CN111529721B - Self-polymerization type nano diagnosis and treatment system and preparation method and application thereof - Google Patents

Self-polymerization type nano diagnosis and treatment system and preparation method and application thereof Download PDF

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CN111529721B
CN111529721B CN202010439406.5A CN202010439406A CN111529721B CN 111529721 B CN111529721 B CN 111529721B CN 202010439406 A CN202010439406 A CN 202010439406A CN 111529721 B CN111529721 B CN 111529721B
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ferroferric oxide
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spio
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CN111529721A (en
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金蓉蓉
胡傲
聂宇
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Sichuan University
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Abstract

The invention provides a self-polymerization type nano diagnosis and treatment system, and belongs to the technical field of biological materials. The nano diagnosis and treatment system comprises a plurality of superparamagnetic ferroferric oxide cores and hydrophilic ligands with functional groups distributed on the surfaces of the ferroferric oxide cores, wherein the functional groups of part or all of the hydrophilic ligands are in key joint with chemotherapeutic drugs by modifying chemical bonds sensitive to tumor microenvironment; the functional group of the hydrophilic ligand on the surface of the ferroferric oxide core can be subjected to electrostatic adsorption or chemical bonding with the functional groups of the hydrophilic ligands on the surface of other ferroferric oxide cores. In a specific microenvironment of the tumor, chemical bonds for bonding chemotherapeutic drugs are broken to release the chemotherapeutic drugs, and exposed functional groups after the chemotherapeutic drugs are released can react with functional groups on the surface of another ferroferric oxide core, so that a plurality of ferroferric oxides are connected to form a nanocluster to reach the T-shaped position at the tumor part2The specificity of magnetic resonance signals is enhanced, the enrichment concentration of chemotherapeutic drugs is improved, and the retention time is prolonged.

Description

Self-polymerization type nano diagnosis and treatment system and preparation method and application thereof
Technical Field
The invention belongs to the technical field of biological materials, and particularly relates to a self-polymerization type nano diagnosis and treatment system and a preparation method and application thereof.
Background
The tumor treatment is still a worldwide problem, and the tumor treatment is usually carried out by adopting a method of surgical resection assisted by radiotherapy or chemotherapy in clinic, but the treatment effect is not obviously improved. The diagnosis and treatment system capable of realizing accurate early diagnosis and real-time effective evaluation of the treatment scheme can greatly improve the treatment efficiency of tumors. Among them, magnetic resonance imaging is favored by cell and molecular level imaging research due to its non-radiation, high spatial resolution, high sensitivity, and broad clinical application prospect.
Superparamagnetic iron oxide (SPIO) nano-composites are good MRI developers, can obviously shorten the longitudinal relaxation time (T1) and the transverse relaxation time T2 of protons under very low concentration, and have higher safety than gadolinium micromolecular contrast agents which are widely used clinically at present and can cause severe renal fibrosis. The large-size SPIO is more superior to the small-size SPIO (more than or equal to 8nm) in the aspect of magnetic resonance imaging, but the larger-size SPIO is high in blood clearing efficiency and short in circulation time, and effective accumulation of a target part cannot be achieved, so that the imaging performance of the SPIO is reduced.
Disclosure of Invention
The invention aims to provide a visible and killing accurate delivery nano diagnosis and treatment system integrating imaging molecules and medicines, aiming at the defects that the existing ferromagnetic oxide resonance contrast agent has low imaging efficiency and can effectively evaluate the treatment effect of medicines in real time.
The purpose of the invention is realized by the following technical scheme:
the nano diagnosis and treatment system comprises a plurality of superparamagnetic ferroferric oxide cores and hydrophilic ligands with functional groups distributed on the surfaces of the ferroferric oxide cores, wherein the functional groups of part or all of the hydrophilic ligands are in key joint with chemotherapeutic drugs by modifying chemical bonds sensitive to tumor microenvironment;
the functional group of the hydrophilic ligand on the surface of the ferroferric oxide core can be subjected to electrostatic adsorption or chemical bonding with the functional groups of the hydrophilic ligands on the surface of other ferroferric oxide cores;
under the microenvironment with the characteristics of tumors, chemical bonds for bonding chemotherapeutic drugs are broken to release the chemotherapeutic drugs, and exposed functional groups after the chemotherapeutic drugs are released can react with functional groups on the surface of another ferroferric oxide core which can be electrostatically adsorbed or chemically bonded with the ferroferric oxide core, so that a plurality of ferroferric oxides are connected together to form a nanocluster.
Furthermore, functional groups of hydrophilic ligands distributed on the surface of each ferroferric oxide core cannot be subjected to electrostatic adsorption or chemical bonding.
Further, the average particle size of the superparamagnetic ferroferric oxide core is 10-100 nm.
Further, the functional group is a positive, negative, mercapto or ethylenic group.
Further, the hydrophilic ligand with functional groups is one or more of N- (trimethoxysilylpropyl) -ethylenediamine triacetate, dopamine, 3- (3, 4-dihydroxyphenyl) propionic acid, bisphenol sulfydryl amide and bisphenol alkene.
Further, the chemotherapeutic drug is at least one of Doxorubicin (DOX), paclitaxel (TAX), Camptothecin (CAM), Gemcitabine (GEM).
Further, the chemical bond bonding the chemotherapeutic drug is one or more of a reduction-sensitive disulfide bond, a diselenide bond, an acid-sensitive acetal bond, a ketal bond, a hydrazone bond and an orthoester bond.
A preparation method of a self-polymerization type nano diagnosis and treatment system comprises the following steps:
1) dispersing ferroferric oxide SPIO in an organic solvent, adding a hydrophilic ligand with functional groups into the SPIO organic solvent under the protection of inert gas, stirring at normal temperature, removing an organic solution after the reaction is finished, washing, drying, dialyzing, centrifuging, and collecting an upper-layer liquid I;
2) dispersing ferroferric oxide SPIO in an organic solvent, adding another hydrophilic ligand with functional groups into the SPIO organic solvent under the protection of inert gas, stirring at normal temperature, removing the organic solution after the reaction is finished, washing, drying, dialyzing, centrifuging, and collecting an upper-layer liquid II; wherein, the functional group of another hydrophilic ligand can be electrostatically adsorbed or chemically bonded with the functional group of the hydrophilic ligand in the step 1);
3) dispersing the upper layer liquid I or the upper layer liquid II in an organic solvent, respectively adding chemotherapeutic drugs into one or two of the upper layer liquid I or the upper layer liquid II, separating and collecting precipitates after complete reaction, and performing vacuum drying to obtain a solution III and/or a solution IV bonded with the chemotherapeutic drugs;
4) and (3) dissolving the upper-layer liquid I and the solution IV, or the upper-layer liquid II and the solution III, or the solution III and the solution IV in a buffer solution, breaking chemical bonds with environmental sensitivity, releasing chemotherapeutic drugs, exposing functional groups, polymerizing superparamagnetic ferroferric oxide cores capable of generating electrostatic adsorption or chemical bonding in a certain mode, and gradually increasing the nano particle size in the solution to reach balance to obtain the product.
Further, in the step 4), the breaking of the chemical bonds with environmental sensitivity is realized by adjusting the pH of the solution or adding an oxidation reducing agent.
Further, the redox agent is one or more of glutathione, NADPH, dithiothreitol, and beta-mercaptoethanol.
Further, the organic solvent is one or more of tetrahydrofuran, toluene, methanol, n-hexane and dichloromethane; the inert gas is nitrogen or argon.
An application of a self-polymerization type nano diagnosis and treatment system in tumor precise diagnosis and treatment products.
Compared with the prior art, the invention has the following beneficial effects:
functional groups in the self-polymerization type nano diagnosis and treatment system can perform chemical reaction in a specific tumor microenvironment, chemical bonds are broken to release chemotherapeutic drugs, and the exposed functional groups after the chemotherapeutic drugs are released can react with functional groups of hydrophilic ligands on the surface of another ferroferric oxide core, so that a plurality of ferroferric oxides are connected together to form a nanocluster, and T at a tumor part is achieved2The specificity of magnetic resonance signals is enhanced, the enrichment concentration of chemotherapeutic drugs is improved, and the retention time is prolonged.
The self-polymerization type nano diagnosis and treatment system has the characteristics of intelligent accurate target tumor killing and aggregation imaging at tumor positions, and can be used for accurate tumor diagnosis and treatment.
Drawings
FIG. 1 is a graph of relaxation efficiency versus iron concentration before and after polymerization of a nano-auto-polymerization system of iron oxide;
FIG. 2 shows the in vitro development effect before and after the polymerization of the iron oxide nano self-polymerization system.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The self-polymerization type nano diagnosis and treatment system, the preparation method and the application of the invention are explained in detail in the following by combining the specific principle.
The nano diagnosis and treatment system comprises a plurality of superparamagnetic ferroferric oxide cores and hydrophilic ligands with functional groups distributed on the surfaces of the ferroferric oxide cores, wherein the functional groups of part or all of the hydrophilic ligands are in key joint with chemotherapeutic drugs by modifying chemical bonds sensitive to tumor microenvironment;
the functional group of the hydrophilic ligand on the surface of the ferroferric oxide core can be subjected to electrostatic adsorption or chemical bonding with the functional groups of the hydrophilic ligands on the surface of other ferroferric oxide cores;
under a specific microenvironment of a tumor, chemical bonds for bonding chemotherapeutic drugs are broken to release the chemotherapeutic drugs, and exposed functional groups after the chemotherapeutic drugs are released can react with functional groups on the surface of another ferroferric oxide core which can be electrostatically adsorbed or chemically bonded with the ferroferric oxide core, so that a plurality of ferroferric oxides are connected together to form a nanocluster.
In the self-polymerization type nano diagnosis and treatment system, the blood circulation time and the tumor tissue infiltration efficiency of the superparamagnetic ferroferric oxide nano particles are improved by reducing the particle size and modifying hydrophilic bodies on the surfaces of the superparamagnetic ferroferric oxide nano particles; the chemotherapeutic drug is bonded on the surface of the SPIO through a chemical bond sensitive to the tumor microenvironment, so that the purpose of improving the concentration of the drug at the tumor part can be realized; the superparamagnetic ferroferric oxide nano particles reaching the tumor part break chemical bonds under the action of a tumor microenvironment, chemotherapeutic drugs are released, functional groups on the surface of the superparamagnetic ferroferric oxide nano particles are exposed, and high-efficiency electrostatic adsorption or click chemical reaction is carried out, so that the aim of gathering the ferroferric oxide nano particles is fulfilled; the chemotherapy drug is released under the condition of a tumor microenvironment to kill tumor cells; the sensitivity of magnetic resonance imaging is improved by the aggregated ferroferric oxide nano particles, and the tumor extravasation capacity is reduced due to the enhancement of the particle size of the aggregated ferroferric oxide nano particles, so that the aim of enriching the ferric oxide nano particles at the tumor part is fulfilled.
Furthermore, functional groups of hydrophilic ligands distributed on the surface of each ferroferric oxide core cannot be subjected to electrostatic adsorption or chemical bonding. If the hydrophilic ligand distributed on the ferroferric oxide inner core can react, the efficiency of the reaction with other ferroferric oxide particles is reduced.
Further, the average particle size of the superparamagnetic ferroferric oxide core is 10-100 nm. The nanoparticles with the particle size range of 10-100nm have a strong EPR effect, and under the condition of the same surface modification, molecules with small particle sizes are low in clearance rate of RES organs, long in blood half-life period and large in amount concentrated on tumor parts.
Further, the functional group is a positive, negative, mercapto or ethylenic group. The positive point and the negative electricity are subjected to electrostatic adsorption, and the sulfydryl and the olefinic bond are chemically bonded to enable a plurality of superparamagnetic ferroferric oxide cores to be connected together to form a nanocluster.
Further, the hydrophilic ligand with functional groups is one or more of N- (trimethoxysilylpropyl) -ethylenediamine triacetate, dopamine-like molecules, 3- (3, 4-dihydroxyphenyl) propionic acid, bisphenol sulfhydramide and bisphenol alkene.
Further, the chemotherapeutic drug is at least one of Doxorubicin (DOX), paclitaxel (TAX), Camptothecin (CAM), Gemcitabine (GEM).
Further, the chemical bond bonding the chemotherapeutic drug is one or more of a reduction-sensitive disulfide bond, a diselenide bond, an acid-sensitive acetal bond, a ketal bond, a hydrazone bond and an orthoester bond.
A preparation method of a self-polymerization type nano diagnosis and treatment system comprises the following steps:
1) dispersing ferroferric oxide SPIO in an organic solvent, adding a hydrophilic ligand with functional groups into the SPIO organic solvent under the protection of inert gas, stirring at normal temperature, removing an organic solution after the reaction is finished, washing, drying, dialyzing, centrifuging, and collecting an upper-layer liquid I;
2) dispersing ferroferric oxide SPIO in an organic solvent, adding another hydrophilic ligand with functional groups into the SPIO organic solvent under the protection of inert gas, stirring at normal temperature, removing the organic solution after the reaction is finished, washing, drying, dialyzing, centrifuging, and collecting an upper-layer liquid II; wherein, the functional group of another hydrophilic ligand can be electrostatically adsorbed or chemically bonded with the functional group of the hydrophilic ligand in the step 1);
in the steps 1) and 2), the adding amount of the hydrophilic ligand and the adding amount of the ferroferric oxide SPIO can be adjusted according to actual needs, and the upper layer liquid I is collected after washing, drying, dialysis and centrifugation, and the conventional operation in the field is adopted.
3) Dispersing the upper layer liquid I or the upper layer liquid II in an organic solvent, respectively adding chemotherapeutic drugs into one or two of the upper layer liquid I or the upper layer liquid II, separating and collecting precipitates after complete reaction, and performing vacuum drying to obtain a solution III and/or a solution IV bonded with the chemotherapeutic drugs;
for step 3), there are three embodiments: adding chemotherapeutic drugs into the upper layer liquid I to obtain a solution III; adding the chemotherapeutic drug into the upper layer liquid II to obtain a solution IV; or adding the chemotherapeutic drugs into the upper layer liquid I and the upper layer liquid II respectively to obtain a solution III and a solution IV respectively. The solution obtained by the first two modes has the advantages that only functional groups of the hydrophilic ligands distributed on the surface of part of the ferroferric oxide core are in key joint with chemotherapeutic drugs, and only the hydrophilic ligands with the functional groups distributed on the surface of the other part of the ferroferric oxide core are in chemical bond fracture under the specific microenvironment of the tumor, so that the chemotherapeutic drugs are not released; in the solution obtained in the third mode, the functional groups of the hydrophilic ligand distributed on the surface of the ferroferric oxide core are bonded with chemotherapeutic drugs, and chemical bond breakage can occur in a specific microenvironment of a tumor to release the chemotherapeutic drugs.
4) And (3) dissolving the upper-layer liquid I and the solution IV, or the upper-layer liquid II and the solution III, or the solution III and the solution IV in a buffer solution, breaking chemical bonds with environmental sensitivity, releasing chemotherapeutic drugs, exposing functional groups, polymerizing superparamagnetic ferroferric oxide cores capable of generating electrostatic adsorption or chemical bonding in a certain mode, and gradually increasing the nano particle size in the solution to reach balance to obtain the product.
The adding amount of the upper layer liquid I and the solution IV, or the upper layer liquid II and the solution III, or the solution III and the solution IV can be adjusted according to the actual situation.
For step 4), the added liquid is ensured to contain two hydrophilic ligands which can generate electrostatic adsorption or chemical bonding, and the functional group of at least one hydrophilic ligand is bonded with the chemotherapeutic drug.
Further, in the step 4), the breaking of the chemical bonds with environmental sensitivity is realized by adjusting the pH of the solution or adding an oxidation reducing agent.
Further, the redox agent is one or more of glutathione, NADPH, dithiothreitol, and beta-mercaptoethanol.
Further, the organic solvent is one or more of tetrahydrofuran, toluene, methanol, n-hexane and dichloromethane; the inert gas is nitrogen.
An application of a self-polymerization type nano diagnosis and treatment system in tumor precise diagnosis and treatment products.
Example 1 preparation of pH-responsive Positive and negative electric phase oxygen-absorbing iron oxide Nano self-polymerization System
1. Preparing the negatively charged iron oxide nanoparticles:
the negatively charged functional groups are provided by a hydrophilic ligand silane coupling agent N- (trimethoxysilylpropyl) -ethylenediamine triacetate (SiCOOH). Dispersing SPIO (4-8nm) in a toluene solution, slowly and dropwise adding a SiCOOH aqueous solution (w/v, 40%) into the SPIO toluene solution according to a certain proportion under the protection of nitrogen, and stirring for 24 hours by using a normal-temperature apparatus. After the reaction is finished, the toluene solution is removed by magnetic separation, redissolved and washed with toluene for three times, and dried in vacuum for 12 hours. The obtained solid black powder was dispersed in deionized water and dialyzed for 48 hours (Mr 8000 to 14000). After dialysis, centrifuging at 10000rpm/min for 15min, collecting the upper solution to obtain product 1(SiCOO/SPIO), and lyophilizing for use. The synthesis is schematically as follows:
Figure BDA0002503563360000081
the particle size and potential distribution of SPIO were evaluated by dynamic scatterometry (DLS) and transmission electron microscopy. The particle size and potential of the products obtained at different feed ratios are shown in Table 1.
TABLE 1 particle size and potential of the products obtained with different ratios SPIO/SiCOOH
Figure BDA0002503563360000082
2. preparing pH response type positively charged iron oxide nanoparticles:
the positive electricity functional group is composed of hydrophilic ligand dopamine molecule (DPA-NH)2) Provided is a method. Dispersing SPIO (4-8nm) in tetrahydrofuran, and adding DPA-NH2Dissolving in tetrahydrofuran, slowly dropping into the dispersed SPIO solution according to a certain proportion under the protection of nitrogen, and reacting for 24 hours under mechanical stirring. After the reaction is finished, removing tetrahydrofuran by magnetic separation, repeatedly washing the obtained precipitate for 3 times by using tetrahydrofuran, and drying for 12 hours in vacuum. The obtained solid black powder was dispersed in deionized water and dialyzed for 48 hours (Mr 8000 to 14000). After dialysis, centrifugation is carried out for 15min at 10000rpm/min, and an upper solution is collected to obtain a product 2(DPA/SPIO), and freeze-drying is carried out for later use. The synthesis is schematically as follows:
Figure BDA0002503563360000091
the particle size and potential distribution of SPIO were evaluated by dynamic scatterometry (DLS) and transmission electron microscopy. The particle size and potential of the products obtained at different feed ratios are shown in Table 2.
TABLE 2 different ratios of SPIO/DPA-NH2The obtained product has particle size and potential
Figure BDA0002503563360000092
100mg of the product 2, namely the positively charged iron oxide nanoparticles, are dispersed in a methanol solution, 280mg of doxorubicin hydrochloride (DOX) is added, and the reaction is carried out for 48 hours. And (3) magnetically separating, collecting the precipitate, and drying in vacuum to obtain a pH response positively charged iron oxide nanoparticle product 3 (DOX-DPA/SPIO). The synthesis steps are as follows:
Figure BDA0002503563360000093
then dissolving the extract in phosphate buffer solution, adding hydrochloric acid to obtain solutions with different pH values, and detecting the release behavior of the drug by High Performance Liquid Chromatography (HPLC).
The reaction steps for linking the three drugs paclitaxel (TAX), Camptothecin (CAM) and Gemcitabine (GEM) are the same as those for doxorubicin. The three medicines are respectively added into the uniformly dispersed DPA/SPIO methanol solution and react for 48 hours. And magnetically separating, collecting the precipitate, and vacuum drying to obtain three pH response products including TAX-DPA/SPIO, CAM-DPA/SPIO and GEM-DPA/SPIO. In the subsequent step 3, in the preparation process of the self-polymerization system, the three products release corresponding drugs of paclitaxel (TAX), Camptothecin (CAM) and Gemcitabine (GEM) as same as DOX-DPA/SPIO, positive groups of DPA/SPIO are exposed, the positive and negative ferric oxide nanoparticles generate electrostatic adsorption reaction, the particle size of the nanoparticles in the solution is gradually increased to reach balance, and the product is finally obtained.
3. preparing a pH response type positive and negative electric ferric oxide nanometer self-polymerization system:
dissolving the obtained negatively charged ferric oxide nanoparticles (SiCOO/SPIO) and pH-responsive positively charged ferric oxide nanoparticles (DOX-DPA/SPIO) in PBS buffer solution according to different proportions, adding hydrochloric acid to reduce the pH value of the solution, breaking hydrazone bonds with pH response, releasing adriamycin, exposing the positively charged groups of the DPA/SPIO, carrying out electrostatic adsorption reaction on the positively charged and negatively charged ferric oxide nanoparticles, gradually increasing the particle size of the nanoparticles in the solution to reach balance, and finally obtaining a product 4 (SiCOO/DPA/SPIO). The synthesis is schematically as follows:
Figure BDA0002503563360000101
and evaluating the particle size and potential distribution of the collected SPIO by a dynamic scatterometer (DLS) and a transmission electron microscope. The particle size and potential of the product obtained by measuring different charge ratios are shown in Table 3.
TABLE 3 aggregation of SPIO of different proportions of positive and negative charges in solutions of different pH
Figure BDA0002503563360000102
The change of relaxation efficiency is detected by MRI before and after SPIO aggregation, and the result is shown in fig. 1 and fig. 2, fig. 1 is a relaxation efficiency-iron concentration curve before and after the polymerization of the iron oxide nanometer self-aggregation system; FIG. 2 shows the in vitro development effect of iron oxide nano-sized self-assembly system (TE 5.3ms, TR 70ms) (1.5T, 25 ℃ C.). The relaxation efficiency of product 4 after polymerization (SiCOO/DPA/SPIO) was 454.71Fe mM-1s-1Relaxation efficiency (64.33Fe mM) compared to Pre-polymerization product 2(DPA/SPIO)-1s-1) Improved by 7 times and is obviously superior to the prior commercial developer Feridex (FeriMag, 98Fe mM)-1s-1) And the magnetic resonance diagnostic performance is good.
Example 2 preparation of pH-responsive Positive-negative electric phase oxygen-absorbing iron oxide Nano self-polymerization System
1. Preparing the negatively charged iron oxide nanoparticles:
the negatively charged functional group is provided by the hydrophilic ligand hydroxypropionic acid. Dispersing SPIO (4-8nm) in tetrahydrofuran, dissolving 3- (3, 4-dihydroxyphenyl) Propionic Acid (PA) in tetrahydrofuran, slowly dropping into the dispersed SPIO solution according to a certain proportion under the protection of nitrogen, and mechanically stirring for reaction for 24 h. After the reaction is finished, removing tetrahydrofuran by magnetic separation, repeatedly washing the obtained precipitate for 3 times by using tetrahydrofuran, and drying for 12 hours in vacuum. The obtained solid black powder was dispersed in deionized water and dialyzed for 48 hours (Mr 8000 to 14000). After dialysis, centrifugation is carried out at 10000rpm/min for 15min, and an upper solution is collected to obtain a product 5(PA/SPIO), and freeze-drying is carried out for later use. The synthesis is schematically as follows:
Figure BDA0002503563360000111
the particle size and potential distribution of SPIO were evaluated by dynamic scatterometry (DLS) and transmission electron microscopy. The particle size and potential of the products obtained at different feed ratios are shown in table 4:
TABLE 4 particle size and potential of the product obtained from SPIO/PA in different proportions
Figure BDA0002503563360000112
Figure BDA0002503563360000121
2. preparing a pH response type positive and negative electric ferric oxide nanometer self-polymerization system:
dissolving the obtained negative-charged ferric oxide nanoparticles (PA/SPIO) and the pH-responsive positive-charged ferric oxide nanoparticles (DOX-DPA/SPIO) in the PBS buffer solution according to different proportions, adding hydrochloric acid to reduce the pH value of the solution, breaking a hydrazone bond with pH response, releasing adriamycin, exposing positive groups of the PA/SPIO, carrying out electrostatic adsorption reaction on the positive-negative ferric oxide nanoparticles, gradually increasing the particle size of the nanoparticles in the solution to reach balance, and finally obtaining a product 6 (PA/DPA/SPIO). The synthesis is schematically as follows:
Figure BDA0002503563360000122
the particle size and potential distribution of SPIO were evaluated by dynamic scatterometry (DLS) and transmission electron microscopy. The particle size and potential of the products obtained at different feed ratios are shown in table 5:
TABLE 5 aggregation of positively and negatively charged SPIO in different pH solutions
Figure BDA0002503563360000123
Example 3 preparation of glutathione reduction-responsive iron oxide NanoTanked self-polymerization System
1. Preparation of glutathione reduction response hydrophilic ligand with sulfhydryl group:
compound1 was synthesized from cystamine dihydrochloride and di-tert-butyl dicarbonate in a solution of triethylamine in methanol. Compound1(3g) was reacted with 3- (3, 4-dihydroxyphenyl) propionic acid (5g) under nitrogen at room temperature for 24h catalyzed by 4g O-benzotriazol-tetramethyluronium Hexafluorophosphate (HBTU) and 4g N, N-Diisopropylethylamine (DIEA). After completion of the reaction, the excess solvent was removed by rotary evaporation and then purified by gel column to give the product Compound 2. The resulting Compound2(3g) was dissolved in Dichloromethane (DCM), then 5g of trifluoroacetic acid (TFA) was added dropwise, reacted overnight at room temperature, and excess solvent was removed by rotary evaporation to give the product Compound 3. Compound4 was synthesized from succinic anhydride and tert-butyl carbazate in dichloromethane containing 4-dimethylaminopyridine. The resulting Compound3(3g) and Compound4(2g) were dissolved in 100ml of DCM, and 4g of HBTU and 4g of DIEA were added, reacted at room temperature for 24 hours under nitrogen, excess solvent was removed by rotary evaporator, and then purified by gel column to give the product Compound 5. Compound5(2g) was dissolved in 50 ml DCM and 4g TFA was added dropwise and reacted at room temperature for 24 h. After the reaction, excess solvent was removed by rotary evaporator to give the product Compound 6 (bisphenol mercapto amide, DA-S-NH)2)。
The resulting product, Compound 6(2g), was dissolved in dry methanol, then 3g of doxorubicin hydrochloride (DOX) was added to the solution and two drops of TFA were added dropwise, and the reaction was carried out under nitrogen at room temperature for 48 h. After the reaction was completed, excess solvent was removed by a rotary evaporator, 10ml of acetonitrile was added, and after stirring sufficiently, the solution was placed in a refrigerator at-20 ℃ and frozen for 24 hours. Finally the frozen solution solvent was removed by rotary evaporation, washed with methanol: the red powder was washed repeatedly with acetonitrile at a ratio of 1:10, and the precipitated product was collected by centrifugation. And finally, drying the obtained product in vacuum to obtain the glutathione reduction response product Compound 7(DA-S-DOX) with the sulfhydryl hydrophilic ligand. The synthesis is schematically as follows:
Figure BDA0002503563360000141
as with the reaction of the product Compound 6 and doxorubicin, paclitaxel (TAX), Camptothecin (CAM), Gemcitabine (GEM) were added to the methanol solution of the product Compound 6, followed by two drops of TFA, followed by reaction under nitrogen at room temperature for 48 h. After the reaction was completed, excess solvent was removed by rotary evaporation, 10ml of acetonitrile was then added, and after stirring sufficiently, the solution was frozen at-20 ℃ for 24 hours. Finally the frozen solvent was removed by rotary evaporation, washed with methanol: the red powder was washed repeatedly with acetonitrile at a ratio of 1:10, and the precipitated product was collected by centrifugation. And finally, drying the obtained product in vacuum to respectively obtain three glutathione reduction response type hydrophilic ligands with sulfhydryl groups, namely DA-S-TAX, DA-S-CAM and DA-S-GEM.
2. Preparation of glutathione reduction response type hydrophilic ligand SPIO with sulfhydryl group:
the functional group with sulfhydryl group is provided by bisphenol sulfhydryl amide adriamycin (DA-S-DOX) which is hydrophilic ligand. Dispersing SPIO in tetrahydrofuran, dissolving hydrophilic ligand bisphenol mercapto amide adriamycin (DA-S-DOX) in the tetrahydrofuran, slowly dropping the solution into the dispersed SPIO solution under the protection of nitrogen, and reacting at room temperature for 24 hours under mechanical stirring. After the reaction is finished, removing tetrahydrofuran by magnetic separation, repeatedly washing the obtained precipitate for 3 times by using tetrahydrofuran, and drying for 12 hours in vacuum. The obtained solid black powder was dispersed in deionized water and dialyzed for 48 hours (Mr 8000 to 14000). After dialysis, centrifugation is carried out at 10000rpm/min for 15min, and the upper solution is collected to obtain the product Compound 8(DA-S-DOX/SPIO), which is freeze-dried for standby. The synthesis is schematically as follows:
Figure BDA0002503563360000151
the reaction steps of the three hydrophilic ligands DA-S-TAX, DA-S-CAM and DA-S-GEM and the SPIO are the same as the above steps, the three hydrophilic ligands DA-S-TAX, DA-S-CAM and DA-S-GEM are respectively dissolved in tetrahydrofuran, slowly dripped into the dispersed SPIO solution under the protection of nitrogen, and the reaction is carried out at room temperature for 24 hours under the mechanical stirring. After the reaction is finished, removing tetrahydrofuran by magnetic separation, repeatedly washing the obtained precipitate for 3 times by using tetrahydrofuran, and drying for 12 hours in vacuum. The obtained solid black powder was dispersed in deionized water and dialyzed for 48 hours (Mr 8000 to 14000). After dialysis, centrifuging at 10000rpm/min for 15min, and collecting the upper solution to obtain DA-S-TAX/SPIO, DA-S-CAM/SPIO and DA-S-GEM/SPIO respectively. In the subsequent step 5, in the preparation process of the self-polymerization system, the three products release corresponding drugs of paclitaxel (TAX), Camptothecin (CAM) and Gemcitabine (GEM) like DA-S-DOX/SPIO, the mercapto group of DA-S/SPIO is exposed, the mercapto group and the olefinic bond can carry out rapid click chemical reaction, the nano particle size in the solution can be gradually increased to reach equilibrium, and the product is finally obtained.
The particle size and potential distribution of SPIO were evaluated by dynamic scatterometry (DLS) and transmission electron microscopy. The particle size and potential of the products obtained at different feed ratios are shown in Table 6:
TABLE 6 different ratios of SPIO/DA-S-NH2The obtained product has particle size and potential
Figure BDA0002503563360000152
3. Synthesis of hydrophilic ligands with ethylenic bonds
3g of Dopamine hydrochloride (Dopamine) and 2g of 4-alkene valeric acid (Allylacetic acid) are dissolved in 100ml of chloroform, and 4g of HBTU and 4g of DIEA are added and reacted at room temperature for 24 hours under the protection of nitrogen. After the reaction is finished, the solvent is removed by rotary evaporation, and then the product 9 bisphenol alkene (DAA) is obtained by purifying through a gel column. The synthesis is schematically as follows:
Figure BDA0002503563360000161
4. synthesis of hydrophilic ligand SPIO with olefinic bond:
the olefinic bond is provided by a bisphenol-ene hydrophilic ligand (DAA). Dispersing SPIO in tetrahydrofuran, dissolving DAA in tetrahydrofuran, slowly dropping the dissolved DAA into the dispersed SPIO solution according to different proportions under the protection of nitrogen, and reacting at room temperature for 24h under mechanical stirring. After the reaction is finished, removing tetrahydrofuran by a magnetic separation method, repeatedly washing the obtained precipitate for 3 times by tetrahydrofuran, and drying for 12 hours in vacuum. The obtained solid black powder was dispersed in deionized water and dialyzed for 48 hours (Mr 8000 to 14000). After dialysis, centrifugation is carried out at 10000rpm/min for 15min, and the upper solution is collected to obtain a product 10(DAA/SPIO), which is freeze-dried for later use. The synthesis is schematically as follows:
Figure BDA0002503563360000162
the particle size and potential distribution of SPIO were evaluated by dynamic scatterometry (DLS) and transmission electron microscopy. The particle size and potential of the products obtained at different feed ratios are shown in Table 7:
TABLE 7 particle size and potential of the products obtained from SPIO/DAA in different proportions
Figure BDA0002503563360000163
Figure BDA0002503563360000171
5. Preparation of glutathione reduction response type iron oxide nano click self-polymerization system
Dissolving the obtained iron oxide nanoparticles (DA-S-DOX/SPIO) with the sulfhydryl hydrophilic ligand and iron oxide nanoparticles (DAA/SPIO) with the ethylenic hydrophilic ligand in PBS buffer solution according to different proportions, adding glutathione for reduction, breaking disulfide bonds with reductase response, releasing adriamycin, exposing the DA-S/SPIO sulfhydryl groups, carrying out rapid click chemical reaction on sulfhydryl groups and ethylenic bonds, and gradually increasing the nanoparticle diameter in the solution to reach balance. Finally, the product 11(DA-S-DAA/SPIO) is obtained. The synthesis is schematically as follows:
Figure BDA0002503563360000172
the particle size and potential distribution of SPIO were evaluated by dynamic scatterometry (DLS) and transmission electron microscopy. The particle size and potential of the products obtained at different feed ratios are shown in Table 8:
TABLE 8 aggregation of thiol/ethylenic SPIO in glutathione reduction (GSH) solutions at different ratios
Figure BDA0002503563360000173
Like glutathione, other reducing agents, such as NADPH, dithiothreitol and beta-mercaptoethanol can achieve the same technical result as glutathione, and the whole process is the same as the process of directly adding glutathione for reduction.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (9)

1. The self-polymerization type nano diagnosis and treatment system is characterized by comprising a plurality of superparamagnetic ferroferric oxide cores and hydrophilic ligands with functional groups distributed on the surfaces of the ferroferric oxide cores, wherein the functional groups of part or all of the hydrophilic ligands are bonded with chemotherapeutic drugs through chemical bonds which modify the microenvironment sensitivity of tumors;
the functional group of the hydrophilic ligand on the surface of the ferroferric oxide core can be subjected to electrostatic adsorption or chemical bonding with the functional groups of the hydrophilic ligands on the surface of other ferroferric oxide cores;
under a specific microenvironment of a tumor, chemical bonds for bonding chemotherapeutic drugs are broken to release the chemotherapeutic drugs, and exposed functional groups after the chemotherapeutic drugs are released can react with functional groups on the surface of another ferroferric oxide core which can be subjected to electrostatic adsorption or chemical bonding with the ferroferric oxide core, so that a plurality of ferroferric oxides are connected together to form a nanocluster;
the functional group is positive electricity, negative electricity, sulfydryl or an olefinic bond group; the hydrophilic ligand with functional groups is one or more of N- (trimethoxysilylpropyl) -ethylenediamine triacetate, dopamine-like molecules, 3- (3, 4-dihydroxyphenyl) propionic acid, bisphenol sulfydryl amide and bisphenol alkene.
2. The self-polymerization type nano diagnosis and treatment system according to claim 1, wherein functional groups of hydrophilic ligands distributed on the surface of each ferroferric oxide core cannot be electrostatically adsorbed or chemically bonded to each other.
3. The self-polymerization type nano diagnosis and treatment system according to claim 1, wherein the average particle size of the superparamagnetic ferroferric oxide core is 10-100 nm.
4. The self-polymerizing nano-diagnostic system according to claim 1, wherein the chemotherapeutic agent is at least one of Doxorubicin (DOX), paclitaxel (TAX), Camptothecin (CAM), and Gemcitabine (GEM).
5. The self-polymerization type nano diagnosis and treatment system according to claim 1, wherein the chemical bond bonding the chemotherapeutic drug is a reduction-sensitive disulfide bond, a diselenide bond; one or more of acid-sensitive acetal bond, ketal bond, hydrazone bond and orthoester bond.
6. The method for preparing the self-polymerization type nano diagnosis and treatment system according to any one of claims 1 to 5, comprising:
1) dispersing ferroferric oxide SPIO in an organic solvent, adding a hydrophilic ligand aqueous solution with functional groups into the SPIO organic solvent under the protection of inert gas, stirring at normal temperature, removing the organic solution after the reaction is finished, washing, drying, dialyzing, centrifuging, and collecting upper-layer liquid I;
2) dispersing ferroferric oxide SPIO in an organic solvent, adding another hydrophilic ligand aqueous solution with functional groups into the SPIO organic solvent under the protection of inert gas, stirring at normal temperature, removing the organic solution after the reaction is finished, washing, drying, dialyzing, centrifuging and collecting an upper-layer liquid II; wherein, the functional group of another hydrophilic ligand can be electrostatically adsorbed or chemically bonded with the functional group of the hydrophilic ligand in the step 1);
3) dispersing the upper layer liquid I or the upper layer liquid II in an organic solvent, respectively adding chemotherapeutic drugs into one or two of the upper layer liquid I or the upper layer liquid II, separating and collecting precipitates after complete reaction, and performing vacuum drying to obtain a solution III and/or a solution IV bonded with the chemotherapeutic drugs;
4) and (3) dissolving the upper-layer liquid I and the solution IV, or the upper-layer liquid II and the solution III, or the solution III and the solution IV in a buffer solution, breaking chemical bonds with environmental sensitivity, releasing chemotherapeutic drugs, exposing functional groups, polymerizing superparamagnetic ferroferric oxide cores capable of generating electrostatic adsorption or chemical bonding in a certain mode, and gradually increasing the nano particle size in the solution to reach balance to obtain the product.
7. The method for preparing the self-polymerization type nano diagnosis and treatment system according to claim 6, wherein in the step 4), the breaking of the chemical bonds with environmental sensitivity is achieved by adjusting the pH of the solution or adding an oxidation-reduction agent.
8. The method for preparing the self-polymerization type nano diagnosis and treatment system according to claim 6, wherein the organic solvent is one or more of tetrahydrofuran, toluene, methanol, n-hexane, and dichloromethane; the inert gas is nitrogen or argon.
9. The use of the self-polymerization type nano diagnosis and treatment system according to any one of claims 1 to 5, wherein the self-polymerization type nano diagnosis and treatment system is used for preparing tumor precise diagnosis and treatment products.
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