in entrapment rate, low in critical micelle concentration and good in stability. The carrier has obvious pH sensitivity, and the medicine is wrapped in blood by the micelle carrier and does not release suddenly, and releases the medicine at the tumor part. Can be used as the reservoir of insoluble drugs and proteins. In vitro release experiments and in vivo pharmacokinetics prove that the acid-sensitive polycarbonate material can control the release of the medicine, improve the in vivo circulation time and has good anti-tumor prospect.
Drawings
FIG. 1 is a diagram showing the synthesis of monomers and polymerization products in example 1 of the present invention 1 HNMR spectrogram.
FIG. 2 is a graph of CMC at different pH values for acid sensitive polycarbonate material of example 3 of this invention.
Fig. 3 is a particle size distribution diagram of the nano-micelle obtained in example 4 of the present invention, which is characterized by dynamic light scattering and a scanning electron microscope.
Fig. 4 is a docetaxel in vitro release profile of PBS nanomicelles of different PH in example 6 of the present invention.
FIG. 5 is a graph showing the pH dependent particle size expansion of micelles under different pH conditions in example 7 of the present invention.
Fig. 6 is a time curve of docetaxel micelle and control docetaxel solution prepared in example 10 of the present invention.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto.
Example 1
m PEG-PCC-Im.
(a) Monomer preparation: 45.0g (0.338mol) of 2, 2-dimethylolpropionic acid (I), with an equimolar amount of KOH (88%, 21.5g, 0.338mol) were dissolved in 500ml of DMF250ml in a eggplant-shaped bottle, reacted at 100 ℃ for 2h, and vigorously stirred until all the crystals were dissolved. An excess of 46ml (0.404mol) of benzyl chloride was slowly added dropwise to the eggplant-shaped bottle under stirring. The mixture was stirred under reflux at 100 ℃ for 18 hours. After filtration, the DMF is evaporated off from the filtrate at 70 to 100 ℃ under reduced pressure. 600ml of an organic phase (n-hexane-ethyl acetate 1: 1) and 200ml of an aqueous phase were used to dissolve the product, and the solution was separated. The upper organic phase was retained and washed twice with 200ml of distilled water. The organic phase was poured into a beaker containing a large amount of anhydrous sodium sulfate and stirred for 1h to remove the residual water. And (5) filtering. The filtrate was rotary evaporated to give a yellow solid. An appropriate amount of toluene was heated in an erlenmeyer flask and added dropwise slowly to the product of the previous step until the product just dissolved. Cooling to room temperature and putting into a refrigerator. After complete cooling, filtration gave 20.9g of benzyl 2, 2-dimethylolpropionate (II) as white crystals, yield: and (5) 55.6%.
57ml (0.410mol) of triethylamine are dissolved in 105ml of cold tetrahydrofuran and added dropwise slowly with constant pressure leak, while stirring in an ice bath, to 375ml of tetrahydrofuran dissolved with 15.2(67.65mmol) of benzyl 2, 2-dimethylolpropionate and 39ml (0.410mol) of ethyl chloroformate. After dropping for about 1 hour, the reaction mixture was stirred at room temperature for 2 hours until completion, and the white insoluble matter was removed by suction filtration. The filtrate was rotary evaporated to remove the solvent to give a pale yellow solid. The product was recrystallized twice from a mixed solvent of tetrahydrofuran and diethyl ether to give 5.75g of the product MBC (III) as white needle crystals in 51.0% yield.
(b) Polymerization: the dried eggplant-shaped bottle was filled with nitrogen, and 20g (2mmol) of PEG (average molecular weight: 5000) was dissolved in 40mL of anhydrous dichloromethane, and stirred until completely dissolved to form a homogeneous phase. 1240uLDBU (2 times molar ratio to initiator) was added and stirring was continued for 3min before adding 40g (160mmol) of MBC. After 20min of reaction, 20mL of chloroform was added for dilution. The solution was poured into 600mL of cold ether and stirred for 20 min. After suction filtration, 25.0g of mPEG-PBC (IV) was obtained as a white solid. Yield: 83.3%, conversion: 86%, degree of polymerization: 8.6.
(c) deprotection of carboxyl group: 24g of PEG-PBC was dissolved in 120mL of dichloromethane, and an equal volume of tetrahydrofuran was added and stirred well. 2g (10% w) of palladium on carbon was weighed into a reaction flask. After purging with nitrogen three times, the reaction flask was filled with hydrogen. The reaction was carried out at 35 ℃ for 24 hours, and the hydrogen balloon was replaced once at 12 hours. After 24 hours, the palladium on carbon was removed by centrifugation to give a clear liquid. The solvent was evaporated off by evaporation to give a white solid. The product was dissolved with 60mL of dichloromethane and poured into 600mL of cold ether. Stirring in ice bath for 20min, and filtering to obtain white solid mPEG-PBC (V) 17.2g, yield: 81.9 percent.
(d) Modification of 1- (3-aminopropyl) imidazole: PEG-PCC (degree of polymerization 35), 20g, was weighed out and dissolved in 40mL of thionyl chloride, 4 drops of DMF were added dropwise and refluxed at 50 ℃ for 12 h. And (3) performing vacuum rotary evaporation on the thionyl chloride by using a water pump, adding 20mL of methylbenzene twice, and performing vacuum rotary evaporation on the methylbenzene by using an oil change pump to obtain a white solid. The white solid was dissolved by adding 100mL of dichloromethane, and 1- (3-aminopropyl) imidazole and triethylamine were dissolved in dichloromethane. The mixture was added dropwise to the freshly prepared acid chloride in an ice bath, stirred for one hour and reacted at room temperature for 48 h. The organic phase was washed twice with 10mL of 1mol/LHCl and twice with 10mL of saturated sodium chloride solution. Adding anhydrous sodium sulfate, stirring to remove water, filtering, and rotary evaporating the organic phase. 10mL of dichloromethane was added to dissolve the rotary evaporated solid, the solution was poured into cold 100mL of anhydrous ether, stirred for 15min and filtered to give a solid, which was precipitated again with ether to give 9.2g of a pale yellow solid (VI). Yield: 46.0 percent
The synthetic route of the imidazole ring modified acid-sensitive polycarbonate (mPEG-PCC-Im) is shown as the following formula:
example 1 the mPEG in the reaction formula may be mPEG 5000 The polyethylene glycol of the present invention is not limited to the above. The molecular weight of the polyethylene glycol may be in the range of 2000-.
Measurement by nuclear magnetic resonance 1 HNMR hydrogen spectroscopy was used to determine the structure of the product of each step in example 1, and the results are shown in FIG. 1. After the monomer is polymerized, peaks at delta 4.7(d,2H) and delta 4.2(d,2H) disappear, and mPEG after the polymerization 113 -PBC 32 The new peak of delta 4.3 in the spectrum of (A) is the repeat unit CH on the polycarbonate 2 The achievement of ring-opening polymerization was demonstrated. mPEG 113 The peak at δ 3.7 was used to quantify the degree of polymerization of the polycarbonate. After deprotection of carboxyl, the peak of the benzene ring at delta 7.3 disappears, and a new peak of carboxyl appears at delta 13.1. After the 1- (3-aminopropyl) imidazole is connected, a characteristic peak of the 1- (3-aminopropyl) imidazole appears at delta 7-8, and the mPEG is proved 113 -PBC 32 -Im was successfully synthesized.
Example 2
2.1 preparation of drug-loaded micelle:
mixing the drug (docetaxel) with the fruitThe vector (mPEG) prepared in example 1 113 -PCC 32 -Im) (1: 4, W/W) of the carrier are simultaneously dissolved in dichloromethane, the carrier is dripped into the water phase and stirred (500rpm) for 5min, probe ultrasound (400W,3min) is carried out under ice bath, and the organic solvent is volatilized after stirring for 12h at 500 rpm.
2.2 screening of drug to carrier ratio (weight ratio):
TABLE 1 comparison of micelle Properties for different drug to vehicle ratios
The results show that: when the ratio of drug to carrier is 1: 1-1: 4, the drug loading and encapsulation efficiency are improved, and when the ratio of the drug to the carrier is 1: 3-1: 4, the drug loading rate can reach more than 80 percent, and the encapsulation rate can reach more than 15 percent.
2.3 ratio (v/v) screening of organic phase (dichloromethane) to aqueous phase:
the other conditions were controlled to be unchanged, and drug-loaded micelles were prepared under item 2.1, and the results are shown in table 2 below:
TABLE 2 comparison of micelle Properties prepared with different organic to aqueous phase ratios
The results show that: increasing the ratio of the organic phase to the aqueous phase to 1; after 9, the change of the particle size and the improvement of the drug loading and the encapsulation efficiency are not obvious, so the ratio of the organic phase to the aqueous phase is set as 1; 3-1; 6(v/v), preferably 1: 6.
2.3 screening of stirring speed:
the other conditions were kept constant, and drug-loaded micelles were prepared under item 2.1, with the results shown in table 3 below:
TABLE 3 comparison of micelle Properties prepared at different agitation speeds
The results show that: the change of the particle size and the improvement of the drug loading and encapsulation efficiency are not obvious after the stirring is increased to 500rpm, so that the stirring speed is set to 300-500 rpm, preferably 500 rpm.
2.3 screening of ultrasonic power:
the other conditions were kept constant, and drug-loaded micelles were prepared under item 2.1, with the results shown in table 4 below:
TABLE 4 comparison of micelle Properties prepared at different ultrasonic powers
The results show that: after the ultrasonic power is increased to 400W, the change of the particle size and the improvement of the drug loading and the encapsulation efficiency are not obvious, so that the ultrasonic power is 200-400W, preferably 400W.
2.4 screening the optimal polymerization degree:
by comparing polycarbonates of different degrees of polymerization, the highest chemical composition of drug loading and encapsulation efficiency was obtained, and the results are shown in table 5.
TABLE 5 polymers mPEG of varying degrees of polymerization 113 -PCC 8 -Im,mPEG 113 -PCC 16 -Im,mPEG 113 -PCC 32 -Im and mPEG 113 -PCC 64 -Im comparison of properties
The results show that: the drug loading and encapsulation efficiency were highest when the degree of polymerization of the polycarbonate was 32.
By comparing polycarbonates of different molecular weights mPEG, the highest chemical composition of drug loading and encapsulation was obtained, and the results are shown in Table 6.
TABLE 6 polymers mPEG of different mPEG molecular weights 45 -PCC 32 Im (average molecular weight 2000), mPEG 113 -PCC 32 Im (average molecular weight 5000), mPEG 227 -PCC 32 Comparison of the-Im (average molecular weight 10000) Properties
From tables 5 and 6, mPEG 113 -PCC 32 Im has the highest drug loading capacity, PEG chain is too long or too short, and polycarbonate chain is too short or too long, so that the drug loading capacity and the encapsulation efficiency are reduced. Particle size and particle size distribution mPEG 113 -PCC 32 the-Im also has the advantage of a smaller and uniform particle size (PDI)<0.2)。
TABLE 7 polymers mPEG of varying degrees of polymerization 113 -PCC 25 -Im,mPEG 113 -PCC 30 -Im,mPEG 113 -PCC 35 -Im，mPEG 113 -PCC 40 -Im and mPEG 113 -PCC 45 -Im comparison of properties
TABLE 8 mPEG molecular weight 3000-7000, mPEG 68 -PCC 32 Im (average molecular weight 3000), mPEG 91 -PCC 32 Im (average molecular weight 4000), mPEG 136 -PCC 32 Im (average molecular weight 6000), mPEG 159 -PCC 32 Comparison of the properties-Im (average molecular weight 7000)
In conclusion, the preferable range of mPEG is 4000-6000, and the preferable range of the polymerization degree of polycarbonate is 30-40, in which the polymer micelle has uniform particle size, the encapsulation rate can reach more than 79.6%, and the drug loading can reach more than 17.7%.
As can be seen by comparing the change of the drug loading condition of the carrier with 1- (3-aminopropyl) imidazole, the drug loading of the carrier can be significantly improved after certain 1- (3-aminopropyl) imidazole substitution is reached, as shown in Table 9.
TABLE 9 comparison of the Effect of linking 1- (3-aminopropyl) imidazole on Carrier drug Loading Capacity
Example 3
Determination of critical micelle concentration of mPEG-PCC-Im polymer:
the method for measuring the critical micelle concentration widely adopts a pyrene fluorescence probe method. Pyrene is a lipid-soluble fluorescent probe, and has weak fluorescence in polar environment and strong fluorescence in non-polar environment. When a micelle or a hydrophobic region exists in the polar solvent, pyrene is spontaneously transferred from a polar environment to a non-polar environment, and fluorescence is enhanced. Generally, this characteristic of pyrene is reflected by the ratio of the intensities of the first and third excitation peaks, and when this ratio is increased significantly, it is considered that pyrene migrates from a polar environment to a non-polar environment, i.e., it is generated in micelles or hydrophobic regions.
Will be 6X 10 -6 A solution of mol/L pyrene in absolute ethanol was added to a 20mL stoppered flask and the absolute ethanol was removed by blowing with a stream of nitrogen. Example 1 (mPEG) accurately weighed 10mg 113 -PBC 32 -Im) was dissolved in 10mL of distilled water to obtain 1 mg/mL. The polymer solution was diluted to a range of concentrations (10) -2 ，10 -4 ，10 -5 ，10 -6 ，10 -7 ，10 -8 ，10 -9 g/mL) of 10mL, and the obtained solution was added to a flask containing pyrene so that the final concentration of pyrene was 6X 10 -7 M, ultrasonic treating for 4h in dark and standing overnight in dark. The fluorescence intensity was measured with a microplate reader. Fixed emission wavelength of 390nm, the scanning range of the excitation wavelength is 330-380nm, and two excitation wavelengths I are taken 1 ＝340nm，I 2 The ratio was 336nm fluorescence intensity.
FIG. 2 shows the critical micelle concentration under different pH conditions, and the results prove that the polymer carrier of the invention has lower critical micelle concentration under the alkaline condition and in normal plasma, is easy to self-assemble to form micelles, and the formed micelles have better dilution stability.
Example 4
Characterization of properties and stability testing of polymeric micelles:
example 2 optimal drug loaded micelles (mPEG) 113 -PCC 32 -Im) at room temperature, and sampling at 0 day, 15 days and 30 days to determine the drug content and particle size distribution. The physical stability of the drug-loaded micelle is carried out in a shaker at 37 ℃, and the drug content, the particle size and the particle size distribution are respectively measured by sampling at 0h, 3h and 30 h.
The stability test results in table 10 demonstrate that the micelle has less drug precipitation during storage, and the micelle has better physical stability and can maintain the stability of the hydrophobic core of the micelle. The particle size distribution diagram of fig. 3 is a dynamic light scattering and scanning electron microscope characterization result of the polymer micelle prepared by the optimal process of example 2, which indicates that the particle size of the polymer micelle is 100nm and the particle size distribution is uniform.
TABLE 10 stability test
Example 5
In vitro release of drug loaded micelles:
examination of mPEG-PCC-Im (mPEG) by dialysis 113 -PBC 32 -Im) in vitro drug release profile of docetaxel loaded micelles. Transferring 1ml of the drug-loaded micelle solution into a dialysis bagThe dialysis bags were clamped at both ends, and placed in conical flasks containing 30mL of a pH 1.2 NaCl solution, pH6.0 PBS, pH 6.5PBS, pH7.4 PBS, and pH8.0PBS release medium, respectively, and examined for in vitro release at 100r/min in a 37 ℃ constant temperature shaker. 3mL samples were taken at 2, 4, 6, 8, 12, 24h, respectively, while 3mL of fresh release medium was supplemented, and the samples were filtered through a 0.45 μm microporous membrane and subjected to HPLC assay.
The results in FIG. 4 show that mPEG-PCC-Im micelles slowly release in PBS at pH8.0 and PBS at pH7.4, and the release after 24 hours reaches only 20%. The drug-loaded micelle can be released quickly under the conditions of PBS (pH 6.0) and PBS (pH 6.5), and the release degree can reach 90% after 24 hours, so that the drug-loaded micelle can keep the form of the micelle in the neutral environment of normal blood plasma, and the drug can be released quickly under the condition that the tumor part is slightly acidic.
Example 6
Particle size expansion test of the drug-loaded micelle under different pH conditions:
1mL of the drug-loaded nanomicelle of example 4 was diluted into 10mL of PBS buffer solutions (pH 6.0, 6.5, 7.4, 8.0) with different pH values, and the change in the particle size of the polymer micelle was observed at a certain time point, using the undiluted micelle as a control, and observing whether the drug was precipitated.
FIG. 5 is a graph showing the change in particle size of pH-sensitive polymer micelles, which is kept small at about 100nm at pH7.4 and 8.0. Under the conditions of pH6.0 and 6.5, the micelle particle size rapidly increases, and the expansion rate is about 2.5 times, which indicates that the synthesized micelle carrier has pH-sensitive property.
Example 7 pharmacokinetic study of docetaxel drug loaded micelles prepared by mPEG-PCC-Im
With mPEG 113 -PBC 32 For example, 12 healthy male rats weighing about 250g were randomly divided into 2 groups and fasted for 12h before administration with free water. One group is docetaxel solution group (control group), the other group is docetaxel drug-loaded micelle, the dose is 5mg/kg, and the blood sampling time point after administration is as follows: 0.083, 0.25, 0.50, 1.0, 2.0, 4.0, 6.0, 8.0, 12h and 24h blood taking 0.5mL through eye orbit at each blood taking time point, immediately moving into a heparin-treated test tube after blood taking, and freezing in a refrigerator at-20 DEG CAfter 24h, melting at room temperature, centrifuging at 13000rpm for 10min, separating plasma, and determining blood concentration. The time course of the drug is shown in FIG. 6, and the pharmacokinetic parameters are shown in Table 11.
TABLE 11 pharmacokinetic parameters
As can be seen from FIG. 6, after administration of docetaxel drug-loaded gel, C was compared with the solution group max Has obvious improvement and the area AUC under the time curve of the drug 0-12h The improvement is 6 times. The enteric material with pH sensitivity of the invention is beneficial to improving the oral bioavailability of the medicine.
The carrier of the invention can also be self-assembled with other antitumor drugs, such as adriamycin, paclitaxel, hydroxycamptothecin, camptothecin, vincristine, nimodipine and mitomycin to form drug micelles, thus improving the bioavailability and the activity of the antitumor drugs.
Claims (5)
1. The application of the polymer micelle in preparing the antitumor drugs is characterized in that the polymer micelle contains imidazole ring modified acid-sensitive polycarbonate and an insoluble drug, and the weight ratio of the insoluble drug to the imidazole ring modified acid-sensitive polycarbonate is 1: 3-1: 4; the indissolvable drug is any substance in taxane antitumor drugs; the structure of the imidazole ring modified acid-sensitive polycarbonate is as follows:
wherein m is 32 and n is 113.
2. The application of the polymer micelle in preparing the medicament for improving the bioavailability of the insoluble medicament is characterized in that the polymer micelle comprises imidazole ring modified acid-sensitive polycarbonate and the insoluble medicament, and the weight ratio of the insoluble medicament to the imidazole ring modified acid-sensitive polycarbonate is 1: 3-1: 4; the indissolvable drug is any substance in taxane antitumor drugs; the structure of the imidazole ring modified acid-sensitive polycarbonate is as follows:
wherein m is 32 and n is 113.
3. The use according to claim 1 or 2, wherein the imidazole ring-modified acid-sensitive polycarbonate is prepared by:
(1) monomer synthesis: reacting 2, 2-dimethylolpropionic acid (I) with benzyl chloride to obtain carboxyl protected benzyl 2, 2-dimethylolpropionate (II), and performing ring-closure reaction on the II and ethyl chloroformate to obtain a monomer (III);
(2) polymerization reaction: taking mPEG as an initiator and 1, 8-diazabicycloundecen-7-ene as a catalyst, and controlling the amount of (III) to obtain white solids with different polymerization degrees;
(3) and (3) carrying out palladium-carbon reduction reaction on the polymer of the formula (IV), removing benzyloxy protection, and obtaining a carboxyl functionalized polymer compound of the formula (V):
(4) reacting the compound shown in the formula (V) with acyl chloride to change carboxyl into acyl chloride, and then connecting the acyl chloride with 1- (3-aminopropyl) imidazole;
4. the use according to claim 1 or 2, wherein the polymeric micelles are prepared by evaporation of an emulsifying solvent.
5. The use according to claim 4, wherein the evaporation of the emulsifying solvent comprises the steps of: the preparation method comprises the steps of simultaneously dissolving the amphiphilic imidazole ring modified acid-sensitive polycarbonate and the insoluble drug in an organic solvent dichloromethane or chloroform, adding the water phase, stirring after ultrasonic treatment to volatilize the organic solvent, and removing the free drug through high-speed centrifugation to obtain the drug-loaded micelle.
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