CN111012928A - Multifunctional nano-cluster and preparation method thereof - Google Patents
Multifunctional nano-cluster and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a multifunctional nano-cluster for targeted drug delivery and magnetic resonance imaging and a preparation method thereof. The preparation method comprises the following steps: step 1, weighing a proper amount of oil-soluble Fe3O4Dissolving nano particles in an organic solvent to obtain a solution A; in addition, a proper amount of folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127) is weighed@ FA) in water to obtain solution B; step 2, mixing the solution A and the solution B, and placing the mixture on an ice bath for ultrasonic treatment; step 3, standing after ultrasonic treatment, extracting after solution layering, and collecting a solution water phase; and 4, obtaining a sample in a solution water phase by adopting a centrifugal or magnetic separation mode, namely obtaining the multifunctional nano-cluster for targeted drug delivery and magnetic resonance imaging. The preparation method is simple, and the prepared magnetic nano material has good magnetic responsiveness and biocompatibility.
Description
Technical Field
The invention belongs to the field of nano biomedicine, and particularly relates to a multifunctional nano cluster for targeted drug delivery and magnetic resonance imaging and a preparation method thereof.
Background
The multifunctional nano material has gained wide attention in the biomedical field, for example, the functional nano material with both fluorescence imaging and drug delivery has great advantages in the early diagnosis and treatment of tumors.
In recent years, magnetic nanomaterials are widely used in biomedical fields such as targeted drug delivery, cell analysis, early diagnosis of tumors and the like because of unique magnetic responsiveness and biocompatibility of the magnetic nanomaterials. Wherein the superparamagnetic ferroferric oxide nano particle (Fe)3O4) The magnetic material is the only material approved and certified by the Food and Drug Administration (FDA) in the numerous magnetic materials so far, the product obtained by the high-temperature pyrolysis method is generally small in particle size, uniform in distribution and good in crystallinity, but the nano particles prepared by the method are generally oil-soluble. Therefore, when the nanoparticles are applied in the biomedical field, the surface of the nanoparticles usually needs surface modification, such as mesoporous silicon modification, polymer modification and the like, on one hand, the water solubility of the nanoparticles is improved, and on the other hand, the nanoparticles can entrap drugs by a physical adsorption or covalent connection method. However, these methods usually involve many steps, are cumbersome to operate, and may cause Fe during the multi-step modification process3O4Oxidation and reduction of iron content, ultimately leading to reduced magnetic properties. Therefore, the research and development of the multifunctional nano material which is simple to prepare, has good biocompatibility and has magnetic resonance imaging and targeted drug delivery has important significance.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of multifunctional nanoclusters for targeted drug delivery and magnetic resonance imaging.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a preparation method of multifunctional nanoclusters comprises the following steps:
in addition, a proper amount of the folic acid targeted modified triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127) is weighed and dissolved in water to obtain a solution B, and the concentration of the folic acid targeted modified triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA) in the solution B is controlled to be 0.1-10 mg/mL;
step 2, mixing the solution A and the solution B, and placing the mixture on an ice bath for ultrasonic treatment;
step 3, standing after ultrasonic treatment, extracting after solution layering, and collecting a solution water phase;
and 4, obtaining a sample in a solution water phase by adopting a centrifugal or magnetic separation mode, namely obtaining the multifunctional nano-cluster for targeted drug delivery and magnetic resonance imaging.
The further technical scheme is as follows: oil-soluble Fe in said step 13O4The preparation method of the nano-particles comprises the following steps:
step a, dissolving iron salt, oleic acid and oleyl ammonium in benzyl alcohol to obtain a solution C, ensuring that the concentration of the iron salt in the solution C is 0.1-0.5mol/L, and stirring until the solution is clear, wherein the volume ratio of the oleic acid to the oleyl amine to the benzyl alcohol is 1:1: 4;
step b, placing the solution C in a polytetrafluoroethylene reaction kettle, sealing, and reacting in an oven at the temperature of 160-200 ℃ for 10-24 h;
step c, after the reaction is finished, cooling the reaction kettle to room temperature;
d, discarding the supernatant in the reaction kettle, washing the product for 3-5 times by water and ethanol in sequence, and then placing the product in a drying oven with the temperature of 30-60 ℃ for vacuum drying for 5-12h to obtain a powdery product, namely the oil-soluble Fe3O4Nanoparticles.
The further technical scheme is as follows: the preparation method of the folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA) in the step 1 is as follows:
dissolving folic acid in dry dimethyl sulfoxide to obtain a solution D;
b, adding N, N-carbonyl-diimidazole into the solution D, and stirring overnight in a dark place; adding a triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127) into the solution D, and continuously stirring for 24-48h in the dark to obtain a reaction solution, wherein the triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127), Folic Acid (FA), N-carbonyl-diimidazole (CDI) and the molar ratio of the three are 1 (2-4) to (1-2);
c, filling the reaction solution into a dialysis bag with the molecular weight cutoff of 1000D for full dialysis, and replacing deionized water every 3-5 h;
and d, freeze-drying the product to obtain the folic acid targeted modified triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA).
The further technical scheme is as follows: in the step 1, the organic solvent is any one of cyclohexane, chloroform and diethyl ether, and the oil-soluble Fe3O4The ultrasonic treatment is assisted in the process of dissolving the nano particles in the organic solvent.
The further technical scheme is as follows: in the step 2, ultrasonic treatment is performed by selecting probe ultrasonic, wherein the ultrasonic treatment power is 40-60W, and the ultrasonic treatment time is 20-60 min.
The further technical scheme is as follows: the solution C is reacted for 12-20h in an oven at 200 ℃ and 180 ℃.
The further technical scheme is as follows: the folic acid, the N, N-carbonyl-diimidazole and the triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127) are placed in a vacuum drying oven for room temperature treatment for more than 24 hours before use.
Another object of the present invention is to provide the multifunctional nanoclusters for targeted drug delivery and magnetic resonance imaging prepared by the preparation method.
The invention has the beneficial effects that:
(1)the preparation process is simple and controllable, and is based on oil-soluble Fe3O4The triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA) targeted by nano particles and folic acid can obtain nano clusters (called nano clusters for short) stably dispersed in an aqueous solution only by controlling an ultrasonic process, and the nano clusters are regular in appearance, uniform in size, uniform in particle size distribution and mainly distributed at about 200 nm. Folic Acid (FA) in a triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA) subjected to folic acid targeting modification serves as a targeting molecule, and a large amount of Fe is coated on the inner core of a hydrophobic chain segment of the triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127)3O4The nano particles can effectively enhance the strength of magnetic resonance signals, and meanwhile, a place is provided for drug loading.
The multifunctional nano cluster has better biocompatibility and targeting property, can load hydrophobic drugs, has higher drug loading (4-14 wt%), can realize pH response type release, greatly reduces the toxic and side effects on normal tissues, and can be used as a targeting drug carrier for antitumor treatment.
The multifunctional nano cluster in the invention has higher T2The relaxation rate can be used for magnetic resonance imaging to synchronously realize the diagnosis and treatment of tumors. The relaxation rate r is measured under the magnetic field of 3.0T2Up to 401.8mM-1s-1Is obviously higher than commercial reagent (by Fe)3O4Commercial T with nano-particles as main component2Relaxation rate r of contrast agent Ferro-magnetic at 3.0T2Is 108mM-1s-1)。
(2) The reason for selecting the probe ultrasound in the invention is as follows: the height of the probe can be adjusted by the ultrasonic wave of the probe, so that the ultrasonic wave generation center is positioned in the water phase and the oil-soluble Fe of the triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127)3O4The phase interface of the organic phase in which the nano particles are positioned can better ensure that the oil is soluble in Fe3O4The nano particles successfully complete the transfer of the organic phase to the aqueous phase and are assembled into a cluster structure.
(3) The reason why folic acid, N-carbonyl-diimidazole and triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127) are placed in a vacuum drying oven for room temperature treatment for at least 24 hours before use is that: the folic acid modified triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene is prepared by esterification reaction of carboxyl of folic acid and carboxyl of triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene, and the reaction conversion rate is influenced by the presence of a small amount of water in a reagent, so that the folic acid modified triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene is placed in vacuum drying pretreatment before use to improve the esterification reaction conversion rate.
Drawings
FIG. 1 is a schematic diagram of the formation of multifunctional nanoclusters of the present invention;
FIG. 2 shows multifunctional nanoclusters (Fe) prepared under different conditions according to the present invention3O4@ F127@ FA) (A-C);
FIG. 3 shows targeting drug-loaded nanoclusters (DOX @ Fe)3O4@ F127@ FA) and comparative example (DOX @ Fe)3O4@ F127) and HepG2 cells after 24 hours of co-culture;
FIG. 4 shows multifunctional nanoclusters (Fe) prepared by the present invention3O4@ F127@ FA) of2A weighted graph (A) and a relaxation rate (B);
FIG. 5 shows multifunctional nanoclusters (Fe) of the present invention3O4@ F127@ FA) and its comparative example nanoclusters (Fe)3O4@ F127) were co-cultured with HepG2 cells, respectively, and then the Fe content in the cells was analyzed;
FIG. 6 shows multifunctional nanoclusters (Fe) of the present invention3O4@ F127@ FA) and its comparative example nanoclusters (Fe)3O4@ F127) cell viability assay after co-culture with HepG2 cells, respectively;
FIG. 7 shows drug-loaded nanoclusters (DOX @ Fe) of the present invention3O4@ F127@ FA), comparative example drug-loaded nanocluster (DOX @ Fe)3O4@ F127) were co-cultured with HepG2 cells, respectively.
Detailed Description
The technical scheme of the invention is more specifically explained by combining the following embodiments:
instruments and reagents
A transmission electron microscope (JEM-1011, Hitachi, Japan); laser confocal microscopy (LSM-710, Seitz, Germany), multifunctional microplate reader (Varioskan Flash, USA thermoelectricity corporation), inductively coupled plasma spectrometer (IRIS Intrepid II XSP, USA thermoelectricity corporation).
Triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127) (pluronic triblock copolymer triblock polymer polyoxyethylene-polyoxypropylene-polyoxyethylene) was purchased from Sigma-Aldrich, usa; n, N-carbonyl-diimidazole (CDI), iron acetylacetonate, and Folic Acid (FA) were obtained from Aladdin reagents, Inc.; doxorubicin HCl (DOX. HCl) and 4', 6-diamidino-2-phenylindole (DAPI) were purchased from beijing solibao technologies ltd, and all other reagents were purchased from national drug group chemicals ltd.
Example 1
The invention relates to a multifunctional nano cluster (Fe)3O4@ F127@ FA) as follows:
step 2, mixing the solution A and the solution B, and placing the mixture on an ice bath for ultrasonic treatment, wherein the ultrasonic treatment power is 40W, and the time is 30 min;
step 3, standing for 12 hours after ultrasonic treatment, extracting and collecting a solution water phase after the solution is layered;
and 4, obtaining a sample in the aqueous phase of the solution by magnetic separation, and washing the sample for multiple times by using water to obtain the multifunctional nano-cluster for targeted drug delivery and magnetic resonance imaging.
Oil-soluble Fe in the above step 13O4Preparing nano particles:
step a, dissolving 0.353g of ferric acetylacetonate, 1.5mL of oleic acid and 1.5mL of oily ammonium in 6mL of benzyl alcohol to obtain a solution C, and stirring until the solution is clear;
b, transferring the solution C into a polytetrafluoroethylene reaction kettle, sealing, and reacting for 10 hours in a 200 ℃ drying oven;
step c, after the reaction is finished, cooling the reaction kettle to room temperature;
d, discarding the supernatant in the reaction kettle, washing the product with water and ethanol for 3 +/-1 times respectively, and then placing the product in a 40 ℃ oven for vacuum drying for 12 hours to obtain a powdery product, namely the oil-soluble Fe3O4Nanoparticles;
synthesizing a folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA) in the step 1:
step a, weighing 1.3g of folic acid solution in 20mL of anhydrous DMSO to obtain a solution D;
step b, weighing 250mg of N, N-carbonyl-diimidazole, adding into the solution D, and stirring overnight in a dark place; adding 12.6g of triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127) into the solution D, and continuing stirring for 24 hours in the dark;
c, filling the reaction solution into a dialysis bag with the molecular weight cutoff of 1000D for full dialysis, and replacing deionized water every 3 hours;
and d, freeze-drying the product to obtain the folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA).
Characterization of the multifunctional nanoclusters:
and (3) performing appearance characterization on the product by using a transmission electron microscope, dripping 10 mu L of sample water solution on a copper net, drying, and observing and taking a picture under a TEM (transmission electron microscope), wherein the product is packed in a spherical cluster in the water solution and well dispersed as shown in part A in the attached figure 2.
Example 2
The invention relates to a multifunctional nano cluster (Fe)3O4@ F127@ FA) as follows:
step 2, mixing the solution A and the solution B, and placing the mixture on an ice bath for ultrasonic treatment, wherein the ultrasonic treatment power is 40W, the ultrasonic treatment is carried out for 2s, the interval is 3s, and the total time is 50 min;
step 3, standing overnight after ultrasonic treatment, extracting and collecting a solution water phase after the solution is layered;
and 4, obtaining a sample in the aqueous phase of the solution by magnetic separation, and washing the sample for multiple times by using water to obtain the multifunctional nano-cluster for targeted drug delivery and magnetic resonance imaging.
Oil-soluble Fe in the above step 13O4Preparation of nanoparticles, synthesis of folic acid targeting modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA) the same as in example 1:
characterization of the multifunctional nanoclusters:
and (3) performing appearance characterization on the product by using a transmission electron microscope, dripping 10 mu L of sample aqueous solution on a copper net, drying, and observing and taking a picture under a TEM (transmission electron microscope), wherein the product is packed in a spherical cluster in the aqueous solution and well dispersed as shown in part B in the attached figure 2.
Example 3
The invention relates to a multifunctional nano cluster (Fe)3O4@ F127@ FA) as follows:
step 2, mixing the solution A and the solution B, and placing the mixture on an ice bath for ultrasonic treatment, wherein the ultrasonic treatment power is 40W, the ultrasonic treatment is carried out for 2s, the interval is 3s, and the total time is 50 min;
step 3, standing overnight after ultrasonic treatment, extracting and collecting a solution water phase after the solution is layered;
and 4, obtaining a sample in the aqueous phase of the solution by magnetic separation, and washing the sample for multiple times by using water to obtain the multifunctional nano-cluster for targeted drug delivery and magnetic resonance imaging.
Oil-soluble Fe in the above step 13O4Preparation of nanoparticlesThe synthesis of a folic acid-targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA) was performed as in example 1:
characterization of multifunctional nanoclusters:
and (3) performing appearance characterization on the product by using a transmission electron microscope, dripping 10 mu L of sample water solution on a copper net, drying, and observing and taking a picture under a TEM (transmission electron microscope), wherein the product is packed in a spherical cluster in the water solution and well dispersed as shown in a part C in the attached figure 2.
Example 4
The invention relates to a multifunctional nano cluster (Fe)3O4@ F127@ FA) as follows:
in addition, a proper amount of the folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA) is weighed and dissolved in water to obtain a solution B, and the concentration of the folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA) in the solution B is controlled to be 5 mg/mL;
step 2, mixing the solution A and the solution B, and placing the mixture on an ice bath for ultrasonic treatment, wherein the ultrasonic treatment power is 30W, and the time is 30 min;
step 3, standing after ultrasonic treatment, extracting after solution layering, and collecting a solution water phase;
and 4, obtaining a sample in the aqueous phase of the solution by magnetic separation, and washing the sample for multiple times by using water to obtain the multifunctional nano-cluster for targeted drug delivery and magnetic resonance imaging.
Oil-soluble Fe in said step 13O4The preparation method of the nano-particles comprises the following steps:
step a, dissolving iron salt, oleic acid and oleyl ammonium in benzyl alcohol to obtain a solution C, ensuring that the concentration of the iron salt in the solution C is 0.3mol/L, wherein the volume ratio of the oleic acid to the oleyl amine to the benzyl alcohol is 1:1:4, and stirring until the solution is clear;
b, placing the solution C in a polytetrafluoroethylene reaction kettle, sealing, and reacting in an oven at 180 ℃ for 15 hours;
step c, after the reaction is finished, cooling the reaction kettle to room temperature;
d, discarding the supernatant in the reaction kettle, washing the product for 4 times by water and ethanol in sequence, and then placing the product in a drying oven at 40 ℃ for vacuum drying for 8 hours to obtain a powdery product, namely the oil-soluble Fe3O4Nanoparticles.
The preparation method of the folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA) in the step 1 is as follows:
dissolving folic acid in dry dimethyl sulfoxide to obtain a solution D;
b, adding N, N-carbonyl-diimidazole into the solution D, and stirring overnight in a dark place; and adding triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127) into the solution D, and continuously stirring for 36 hours in the dark to obtain a reaction solution, wherein the molar ratio of the F127 to the FA to the CDI is 1: 2: 1;
c, filling the reaction solution into a dialysis bag with the molecular weight cutoff of 1000D for full dialysis, and replacing the deionized water every 4 hours;
and d, freeze-drying the product to obtain the folic acid targeted modified triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA).
Characterization of the multifunctional nanoclusters:
and performing appearance characterization on the product by using a transmission electron microscope, dripping 10 mu L of sample aqueous solution on a copper net, drying, and observing and photographing under a TEM (transmission electron microscope), wherein the sample aqueous solution is packed in a spherical cluster in the aqueous solution and is well dispersed.
Example 5
The invention relates to a multifunctional nano cluster (Fe)3O4@ F127@ FA) as follows:
in addition, a proper amount of the folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA) is weighed and dissolved in water to obtain a solution B, and the concentration of the folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA) in the solution B is controlled to be 0.1 mg/mL;
step 2, mixing the solution A and the solution B, and placing the mixture on an ice bath for ultrasonic treatment, wherein the ultrasonic treatment power is 40W, and the time is 20 min;
step 3, standing after ultrasonic treatment, and collecting a lower layer of the solution after the solution is layered;
and 4, obtaining a sample in the lower layer of the solution by adopting a centrifugal or magnetic separation mode, and then carrying out vacuum drying to obtain the multifunctional nano-cluster for targeted drug delivery and magnetic resonance imaging.
Oil-soluble Fe in said step 13O4The preparation method of the nano-particles comprises the following steps:
step a, dissolving iron salt, oleic acid and oleyl ammonium in benzyl alcohol to obtain a solution C, ensuring that the concentration of the iron salt in the solution C is 0.1mol/L, and stirring until the solution is clear, wherein the volume ratio of the oleic acid to the oleyl amine to the benzyl alcohol is 1:1: 4;
b, placing the solution C in a polytetrafluoroethylene reaction kettle, sealing, and reacting in a 160 ℃ oven for 12 hours;
step c, after the reaction is finished, cooling the reaction kettle to room temperature;
d, discarding the supernatant in the reaction kettle, washing the product for 3 times by water and ethanol in sequence, and then placing the product in a 30 ℃ oven for vacuum drying for 5 hours to obtain a powdery product, namely the oil-soluble Fe3O4Nanoparticles.
The preparation method of the folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA) in the step 1 is as follows:
dissolving folic acid in dry dimethyl sulfoxide to obtain a solution D;
b, adding N, N-carbonyl-diimidazole into the solution D, and stirring overnight in a dark place; and adding triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127) into the solution D, and continuously stirring for 24 hours in the dark to obtain a reaction solution, wherein the molar ratio of the F127 to the FA to the CDI is 1: 2: 2;
c, filling the reaction solution into a dialysis bag with the molecular weight cutoff of 1000D for full dialysis, and replacing deionized water every 3 hours;
and d, freeze-drying the product to obtain the folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA).
Characterization of the multifunctional nanoclusters:
and performing appearance characterization on the product by using a transmission electron microscope, dripping 10 mu L of sample aqueous solution on a copper net, drying, and observing and photographing under a TEM (transmission electron microscope), wherein the sample aqueous solution is packed in a spherical cluster in the aqueous solution and is well dispersed.
Example 6
The invention relates to a multifunctional nano cluster (Fe)3O4@ F127@ FA) as follows:
in addition, a proper amount of the folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA) is weighed and dissolved in water to obtain a solution B, and the concentration of the folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA) in the solution B is controlled to be 10 mg/mL;
step 2, mixing the solution A and the solution B, and placing the mixture on an ice bath for ultrasonic treatment, wherein the ultrasonic treatment power is 60W, and the time is 60 min;
step 3, standing after ultrasonic treatment, and collecting a lower layer of the solution after the solution is layered;
and 4, obtaining a sample in the lower layer of the solution by adopting a centrifugal or magnetic separation mode, and then carrying out vacuum drying to obtain the multifunctional nano-cluster for targeted drug delivery and magnetic resonance imaging.
Oil-soluble Fe in said step 13O4The preparation method of the nano-particles comprises the following steps:
step a, dissolving iron salt, oleic acid and oleyl ammonium in benzyl alcohol to obtain a solution C, ensuring that the concentration of the iron salt in the solution C is 0.5mol/L, wherein the volume ratio of the oleic acid to the oleyl amine to the benzyl alcohol is 1:1:4, and stirring until the solution is clear;
b, placing the solution C in a polytetrafluoroethylene reaction kettle, sealing, and reacting in a drying oven at 200 ℃ for 20 hours;
step c, after the reaction is finished, cooling the reaction kettle to room temperature;
d, discarding the supernatant in the reaction kettle, washing the product for 5 times by water and ethanol in sequence, and then placing the product in a 60 ℃ oven for vacuum drying for 12 hours to obtain a powdery product, namely the oil-soluble Fe3O4Nanoparticles.
The preparation method of the folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA) in the step 1 is as follows:
dissolving folic acid in dry dimethyl sulfoxide to obtain a solution D;
b, adding N, N-carbonyl-diimidazole into the solution D, and stirring overnight in a dark place; and adding triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127) into the solution D, and continuously stirring for 48 hours in the dark to obtain a reaction solution, wherein the molar ratio of the F127 to the FA to the CDI is 1: 2: 1;
c, filling the reaction solution into a dialysis bag with the molecular weight cutoff of 1000D for full dialysis, and replacing the deionized water every 5 hours;
and d, freeze-drying the product to obtain the folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127@ FA).
Characterization of the multifunctional nanoclusters:
and performing appearance characterization on the product by using a transmission electron microscope, dripping 10 mu L of sample aqueous solution on a copper net, drying, and observing and photographing under a TEM (transmission electron microscope), wherein the sample aqueous solution is packed in a spherical cluster in the aqueous solution and is well dispersed.
Example 7 (Fe-a multifunctional nanocluster according to the invention)3O4Comparative example of @ F127@ FA)
Nanocluster of Fe3O4The preparation method of @ F127 is as follows:
step 2, mixing the solutions 1 and 2, and placing the mixture on an ice bath for ultrasonic treatment of 40W, wherein the ultrasonic treatment is carried out for 2s at intervals of 3s, and the total time is 50 min;
step 3, standing after ultrasonic treatment, and collecting a lower layer of the solution after the solution is layered;
step 4, drying the collected sample in vacuum to obtain Fe3O4@ F127 nanoclusters.
Example 8
Using multifunctional nanoclusters of Fe3O4Preparation of drug-loaded nanocluster DOX @ Fe by @ F127@ FA3O4@ F127@ FA (or its use in a comparative nanocluster Fe3O4@ F127 preparation of drug-loaded nanocluster DOX @ Fe3O4@F127):
(1) Nano cluster of Fe3O4@ F127@ FA (or nanocluster Fe)3O4@ F127) was dispersed in water at a concentration of 10 mg/mL;
(2) dissolving doxorubicin hydrochloride in DMSO, and controlling the concentration to be 5 mg/mL;
(3) mixing the two solutions, and stirring at room temperature overnight;
(4) fully washing and centrifuging to obtain DOX @ Fe3O4@ F127@ FA (or its comparative example DOX @ Fe)3O4@F127);
The targeting modified drug-loaded nano-DOX @ Fe3O4@ F127@ FA and comparative example DOX @ Fe3O4The cell survival rate of the @ F127 and HepG2 cells after co-culture is 24 hours, and the cell survival rate is analyzed by adopting an MTT method, and the result is shown in figure 3, the survival rate of the cells treated by the targeted modified drug-loaded nano-cluster group is lower than that of the drug-loaded nano-cluster group without targeted modification, and the cells show greater toxic effect on tumor cells.
Example 9
The invention is multifunctionalRice cluster Fe3O4Relaxation Rate test of @ F127@ FA:
(1) preparing nanocluster Fe with different concentrations3O4@ F127@ FA was dispersed in 2mL of 0.1% agarose at Fe concentrations of 10. mu.M, 20. mu.M, 30. mu.M, 40. mu.M and 50. mu.M, respectively, and placed in 5mL EP tubes.
(2) A 3.0T magnetic resonance scanner was used to scan according to the following parameters: echo Time (TE) 20, 40, 60, 80, 100 and 120ms, repetition Time (TR) 3000ms, matrix 320 × 320, field of view (FOV): 20mm by 20mm, with a layer thickness of 4.0mm, the image obtained is shown in part A of FIG. 4.
(3) Transverse relaxation Rate (r)2) Are respectively 1/T2As ordinate and iron concentration as abscissa, as shown in part B, r in FIG. 42=401.8mM-1s-1。
The transverse relaxation rate of commercial contrast agent Ferriex (Feridex) is about 108mM when measured under 3.0T magnetic field-1s-1The relaxation rate of the multifunctional nano-cluster is obviously higher than that of the phenanthridine magnetic resonance contrast agent, so that the multifunctional nano-cluster can be used as a high-efficiency magnetic resonance contrast agent, and can be co-cultured with HepG2 cells expressing folate receptors, and the T of the cells2The signal was significantly enhanced compared to cells not treated with contrast agent.
Example 10
The invention relates to multifunctional nano-cluster Fe3O4Targeting evaluation of @ F127@ FA:
HepG2 cells expressing folate receptor were selected as a model and after the cells had grown for a logarithmic phase, they were grown at 5X 104Inoculating each cell to 24-well culture plate, culturing overnight, and changing culture medium to contain nanocluster Fe3O4@ F127@ FA or nanocluster Fe3O4The culture medium of @ F127 was co-cultured for 24 hours, then washed three times or more with pre-warmed PBS, and then cells were collected by trypsinization. And (3) repeatedly freezing and thawing the collected cell sample for a plurality of times, adding hydrochloric acid, adding pure water to a constant volume of 10mL after the particles are completely dissolved, and finally measuring the iron uptake of the cells by using an inductively coupled plasma spectrometry (ICP).
FIG. 5 shows ICP measurements of intracellular Fe uptakeThe measurement and result show that the nano cluster Fe is targeted3O4@ F127@ FA and comparative example non-target modified nanocluster Fe3O4The cellular uptake of the @ F127 two materials is concentration-dependent, and the cellular uptake is higher with the increase of the Fe concentration, indicating that the non-target modified nano-cluster Fe of the comparative example is3O4@ F127 can enter cells by means of endocytosis or diffusion, and the Fe prepared by the method can enter cells under the same Fe concentration3O4The @ F127@ FA targeting contrast agent has higher endocytosis after being co-cultured with HepG2 cells, and shows stronger targeting effect.
Example 11
The invention relates to multifunctional nano-cluster Fe3O4Cytotoxicity evaluation of @ F127@ FA:
and (3) determining the activity of the HepG2 cell by using the HepG2 cell as a model cell through an MTT colorimetric method to detect the cytotoxicity of the prepared nano-cluster. HepG2 cells were separately treated with the same concentration of comparative example Fe3O4@ F127 and targeted nanocluster Fe prepared by invention3O4Cell viability was calculated by co-culturing @ F127@ FA for 24 hours, followed by MTT treatment and measuring absorbance at 570 nm. Fe compared to cell control group3O4@ F127 and Fe3O4@ F127@ FA showed no significant difference in viability of HepG2 cells over the experimental concentration range, exhibiting no cytotoxicity (FIG. 6).
Example 12
The invention carries medicine nanometer cluster DOX @ Fe3O4Cellular endocytosis experiments of @ F127@ FA:
after the cells had grown for a logarithmic phase at 5X 104Each cell was plated on a 24-well plate, and after overnight culture, the medium was changed to contain DOX @ Fe3O4@ F127@ FA or DOX @ Fe3O4@ F127, after 4 hours of co-cultivation, the cells were washed three times with PBS, fixed for 15min at room temperature with 4% paraformaldehyde, then stained for cytoskeleton with FITC, stained for nuclei with DAPI, glycerol mounted and observed under a confocal laser microscope, as shown in FIG. 7 (FIG. 5 provides color staining due to fluorescent staining of cells)A photograph). The red fluorescence comes from DOX, the DOX is directly distributed in cell nucleus when being co-cultured with cells, when a medicine carrying system containing the DOX is co-cultured with the cells, the red fluorescence is mainly distributed in cytoplasm, and simultaneously the DOX enters acidic lysosomes in the cells and is released into the cell nucleus in a small amount to enable the cell nucleus to present the red fluorescence. In addition, the red fluorescence of the drug carrier system group modified by the folic acid in a targeted way is stronger than that of the drug carrier system group not modified by the folic acid in a targeted way, which shows that the multifunctional nano-cluster Fe designed by the invention3O4@ F127@ FA has a better targeting effect.
Claims (8)
1. The preparation method of the multifunctional nanocluster is characterized by comprising the following steps of:
step 1, weighing a proper amount of oil-soluble Fe3O4Dissolving nanoparticles in organic solvent to obtain solution A, and controlling the oil-soluble Fe in the solution A3O4The concentration of the nano particles is 5-50 mg/mL;
in addition, a proper amount of the folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene is weighed and dissolved in water to obtain a solution B, and the concentration of the folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene in the solution B is controlled to be 0.1-10 mg/mL;
step 2, mixing the solution A and the solution B, and placing the mixture on an ice bath for ultrasonic treatment;
step 3, standing after ultrasonic treatment, extracting after solution layering, and collecting a solution water phase;
and 4, obtaining a sample in a solution water phase by adopting a centrifugal or magnetic separation mode, namely obtaining the multifunctional nano-cluster for targeted drug delivery and magnetic resonance imaging.
2. The method for preparing the multifunctional nanocluster of claim 1, wherein the oil soluble Fe is used in step 13O4The preparation method of the nano-particles comprises the following steps:
step a, dissolving iron salt, oleic acid and oleyl ammonium in benzyl alcohol to obtain a solution C, ensuring that the concentration of the iron salt in the solution C is 0.1-0.5mol/L, and stirring until the solution is clear, wherein the volume ratio of the oleic acid to the oleyl amine to the benzyl alcohol is 1:1: 4;
step b, placing the solution C in a polytetrafluoroethylene reaction kettle, sealing, and reacting in an oven at the temperature of 160-200 ℃ for 10-24 h;
step c, after the reaction is finished, cooling the reaction kettle to room temperature;
d, discarding the supernatant in the reaction kettle, washing the product for 3-5 times by water and ethanol in sequence, and then placing the product in a drying oven with the temperature of 30-60 ℃ for vacuum drying for 5-12h to obtain a powdery product, namely the oil-soluble Fe3O4Nanoparticles.
3. The method for preparing the multifunctional nanocluster of claim 1, wherein the folic acid targeted modified block copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene in the step 1 is prepared by the following method:
dissolving folic acid in anhydrous dimethyl sulfoxide to obtain a solution D;
b, adding N, N-carbonyl-diimidazole into the solution D, and stirring overnight in a dark place; adding triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene into the solution D, and continuously stirring for 24-48h in a dark place to obtain a reaction solution, wherein the molar ratio of the triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene to the folic acid to the N, N-carbonyl-diimidazole is 1 (2-4) to 1-2;
c, filling the reaction solution into a dialysis bag with the molecular weight cutoff of 1000D for full dialysis, and replacing deionized water every 3-5 h;
and d, freeze-drying the product to obtain the folic acid targeted modified triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene.
4. The method for preparing the multifunctional nanocluster of claim 1, wherein the organic solvent in the step 1 is any one of cyclohexane, chloroform and diethyl ether, and the oil-soluble Fe is3O4The ultrasonic treatment is assisted in the process of dissolving the nano particles in the organic solvent.
5. The method for preparing the multifunctional nanocluster of claim 1, wherein in the step 2, the ultrasonic treatment is performed by selecting probe ultrasound, wherein the ultrasonic treatment power is 40-60W, and the ultrasonic treatment time is 20-60 min.
6. The method for preparing the multifunctional nanocluster as claimed in claim 2, wherein the solution C is reacted in an oven at a temperature of 160-200 ℃ for 12-20 h.
7. The method for preparing the multifunctional nanocluster of claim 3, wherein the folic acid, the N, N-carbonyl-diimidazole and the triblock copolymer polyoxyethylene-polyoxypropylene-polyoxyethylene (F127) are placed in a vacuum drying oven for room temperature treatment for more than 24 hours before use.
8. The multifunctional nanoclusters prepared by the preparation method of any one of claims 1 to 7 for targeted drug delivery and magnetic resonance imaging.
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