CN107722200B - Multiple stimulus responsive Fe3O4Graft copolymer heterozygotes, and preparation method and application thereof - Google Patents

Multiple stimulus responsive Fe3O4Graft copolymer heterozygotes, and preparation method and application thereof Download PDF

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CN107722200B
CN107722200B CN201710932570.8A CN201710932570A CN107722200B CN 107722200 B CN107722200 B CN 107722200B CN 201710932570 A CN201710932570 A CN 201710932570A CN 107722200 B CN107722200 B CN 107722200B
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罗延龄
王园
张雪银
徐峰
陈亚芍
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Shaanxi Normal University
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Abstract

The invention discloses a Fe with multiple stimulus responses3O4Graft copolymer heterozygotes, and methods of preparation and use thereof. The hybrids of the invention are magnetically responsive to Fe3O4The pH sensitive polyacrylic acid and the redox sensitive poly (ferrocenyl methyl oxylacetate) are prepared. The preparation process involves Fe3O4Introducing a surface chain transfer agent, and finally grafting polyacrylic acid and poly (ferrocenyl methyl formyl oxyethyl methacrylate) to Fe through two-step continuous reversible addition-fragmentation chain transfer polymerization3O4Surface to obtain Fe3O4Grafted acrylic acid-ferrocenecarbonyloxyethyl methacrylate block copolymer heterozygote. The hybrid can be self-assembled into a spherical core-shell micelle in water, and shows magnetism, pH and redox stimulus responsiveness; and the anticancer drug taxol has the release characteristic of multiple stimulation responses, and can be used as a carrier of a hydrophobic drug for the targeted therapy of cancer.

Description

Multiple stimulus responsive Fe3O4Graft copolymer heterozygotes, and preparation method and application thereof
Technical Field
The invention belongs to the technical field of biomedical high polymer materials, and particularly relates to Fe with multiple stimulus responses3O4Grafted acrylic acid-methyl acrylic acid ferrocene formyloxyethyl ester block copolymer heterozygote, and its preparation method and application in drug controlled release are disclosed.
Background
Stimulus responsive Drug Delivery Systems (DDS) are a class of functional nano-drug delivery systems. As a carrier for drug release, stimuli-responsive block copolymer micelles have attracted a great deal of attention due to their unique properties and wide biomedical nanotechnology applications. Such drug delivery vehicles can rapidly deliver drugs by structural, conformational and conformational changes of some specific biological environment stimulating vehicles in vivo/in vitro, or by physical or chemical factors such as light, temperature, pH, ultrasound, mechanical stress, reduction/oxidation, enzymes, ions, glucose, magnetic fields, solvents, voltage and electrochemistry. The stimuli-reactive DDS has the advantage of reducing or avoiding premature release of the drug, and can improve the release efficiency of the drug in the target area. To date, stimuli-responsive drug carrier materials sensitive to external environmental factors have been the focus of targeted formulation research. However, most researchers have investigated single stimulus responsive drug delivery systems. In general, the stimulatory factors in the tumor microenvironment and/or pathological environment are not the result of a single stimulus, but include pH, temperature, reducing substances, enzyme concentration, Reactive Oxygen Species (ROS), and adenosine-5' -triphosphate (ATP). Therefore, the single stimuli-responsive drug carriers are not well adapted to the complex functions and environments of living systems, are subject to problems of low release accuracy and some side effects, and do not achieve optimal therapeutic efficiency and meet the requirements of the overall therapy. Although some efforts have been made to develop dual stimuli-responsive drug release systems, such as temperature/pH, magnetic field/pH, light/temperature, magnetic field/temperature dual stimuli-responsive DDS, therapeutic efficacy is still limited, and more precise drug release in cancer microenvironment remains to be improved. Therefore, the design and development of new (polymeric) materials with a variety of stimuli-responsive properties remains a challenging and important task.
A plurality of stimulus response (polymer) materials are used as a novel 'intelligent' material, have sensing, information processing and executing functions and can show more remarkable physicochemical properties when triggered by micro environmental stimuli. Due to their unique characteristics, they are widely used in the fields of drug delivery, diagnostics, tissue engineering, "smart" optical systems, biosensors, micro-electro-mechanical systems (MEMS), coatings, textiles, and the like. In particular, the multi-stimulus responsive smart material provides a good carrier platform for anticancer drug delivery by incorporating three or more stimulus responsive elements in the DDS, with unique advantages and great development potential. Thus, the preparation of new materials that can respond to specific changes in a variety of stimuli would be very beneficial for achieving better controlled release characteristics of the drug and for achieving better therapeutic effects and more systemic release kinetics. The multiple stimulus response intelligent material comprises hydrogel, magnetic nano particles and/or microspheres, block copolymers, organic-inorganic hybrid and the like. Among these, redox potential, pH, temperature, enzymes, ATP, optical and magnetic response smart materials are particularly attractive because more parameters can achieve more functionality and better modulation. By introducing or combining various responsive moieties, i.e., by combining monomeric units having pH, temperature, electrical, optical, and magnetic responses, etc., a multi-stimulus responsive polymeric material can be obtained. However, little information is available in the literature to study materials with multiple stimuli-reactivity, particularly multiple stimuli-reactive micelles. Wu et al (Wu, G.; Chen, S.C.; Liu, C.L.; Wang, Y.Z. direct a group self-assembly of an ampphilic di-block copolymer fluorescent multi-stimuli-responsive fluorescent behavior of ACS Nano2015,9, 4649-one 4659) reported multiple stimulus-responsive fluorescent behavior of polymeric acids with oligoanilines, triphenylamines and fluorine groups. Amphiphilic diblock copolymers self-assembling multimolecular-response fluorescent anisotropic micelles were studied strictly (Yan, Y.; Sun, N.; Li, F.; Jia, X.; Wang, C.; Chao, D. Multiple still-responsive fluorescence scanner of novel polymeric acid bearing oligoaniline, triphenylamine and fluorine groups, ACS appl. Mater. interfaces 2017,9, 6497) and 6503.). Several researchers reported the formation of microcapsules and examined the response to temperature and light, and the effect of chain length on micelle formation, improving the problem of oral absorption of poorly soluble drugs.
Tumor cells often exhibit various microenvironments. It has been reported that the heterostructures and distribution of tumor vessels may lead to unique features of intratumoral circulation, such as relatively high temperature (>37 ℃), relatively low pH (5.8-7.1) and high ROS content compared to normal cells. These extracellular microenvironments of tumors provide new strategies to increase tumor selectivity and to deliver drugs more efficiently through synergistic effects. Magnetic iron oxide nanoparticles are widely used in the biomedical field, and as a main agent and a magnetic targeting agent, multiple functions can be achieved by conjugation with various targeting moieties on the surface of magnetic iron oxide nanoparticles, and thus highly ideal multiple stimulus-responsive (polymer) materials can be developed.
In view of the above problems, it would be highly necessary and meaningful to design and synthesize a multi-stimuli responsive (polymer) material to modulate the physicochemical properties and drug release behavior of the assembled micelle, to adapt to the needs of various microenvironment changes, to maximize the release of the drug at the site of a lesion or cancer, to improve the bioavailability and targeted drug release efficiency of the drug, and to precisely open and close the release of the encapsulated guest drug molecules.
Disclosure of Invention
The invention aims to solve the technical problems that the defect of single responsiveness of the existing block copolymer micelle is overcome, the complex environment of a cancer change part in a human body cannot be well met, and the pathological change environment is fully and effectively utilized, so that the advantages of a drug carrier are exerted to the maximum extent, and the optimization of drug release kinetics is realized.
To solve the above problems, the present invention provides a multi-stimulus-responsive Fe having redox, pH and magnetic responses3O4Grafted acrylic acid-ferrocenecarbonyloxyethyl methacrylate block copolymer heterozygote. The hybrid material can lead the medicine to be oriented to the lesion part of the cancer through a magnetic targeting carrier under the guiding action of an external magnetic field, and utilizes the high active oxygen species concentration and pH value of the cancer part<7.2(4.8-7.2), and the drug is released to the cancerous part to the maximum extent, so that the toxic and side effects are reduced, and the optimal targeting effect is achieved.
Another technical problem to be solved by the present invention is Fe responsive to the above-mentioned multiple stimuli3O4Grafted propyleneA preparation method of an olefine acid-ferrocenyl formyl oxyethyl ester block copolymer heterozygote material is provided.
Multiple stimulus responsive Fe for solving the above technical problems3O4The structure of the grafted acrylic acid-ferrocenecarbonyloxyethyl methacrylate block copolymer hybrid is shown as follows:
wherein m is 60-150 and n is 35-140.
Fe of the above multiple stimulus response3O4The reaction flow and preparation method of the grafted acrylic acid-methyl acrylic acid ferrocene formyloxyethyl ester block copolymer heterozygote are as follows:
1. preparation of Fe3O4Polymerization chain transfer agent for surface reversible addition-fragmentation chain transfer
Bonding 4-cyano-4- (thiobenzoic acid) pentanoic acid (CPADB) to aminated Fe by amidation reaction with dichloromethane as solvent, 1-Hydroxybenzotriazole (HOBT) as amide protecting agent and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl) as dehydrating agent3O4Surface to obtain Fe shown in formula I3O4Surface reversible addition-fragmentation chain transfer polymerization chain transfer agent (Fe)3O4@CPADB)。
2. Surface RAFT polymerization synthesis of Fe3O4Grafted polyacrylic acid hybrids
Using 1, 4-dioxane as solvent, Acrylic Acid (AA) as monomer, Fe3O4The reaction is carried out for 16-36 hours at 70-80 ℃ under the conditions of no water, no oxygen and nitrogen protection by using @ CPADB as a chain transfer agent and Azobisisobutyronitrile (AIBN) as an initiator to obtain Fe shown in formula II3O4Grafted polyacrylic acid hybrid (Fe)3O4-g-PAA)。
3. Synthesis of multiple stimulus-responsive Fe by surface RAFT polymerization3O4Grafted acrylic acid-methyl acrylic acid ferrocene formyl oxygen ethyl ester block copolymer heterozygote
1, 4-dioxane is taken as a solvent, ferrocene formyloxyethyl Methacrylate (MAEFC) is taken as a monomer, AIBN is taken as an initiator, and Fe3O4-g-PAA is a macromolecular chain transfer agent, reacts for 16-36 hours at 70-80 ℃ under the conditions of no water, no oxygen and nitrogen protection, and MAEFC is grafted and polymerized to Fe3O4Surface, obtaining multiple stimulus response Fe3O4Grafted acrylic acid-methyl acrylic acid ferrocene formyloxyethyl ester block copolymer heterozygote (Fe)3O4-g-PAA-b-PMAEFC)。
In the above step 2, Fe is preferable3O4The molar ratio of @ CPADB, AIBN and AA is 1:0.25: 75-150.
In the above step 3, Fe is preferable3O4The molar ratio of the-g-PAA to the AIBN to the MAEFC is 1:0.25: 50-200.
Fe of the invention3O4The application of-g-PAA-b-PMAEFC as a paclitaxel drug carrier of an anticancer drug comprises the following specific application methods:
mixing Fe3O4-g-PAA-b-PMAEFC and paclitaxel are completely dissolved in N, N-dimethylformamide solvent according to the mass ratio of 10:1, the obtained solution is filled into a dialysis bag with the molecular weight cutoff of 2000Da, the dialysis bag is placed in deionized water or PBS buffer solution with the pH value of 7.4 for dialysis, the uncoated drugs are removed by centrifugal separation, and then the polymer hybrid micelle carrying the drugs is frozen and dried to obtain the copolymer hybrid pharmaceutical preparation with the coating paclitaxel and multiple stimulus responses.
Compared with the prior art, the invention has the following beneficial effects:
1. fe of the invention3O4the-g-PAA-b-PMAEFC can form micelles with high Zeta potential and high stability in aqueous solution, and has sensitive pH responsiveness, and the pH phase transition point is 4.75-5.35.
2. Fe of the invention3O4The ferrocene chain segment in the g-PAA-b-PMAEFC can realize oxidation state and reductionState (Fc)+-Fc). Therefore, the formed micelle has obvious redox responsiveness and redox reversibility.
3. Fe of the invention3O4-g-PAA-b-PMAEFC has good superparamagnetism. When an external magnetic field exists, the copolymer heterozygote micelle can be quickly separated from a reaction medium; when the external magnetic field disappears, the magnetic particles can be dispersed again through simple vibration. The magnetic effect can enable the copolymer hybrid micelle to have good application value in the aspect of magnetic targeting treatment.
4. Fe of the invention3O4-g-PAA-b-PMAEFC can be used for coating the anticancer drug taxol. H in acid microenvironment and certain concentration2O2Under stimulation, the accumulative release amount of the medicine is far higher than that of the medicine under a single stimulation condition, and an excellent synergistic effect is shown. Thus, the Fe of the present invention3O4the-g-PAA-b-PMAEFC can be used as a drug carrier to effectively realize the rapid, efficient and fixed-point targeted release of the cancerous lesion.
5. Fe of the invention3O4the-g-PAA-b-PMAEFC can be used as a drug controlled release carrier, can also be used in the fields of magnetic separation, catalysis, magnetic resonance imaging, biotechnology, biomedicine and the like, and is an important multifunctional material.
Drawings
FIG. 1 is magnetic Fe3O4Nanoparticles (a) and aminated Fe3O4(b)、Fe3O4@ CPADB (c), Fe prepared in example 13O4-g-PAA (d) and Fe3O4-infrared spectrum of g-PAA-b-PMAEFC (e).
FIG. 2 is Fe prepared in example 13O4-nuclear magnetic resonance hydrogen spectrum of g-PAA-b-PMAEFC.
FIG. 3 is magnetic Fe3O4Nanoparticles (a) and aminated Fe3O4(b) Fe prepared in example 13O4-XRD pattern of g-PAA-b-PMAEFC (c).
FIG. 4 is Fe of examples 1 and 43O4-g-PAA-b-PMAEFC forming micellesVariation of zeta potential values in solutions of different pH values.
FIG. 5 shows magnetic nano-Fe3O4Fe prepared in examples 1 to 43O4Hysteresis loop of g-PAA-b-PMAEFC.
FIG. 6 shows Fe prepared in examples 1 to 43O4Electrochemical behavior of-g-PAA-b-PMAEFC (scanning Rate: 0.01V s)-1)。
FIG. 7 is Fe prepared in example 43O4Electrochemical behavior of g-PAA-b-PMAEFC at different scan rates (solution concentration: 2mg mL)-1The scanning range is 0.01-0.05V s-1Supporting electrolyte concentration: (CH)3CH2CH2CH2)4N(PF6) THF (0.1M)), where the inset is the current value vs the scan rate squared value v1/2A linear curve.
FIG. 8 is Fe prepared in examples 2 and 43O4UV absorption spectrum of g-PAA-b-PMAEFC.
FIG. 9 is Fe prepared in example 43O4-g-PAA-b-PMAEFC at H2O2Concentrations of 0.0, 1.8, 3.6, 5.9 wt% and 5.9 wt% H2O2Ultraviolet absorption spectra of the copolymer hybrid solution after oxidation followed by reduction with ascorbic acid.
FIG. 10 is Fe prepared in example 43O4-g-PAA-b-PMAEFC forming micelles (a) and the micelles are covered by H2O2Complete oxidation of (b) and the micelle is H2O2Transmission electron micrograph of (c) reduced with ascorbic acid after complete oxidation.
FIG. 11 is Fe prepared in example 43O4-g-PAA-b-PMAEFC forming micelles (a) and the micelles are covered by H2O2Complete oxidation of (b) and the micelle is H2O2Scanning electron micrographs of (c) reduced with ascorbic acid after complete oxidation.
FIG. 12 is Fe prepared in example 33O4The drug release curve (temperature 37 ℃ C.) of the drug preparation obtained by coating the anticancer drug paclitaxel by using-g-PAA-b-PMAEFC as a carrier under a simulated in-vivo microenvironment): (a) pH 7.4, (b) pH 6.3, (c) pH 5.3, (d) pH 5.3 and 0.2% H2O2(e) pH 5.3 and 0.8% H2O2。
Detailed Description
The invention will be described in more detail below with reference to the following figures and examples, but the scope of the invention is not limited to these examples.
Example 1
1. Preparation of Fe3O4Polymerization chain transfer agent for surface reversible addition-fragmentation chain transfer
Powdered magnetic Fe is obtained according to the methods of the documents [ Ding, Y.L., et al, Mater.Sci.Eng.C.48,487-498(2015) ]3O4Nanoparticles, and magnetic Fe powder prepared by the method of Makhluf, S.B., et al, Small 4, 1453-3O4The surface of the nano particles is modified to introduce amino to obtain aminated Fe3O4Nanoparticles (amino group content 18.25 mmol. multidot.g)-1). Amination of Fe3O4Nanoparticles (0.0105g, 0.1916mmol) were ultrasonically dispersed in 25mL dry dichloromethane, CPADB (100mg, 0.3579mmol) and HOBT (0.0394g, 0.2915mmol) were dissolved in 25mL dry dichloromethane, and the two solutions were mixed and transferred to a 150mL three-neck flask and mechanically stirred at 1000rpm under nitrogen for 20 min. EDC/HCl (0.1608g, 0.8388mmol) was dissolved in 10mL of dry dichloromethane, and the solution was added dropwise to the above mixed solution, and the mixture was reacted at room temperature for 48 hours under a nitrogen atmosphere with mechanical stirring. After the reaction is finished, alternately washing the mixture by absolute ethyl alcohol and deionized water until the supernatant is neutral, and carrying out vacuum drying at constant temperature of 40 ℃ to obtain powdery Fe3O4@CPADB。
2. Surface RAFT polymerization synthesis of Fe3O4Grafted polyacrylic acid hybrids
Mixing Fe3O4@ CPADB (0.0262g, 0.192mmol), AA (0.986mL, 14.3718mmol), AIBN (0.0078g, 0.0479mmol) in waterIn a 50mL Schlenk bottle containing 8mL of 1, 4-dioxane, 3 times of freezing-vacuumizing-unfreezing circulation treatment is carried out in a closed system to ensure that oxygen and water in the system are completely removed, then the temperature is raised to 80 ℃, and the reaction is carried out for 24 hours in a nitrogen atmosphere. Repeatedly precipitating the crude product in anhydrous ether for 5 times, freeze drying the purified product to obtain solid powdered Fe3O4-g-PAA, yield 86%. The number average molecular weights obtained by nuclear magnetic estimation and gel permeation chromatography are 4900 and 8640 respectively, and are recorded as Fe3O4-g-PAA68。
3. Synthesis of multiple stimulus-responsive Fe by surface RAFT polymerization3O4Grafted acrylic acid-methyl acrylic acid ferrocene formyl oxygen ethyl ester block copolymer heterozygote
Mixing Fe3O4-g-PAA68(0.04039g，2.02×10-5mol) was sufficiently dissolved in 2mL of deionized water, and MAEFC (0.3448g, 1mmol), AIBN (0.0008g, 4.87X 10-3mmol) is dissolved in 8mL of 1, 4-dioxane, the two solutions are fully mixed and transferred to a Schlenk bottle, the Schlenk bottle is subjected to 3 times of freezing-vacuumizing-unfreezing circulation treatment in a closed system to ensure that oxygen and water are completely removed, and then the temperature is raised to 80 ℃ to react for 24 hours under the nitrogen atmosphere. Repeatedly precipitating the crude product in n-hexane for 5 times, and freeze drying to obtain solid powder Fe3O4-g-PAA-b-PMAEFC, yield 86%. The number average molecular weights of the obtained product are 18270 and 22030 respectively measured by nuclear magnetic estimation and gel permeation chromatography, and the obtained product is marked as Fe3O4-g-PAA68-b-PMAEFC39Or P2。
Example 2
In step 3 of example 1, Fe3O4-g-PAA68(0.04039g，2.02×10-5mol) was sufficiently dissolved in 2mL of deionized water, and MAEFC (0.6896g, 2mmol), AIBN (0.0008g, 4.87X 10-3mmol) was obtained in the same manner as in example 1 to obtain powdery Fe3O4-g-PAA-b-PMAEFC, yield 85%. The number average molecular weights of the obtained product are 30560 and 37120 respectively through nuclear magnetic estimation and gel permeation chromatography, and the obtained product is marked as Fe3O4-g-PAA68-b-PMAEFC75Or P1。
Example 3
In step 2 of example 1, Fe3O4@ CPADB (0.0262g, 0.192mmol), AA (1.972 mL, 28.7436mmol), AIBN (0.0078g, 0.0479mmol) were dissolved in a 50mL Schlenk bottle containing 8mL of 1, 4-dioxane, and other steps were carried out in the same manner as in example 1 to obtain solid powder of Fe3O4-g-PAA, yield 86%, number average molecular weight 9360 and 21620, respectively, by nuclear magnetic estimation and gel permeation chromatography, and noted Fe3O4-g-PAA130. Then, Fe was further treated in the same manner as in step 3 of example 13O4-g-PAA130(0.04039 g，2.02×10-5mol) was sufficiently dissolved in 2mL of deionized water, and MAEFC (0.6896g, 2mmol), AIBN (0.0008g, 4.87X 10-3mmol) and the other steps were the same as in example 1 to obtain Fe3O4-g-PAA-b-PMAEFC, yield 86%. The number average molecular weights of the obtained product are 36840 and 44700 respectively by nuclear magnetic estimation and gel permeation chromatography, and the obtained product is recorded as Fe3O4-g-PAA130-b-PMAEFC80Or P4。
Example 4
In step 3 of example 3, Fe3O4-g-PAA130(0.04039g，2.02×10-5mol) was sufficiently dissolved in 2mL of deionized water, and MAEFC (1.3792g, 4mmol), AIBN (0.0008g, 4.87X 10-3mmol) in the same manner as in example 3 to obtain powdery Fe3O4-g-PAA-b-PMAEFC, yield 86%. Measured by nuclear magnetic estimation and gel permeation chromatographyThe number average molecular weights of 56580 and 57290, respectively, are recorded as Fe3O4-g-PAA130-b-PMAEFC138Or P3。
Fe prepared in the above example 13O4The structure of the-g-PAA-b-PMAEFC is characterized and confirmed by FTIR, NMR and XRD, and the results are shown in figures 1-3. As can be seen, Fe3O4And aminated Fe3O4Characteristic XRD diffraction peaks at 2 theta of 18.33, 30.05, 35.60, 42.95, 45.47, 56.95, 62.60 and 74.01 deg. corresponding to [110 ]]、[220]、[311]、[400]、[422]、[511]、[440]And [533]A crystal plane. This corresponds well with the standard XRD diffraction pattern of crystalline magnetite (JCPDS card number 85-1436 or PDF #19-0629) with a regular octahedral cubic spinel structure. Fe3O4And aminated Fe3O4The average crystal grain size (D) of (a) was calculated according to the Scherrer formula (D ═ K λ/(β cos θ)) to be 10.5nm and 15.9nm, respectively.
The inventors prepared 50mg of Fe prepared in examples 1 to 4, respectively3O4-g-PAA-b-PMAEFC is dissolved in 5mL of DMF, deionized water is added dropwise under the stirring condition until milky white appears, namely copolymer hybrid micelles are formed, the stirring is continued for 12 hours, then 1000mL of deionized water is used for dialysis at room temperature for 48 hours, the cut-off molecular weight of a dialysis bag is 2000, the deionized water is replaced every hour for 3 hours, and then the deionized water is replaced every 8 hours to remove the DMF. Critical Micelle Concentration (CMC) of copolymer hybrid micelles was tested using a Perkin Elmer LS55 type fluorescence spectrophotometer (excitation and emission wavelengths 339 and 394nm, respectively, slit width 10 nm); hydrodynamic diameter (D) of micelles at room temperature was determined using a dynamic light scattering apparatus of the type BI-90Plus equipped with an argon ion laser in the United statesh) (wavelength 660nm, deflection angle 90 degrees, output power 15 mW); micelle surface charge was analyzed by a Delsa Nano model S laser particle size zeta potential analyzer from Beckmann Coulter, USA, and the test results are shown in Table 1.
TABLE 1 physicochemical parameters of copolymer hybrid micelles
The change in zeta potential (ξ) at the corresponding pH of the corresponding micelle of examples 1 and 4 was measured using a dynamic light scattering instrument to investigate the pH response, and the results are shown in FIG. 4. It is clearly noted that ξ hardly changes below pH 4.46 (pKa of PAA) due to protonation of the carboxyl groups and formation of hydrogen bonding interactions between the — COOH groups. As the pH increases (>pKa of PAA), the PAA moieties start to be partially ionized, and the hydrogen bonds are gradually broken. Therefore, the absolute value of ξ (unless otherwise stated, ξ refers to the absolute value below) abruptly increases. Deprotonation or decomposition of the carboxyl groups results in the formation of a large number of carboxylate anions and therefore a large number of negative charges on the micelle surface. When P is present2Has a pH value of more than 6.03 or P3(>pKa of PAA) of 5.48, the acrylic chain is completely ionized and nearly completely stretched, and the negative charge fills the micelle surface. As a result, the xi value reaches a maximum value (P)2Is-113.4 mV, P3At-135 mV). This means that the copolymer hybrid micelle prepared has excellent pH sensitivity. From FIG. 5, it is found that P2Has a pH phase transition point of about 5.21, P3Is 4.94, slightly higher than the pKa of the PAA moiety. P2And P3The difference between the xi value and the pH phase transition point is due to the difference in P3To which more PAA chains are grafted. The separation of hydrogen bonds and the ionization of the multiple-COO-groups are distributed in the outer layer (micellar shell). Thus, P3Ratio P2With a higher ξ. A high ξ at pH 5.21 and/or 4.94 indicates a high stability of the micelle in a simulated physiological environment. Also, P was found1And P4Have similar pH responsiveness and pH transition points of about 4.75 and 5.35, respectively. pH induced responsiveness also can be measured by DLS DhChanges were confirmed as shown in table 1. It is clear that for all copolymer hybrids prepared, D has a pH of 4.8hD at a value greater than pH 7.4hThis is probably due to micelle aggregation caused by hydrogen bonds between protonated carboxyl groups in PBS buffer at pH 4.8. This will result in a small zeta potential, consistent with the discussion above. In contrast, in PBS buffer at pH 7.4, Fe due to its large specific surface area3O4Nanoparticles, a plurality of-COO-The ions spread over the small size micelle surface, resulting in a rather high zeta potential. The pH response provides a new option for controlled release of the drug.
Hysteresis loops were measured on the copolymer hybrid powder samples of examples 1 to 4 using a vibrating sample magnetometer (VSM, 300K). As can be seen from FIG. 5, sample P, which is a copolymer hybrid having ferromagnetism1、P2、P3、 P4Saturation magnetization (M)s) The value was 1.95emu g in order-1、4.71emu g-1、0.42emu g-1And 3.08emu g-1And pure Fe3O4Has a saturation magnetization value of 58.14emu g-1. It is clear that these copolymer hybrids P1、 P2、P3、P4The magnetic property data of (a) well illustrate that they possess the salient features of soft magnetic materials, with good superparamagnetism. Thus, this property of the copolymer hybrid can be exploited to achieve a rapid separation from the reaction medium; when the external magnetic field disappears, the magnetic particles can be dispersed again by simple vibration, and the magnetic response material has good application value in the field of magnetic targeting therapy.
Fe of examples 1 to 4 was investigated using an electrochemical workstation3O4The redox property of the hybrid of the acrylic acid-methacrylic acid ferrocene formyloxyethyl ester block copolymer is grafted. FIG. 6 is Polymer P1、P2、P3、P4Cyclic Voltammetry (CV). P1And P2、P3And P4Has an anodic oxidation potential Ep of 0.813, 0.800, 0.871 and 0.829V in this order, by comparison of P1And P2，P3And P4And P2And P3It is presumed that an increase in the MAEFC/AA composition ratio leads to a high anodic oxidation potential Ep. The shift of oxidation potential and reduction potential in the electrochemical cyclic voltammogram is due to the presence of ferrocene reactive end in the amphiphilic block polymer, not due to the influence of solvent and diffusion coefficient. Fe3O4High grafting amount of ferrocene segment in g-PAA-b-PMAEFC has lower redox potential, polymerizationThe ferrocene chain segment in the material is easy to change from reduced state Fc to oxidized state Fc+. At the same time, Fe3O4The lower the ferrocene content in g-PAA-b-PMAEFC, the better the reversibility of the electrode process (P)1、P2、P3And P4Potential difference between cathode and anodep(ΔEp＝Ep, anode-Ep, cathode) 0.264, 0.244, 0.425, and 0.203V, in that order).
With the copolymer hybrid P of example 43And researching the change rule of the cyclic voltammogram under different scanning rates for the model. As can be seen from FIG. 7, the faster the scan rate, the more the oxidation and reduction peaks shift to the anode and cathode, respectively, resulting in a difference in anode and cathode potentials Δ EpThe larger the value, and the modified Δ E of the electrodepThe values increase linearly with increasing scan rate, indicating that the electrode process is quasi-reversible. In addition, it was found that the redox peak current value was dependent on the scan rate (v)1/2) Increased and linearly increased peak current intensity (I)p) Square root of scanning rate (v)1/2) The good linear relation is presented, and the linear relation equation is as follows: i isp,c＝-1.4453ν1/2+0.5748(R20.9761) and Ip,a＝1.2546ν1/2+0.7655(R20.9945), indicating that the redox electrochemical process of the copolymer hybrid is a quasi-reversible diffusion-controlled process.
The Fe prepared in examples 2 and 4 was further investigated by ultraviolet-visible spectroscopy (UV-vis)3O4Reversible redox responsiveness of-g-PAA-b-PMAEFC, as shown in fig. 8 and fig. 9. As can be seen from FIG. 8, due to the special pi-pi conjugated structure of the ferrocenyl moiety, the copolymer hybrid P3Characteristic peaks of reduced ferrocene parent bodies appear at the wavelengths of 442nm, 349 nm and 308 nm; the peak intensity varied with ferrocene content or MAEFC/AA composition ratio. By means of oxidizing agent H of different concentrations2O2After oxidation, ferrocene is converted from a neutral Fc in its reduced state to a ferrocenium cation parent Fc in its oxidized state+The electronic spectrum of these features diminishes or disappears as shown in fig. 9. And when a reducing agent ascorbic acid (Vc) is added to the above solution, Fc+The cations being converted into a neutral stateFc realizes reduced-oxidized state (Fc-Fc)+) With oxidation-reduction (Fc)+-Fc). Thus, Fe3O4The redox process of the-g-PAA-b-PMAEFC is reversible and can achieve a reversible "smart" on-off process.
Preparation of Fe by Transmission Electron Microscopy (TEM) for example 4 at different redox states3O4The morphology of the micelles formed by-g-PAA-b-PMAEFC was characterized and the results are shown in FIG. 10. As can be seen from FIG. 10(a), the micelle has a good spherical core-shell structure, the particle size distribution is 160-400 nm, and the average particle size is 266 nm. As can be seen from FIG. 10(b), H2O2The average particle size of the oxidized micelle is 420 +/-30 nm. This may be due to the neutral Cp in the micellar shell structure2Conversion of Fe to cationic Cp2Fe+The swelling capacity of the hydrophobic chain segment ferrocenium salt micelle solution is enhanced, and simultaneously the inner shell is cationic Cp2Fe+The strong electrostatic repulsion between ions increases the micelle size. H2O2Is a neutral oxidant, and can effectively remove hydrophobic ferrocenyl (Cp) groups in the inner shell2) Conversion to the hydrophilic cation ferrocenium salt (Cp)2Fe+) And the electrostatic repulsive force, the hydrophilicity and the swelling property of the PMAEFC of the micelle core are improved. The micellar inner shell PMAEFC is formed by the cation Cp when the reducing agent ascorbic acid Vc is added2Fe+Conversion to the neutral molecule Cp2Fe. At this time, the hydrophilicity and electrostatic repulsive force of the inner shell of the micelle are weakened until the inner shell disappears, and the particle size of the reduced nano-micelle shown in fig. 10(c) is reduced to 260 ± 70nm, which is substantially consistent with the particle size of the original micelle solution. The result of TEM measurement shows Fe3O4the-g-PAA-b-PMAEFC micelle has good redox reversibility.
The Fe prepared in example 4 in various redox states was observed using a cold Field Emission Scanning Electron Microscope (FESEM)3O4The change in the microstructure of the micelles formed by g-PAA-b-PMAEFC, as shown in FIG. 11. As can be seen from FIG. 11(a), the unoxidized primary micelle particles are spherical, and have a wide average particle size distribution, wherein the particle size range is 150-370 nm, and most of the particles are 340-350 nm. Appear on the surface of the oxidized micelle sphereThe irregular growth is evident, and the size of most micelles is enlarged to about 520nm, the size range is 480-700 nm, but the particle size distribution becomes more uniform, as shown in fig. 11 (b). This is because hydrophilic ferrocenium cations (Fc) are formed in the PMAEFC structure+) The swelling and electrostatic repulsion of the micelle core is enhanced. The morphology of the micelle after adding ascorbic acid reducing agent is not significantly different from the morphology after oxidation, but the particle size is reduced, as shown in FIG. 11(c), the particle size is reduced to about 250-450 nm, the average size is about 350nm, and the size is close to the original micelle size and size distribution. It is concluded from the changes in the morphology and size of the micelles before and after redox that the copolymer hybrid micelles of the invention have good reversible redox stress or switching properties.
Example 5
Fe prepared in example 33O4The application of-g-PAA-b-PMAEFC as a paclitaxel drug carrier of an anticancer drug comprises the following specific application methods:
first, P is weighed4Sample 20mg and Paclitaxel (PTX)2mg are fully dissolved in 5mL DMF, the obtained solution is filled into a dialysis bag with the molecular weight cutoff of 2000Da and is placed into deionized water for dialysis for 24h, then the low-speed centrifugation is carried out to remove the unencapsulated drug, and the polymer hybrid micelle carrying the drug is frozen and dried to obtain the copolymer hybrid drug preparation with the coating paclitaxel and multiple stimulus responses.
The obtained copolymer heterozygote medicinal preparation coated with the paclitaxel and having multiple stimulus responses is subjected to an in-vitro medicament release test, and the specific test method and the test result are as follows:
1. drug encapsulation assay
The paclitaxel-coated copolymer hybrid drug preparation with multiple stimulus responses was completely dissolved in DMF, and the absorbance at a fixed absorption wavelength of 228nm was measured using an ultraviolet-visible spectrometer of hitachi, japan, model number U-3900/3900H, and the drug Loading (LC) and Encapsulation Efficiency (EE) were calculated according to the following formulas:
LC (wt%) × 100% (mass of drug in pharmaceutical preparation/mass of pharmaceutical preparation)
EE (wt%) × 100% (mass of drug in pharmaceutical preparation/mass of drug added)
Calibration curves were drawn by measuring the absorbance of different concentrations of free drug in DMF. Fe3O4The coating efficiency (EE) and drug Loading Capacity (LC) of the micelles formed by g-PAA-b-PMAEFC on PTX are 42.8% and 10.7%, respectively.
2. In vitro drug Release test
Paclitaxel-coated multi-stimulus responsive copolymer hybrid drug formulation 3mg was dissolved in 3mL of PBS buffer under specific conditions: (a) pH 7.4, (b) pH 6.3, (c) pH 5.3, (d) pH 5.3 and 0.2% H2O2(e) pH 5.3 and 0.8% H2O2After being fully dissolved, the mixture is placed in a dialysis bag with the molecular weight cutoff of 2000Da, and the drug release in the environment of canceration cells with different pH values and different concentrations of Reactive Oxygen Species (ROS) at 37 ℃ is simulated. 3mL of solution was removed from the release system at regular intervals and transferred to sample tubes and supplemented with an equal amount of fresh buffer for 4 days. The absorbance value of the sample solution at a wavelength of 210nm was measured by an ultraviolet-visible spectrophotometer (UV-vis) and the amount of the released was calculated according to the following formula:
cumulative drug release%t/M0×100％
In the formula MtIs the amount of drug released at time t, M0Is the amount of drug in the pharmaceutical formulation. The results are shown in FIG. 12.
As can be seen from fig. 12, the drug release amount of the pharmaceutical preparation was significantly increased in the redox and pH environments. As can be seen from FIGS. 12(a) - (c), the release of PTX was only 7.8% when the release was sustained at pH 7.4 for 72 h. However, at pH 5.3 and pH 6.3, PTX release amounts were 34.1% and 26.2%, respectively, and the PTX drug release rate was accelerated as the pH value was lowered, and thus, the pharmaceutical preparation had good pH responsiveness. The single pH-responsive drug release rate was low, however, when oxidant H was added2O2The PTX drug release is followed by H2O2The hydrogen peroxide concentration increased significantly, and this result is seen in fig. 12(c) - (e). After sustained release for 72H, oxidant H2O2The cumulative release amounts of the drugs at the concentrations of 0.2% and 0.8% were 52.8% and 72.7%, respectively. To pairAs can be seen, the drug release amount induced by the double stimulation is far higher than that under the condition of single stimulation. Thus, the Fe of the present invention3O4the-g-PAA-b-PMAEFC taken as the taxol drug carrier of the anticancer drug can effectively realize the controllable release of the drug, thereby realizing the rapid and efficient site-specific release of the lesion of the canceration. Cancer focus and normal cells in pH microenvironment and oxygen free radical H2O2There is a large difference in concentration.
From the above test results, it can be seen that the Fe of the present invention has triple stimuli responsiveness in pH, oxidation reduction and magnetism3O4the-g-PAA-b-PMAEFC is used as a taxol drug carrier of an anticancer drug, and can realize controllable high-efficiency drug release to the maximum extent.

Claims (5)

1. Multi-stimulus response Fe3O4The grafted acrylic acid-ferrocenecarbonyloxyethyl methacrylate block copolymer hybrid is characterized in that the structure of the hybrid is as follows:
wherein m is 60-150 and n is 35-140.
2. The multi-stimulus responsive Fe of claim 13O4The preparation method of the grafted acrylic acid-methyl acrylic acid ferrocene formyloxyethyl ester block copolymer heterozygote is characterized by comprising the following steps:
(1) preparation of Fe3O4Polymerization chain transfer agent for surface reversible addition-fragmentation chain transfer
Methylene dichloride is used as a solvent, 1-hydroxybenzotriazole is used as an amido protective agent, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is used as a dehydrating agent, and 4-cyano-4- (thiobenzoic acid) valeric acid is bonded to aminated Fe by amidation reaction3O4Surface to obtain Fe shown in formula I3O4A surface reversible addition-fragmentation chain transfer polymerization chain transfer agent;
(2) surface RAFT polymerization synthesis of Fe3O4Grafted polyacrylic acid hybrids
Using 1, 4-dioxane as solvent, acrylic acid as monomer and Fe3O4The surface reversible addition-fragmentation chain transfer polymerization chain transfer agent is a chain transfer agent, azodiisobutyronitrile is an initiator, and the reaction is carried out for 16-36 hours at 70-80 ℃ under the conditions of no water, no oxygen and nitrogen protection to obtain Fe shown in the formula II3O4Grafted polyacrylic acid hybrids;
(3) synthesis of multiple stimulus-responsive Fe by surface RAFT polymerization3O4Grafted acrylic acid-methyl acrylic acid ferrocene formyl oxygen ethyl ester block copolymer heterozygote
Using 1, 4-dioxane as solvent, ferrocene formyloxyethyl methacrylate as monomer, azodiisobutyronitrile as initiator, Fe3O4Grafting polyacrylic acid heterozygote as a macromolecular chain transfer agent, reacting for 16-36 hours at 70-80 ℃ under the conditions of no water, no oxygen and nitrogen protection, and grafting and polymerizing the ferrocene formyloxyethyl methacrylate to Fe3O4Surface, obtaining multiple stimulus response Fe3O4Grafted acrylic acid-ferrocenecarbonyloxyethyl methacrylate block copolymer heterozygote.
3. Multi-stimulus responsive Fe according to claim 23O4The preparation method of the grafted acrylic acid-methyl acrylic acid ferrocene formyloxyethyl ester block copolymer heterozygote is characterized by comprising the following steps: in step (2), the Fe3O4The molar ratio of the surface reversible addition-fragmentation chain transfer polymerization chain transfer agent to the azodiisobutyronitrile to the acrylic acid is 1:0.25: 75-150.
4. Multi-stimulus responsive Fe according to claim 23O4The preparation method of the grafted acrylic acid-methyl acrylic acid ferrocene formyloxyethyl ester block copolymer heterozygote is characterized by comprising the following steps: in step (3), the Fe3O4The molar ratio of the grafted polyacrylic acid hybrid to the azodiisobutyronitrile to the ferrocenecarbonyloxyethyl methacrylate is 1:0.25: 50-200.
5. Multi-stimulus responsive Fe according to claim 13O4The application of the grafted acrylic acid-methyl acrylic acid ferrocene formyloxyethyl ester block copolymer heterozygote as an anticancer drug paclitaxel drug carrier.
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