CN107670036B - Dissociation method of iron coordination polymer nanoparticles and application thereof - Google Patents
Dissociation method of iron coordination polymer nanoparticles and application thereof Download PDFInfo
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- CN107670036B CN107670036B CN201710915116.1A CN201710915116A CN107670036B CN 107670036 B CN107670036 B CN 107670036B CN 201710915116 A CN201710915116 A CN 201710915116A CN 107670036 B CN107670036 B CN 107670036B
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- 239000013256 coordination polymer Substances 0.000 title claims abstract description 119
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- 229910052742 iron Inorganic materials 0.000 title claims abstract description 115
- 238000010494 dissociation reaction Methods 0.000 title claims abstract description 101
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- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 claims abstract description 32
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- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical class [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 claims abstract description 7
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- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/12—Macromolecular compounds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
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Abstract
The invention provides a dissociation method of iron coordination polymer nanoparticles, which comprises the following steps: dissociating the iron coordination polymer nano-particles by adopting a dissociating agent, wherein the dissociating agent is selected from one or more of deferoxamine, deferiprone, ethylenediamine tetraacetic acid and ethylenediamine tetraacetic acid disodium salt; the iron coordination polymer nanoparticles are prepared from polyphenol, ferric iron salt and high molecular polymer. According to the invention, a specific dissociation agent is adopted to dissociate the iron coordination polymer nanoparticles, and the iron coordination polymer nanoparticles can be rapidly dissociated into small nanoparticles or small molecule solutions under the action of the dissociation agent. The dissociation method can rapidly remove iron coordination polymer nanoparticles in vivo, especially iron coordination polymer nanoparticles at liver, and reduce potential damage to liver.
Description
Technical Field
The invention relates to the technical field of new biomedical materials, in particular to a dissociation method of iron coordination polymer nanoparticles.
Background
Currently, for the treatment of tumors, nanoparticles with photothermal function are commonly used: fe3O4、Bi2Se3、MoS2The nano particles have EPR effect, can realize good aggregation at tumor, have good imaging function, have the advantage of multifunction, such as Bi with photothermal function2Se3The nano particles can guide the photothermal therapy of the tumor while carrying out multi-mode imaging on the tumor, and realize accurate diagnosis and accurate treatment on the tumor. However, nanoparticles are at the tumor site due to the EPR effectAt the same time, the accumulation of the blood is accompanied by a large amount of retention in the endoplasmic reticulum tissue such as the liver, which may cause a certain damage to the liver.
Currently, most nanomaterials accumulate at tumors and at the same time, there is a large accumulation at the liver site (see Zhenglin Li, Jingliu, Ying Hu, et al. Multimodal Imaging-Guided anti inflammatory photometal Therapy and Drug Delivery Using Bismith Selenide spatial sphere. ACS Nano,2016,10, 9646-. Although these nanoparticles have good imaging and tumor treatment effects, their long-term toxicity limits their clinical applications despite their good cancer treatment effects. However, although smaller molecules or nanoparticles cannot be captured by endothelial reticulocytes, rapid renal clearance can be achieved, and toxic and side effects are reduced, the smaller molecules or nanoparticles have shorter in vivo blood circulation and no EPR effect, so that the accumulation and retention of tumors are poor, and the treatment effect is affected. Therefore, ideally, in order to improve the therapeutic effect and reduce the toxicity, the prepared material is expected to have the EPR effect and realize the controllable and rapid renal clearance function.
In order to reduce the harm of the nanoparticles to the liver and slow down the potential harm of the iron coordination polymer nanoparticles to the liver, a dissociation method needs to be developed, the nanoparticles at the liver part are dissociated to be small nanoparticles or small molecular solution, the rapid elimination through the kidney is realized, and the toxic and side effects of the material are reduced.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a dissociation method for iron coordination polymer nanoparticles, which can rapidly dissociate iron coordination polymer nanoparticles and reduce toxic and side effects thereof.
The invention provides the use of a compound in dissociative photothermal therapy, photoacoustic imaging or magnetic resonance imaging; the compound is one or more of deferoxamine, deferiprone, ethylene diamine tetraacetic acid and ethylene diamine tetraacetic acid disodium salt.
Preferably, the photothermal therapeutic agent, photoacoustic imaging agent, or magnetic resonance imaging agent is an iron-coordinating polymer nanoparticle.
Preferably, the application dose of the dissociation agent is 20-80 mg/kg.
The invention provides a dissociation method of iron coordination polymer nanoparticles, which comprises the following steps:
dissociating the iron coordination polymer nano-particles by adopting a dissociating agent, wherein the dissociating agent is selected from one or more of deferoxamine, deferiprone, ethylenediamine tetraacetic acid and ethylenediamine tetraacetic acid disodium salt; the iron coordination polymer nanoparticles are prepared from polyphenol, ferric iron salt and high molecular polymer.
Preferably, the mass ratio of the iron coordination polymer nanoparticles to the dissociation agent is 1: (0.01-100).
Preferably, the dissociation method specifically comprises:
dispersing iron coordination polymer nanoparticles, adding a dissociating agent, uniformly mixing by vortex, and magnetically stirring.
Preferably, the stirring time is 30s to 10 min.
Preferably, the polyphenol is selected from one or more of epigallocatechin gallate, epigallocatechin, epicatechin gallate, pelargonidin, cyanidin, delphinidin, peoniflorin, morning glory, malvidin, danshensu, luteolin, tannic acid, catechol and dopamine; the ferric salt is ferric chloride.
Preferably, the high molecular polymer is selected from one or more of polyvinylpyrrolidone, hyaluronic acid, dextran, chitosan and polyethylene glycol modified polyglutamic acid.
Preferably, the molar ratio of the high molecular polymer, the ferric salt and the polyphenol is 1: (1-100): (1-100).
Compared with the prior art, the invention provides a dissociation method of iron coordination polymer nanoparticles, which comprises the following steps: dissociating the iron coordination polymer nano-particles by adopting a dissociating agent, wherein the dissociating agent is selected from one or more of deferoxamine, deferiprone, ethylenediamine tetraacetic acid and ethylenediamine tetraacetic acid disodium salt; the iron coordination polymer nanoparticles are prepared from polyphenol, ferric iron salt and high molecular polymer. According to the invention, a specific dissociation agent is adopted to dissociate the iron coordination polymer nanoparticles, and the iron coordination polymer nanoparticles can be rapidly dissociated into small nanoparticles or small molecule solutions under the action of the dissociation agent. The dissociation method can rapidly remove iron coordination polymer nanoparticles in vivo, especially iron coordination polymer nanoparticles at liver, and reduce potential damage to liver.
Drawings
FIG. 1 is a color change chart before and after dissociation of iron coordination polymer nanoparticles obtained in example 25;
FIG. 2 TEM image of iron coordination polymer nanoparticles obtained in example 25 before and after dissociation;
FIG. 3 is a diagram of in vitro photoacoustic imaging measurements taken before and after dissociation of iron-coordination polymer nanoparticles obtained in example 30;
FIG. 4 is a graph of photoacoustic imaging detection of liver tissue in vivo before and after dissociation (30h) of iron coordination polymer nanoparticles obtained in example 31;
FIG. 5 is a diagram showing the results of in vitro magnetic resonance imaging before and after dissociation of iron-coordination polymer nanoparticles obtained in example 32;
FIG. 6 is a graph of in vivo magnetic resonance imaging examination of liver tissue before and after dissociation (30h) of iron-coordination polymer nanoparticles obtained in example 33;
FIG. 7 is a graph showing the in vivo metabolism of iron coordination polymer nanoparticles obtained in example 34 before and after dissociation (30 h).
Detailed Description
The invention provides a dissociation method of iron coordination polymer nanoparticles, which comprises the following steps:
dissociating the iron coordination polymer nano-particles by adopting a dissociating agent, wherein the dissociating agent is selected from one or more of deferoxamine, deferiprone, ethylenediamine tetraacetic acid and ethylenediamine tetraacetic acid disodium salt; the iron coordination polymer nanoparticles are prepared from polyphenol, ferric iron salt and high molecular polymer.
The dissociation method of the invention is directed to the dissociation method of the specific iron coordination polymer nano-particles. The iron coordination polymer nanoparticles are prepared from polyphenol, ferric iron salt and high molecular polymer.
The iron coordination polymer nanoparticle has a proper nano size, can realize an EPR effect, can realize a magnetic resonance imaging and photoacoustic imaging dual-mode imaging function in vivo, and can perform accurate photothermal therapy under the guidance of dual-mode imaging.
The iron coordination polymer nanoparticles can be rapidly dissociated into small nanoparticles or small molecule solutions under the action of a dissociating agent. The dissociation method can rapidly remove iron coordination polymer nanoparticles in vivo, especially iron coordination polymer nanoparticles at liver, and reduce potential damage to liver.
According to the invention, the dissociation method is preferably embodied as follows:
dispersing iron coordination polymer nanoparticles, adding a dissociating agent, uniformly mixing by vortex, and carrying out magnetic stirring to obtain small nanoparticles or small molecule solution.
The iron coordination polymer nanoparticle dispersion mode is not limited in the invention, and the iron coordination polymer nanoparticle dispersion mode is well known to those skilled in the art; the concentration of the iron coordination polymer nanoparticles is preferably 0.1-10 mg/mL;
the invention is not limited to the specific manner of vortex mixing and magnetic stirring, and those skilled in the art will be familiar with the invention.
In the invention, the stirring time is preferably 30 s-10 min; more preferably 1-8 min; most preferably 1-5 min.
The temperature of the dissociation is not limited, and the temperature can be 25-35 ℃ at room temperature.
In the invention, the dissociating agent is selected from one or more of deferoxamine, deferiprone, ethylenediamine tetraacetic acid and disodium ethylenediamine tetraacetic acid; preferably one or more selected from deferoxamine and disodium ethylene diamine tetraacetate; more preferably deferoxamine and ethylenediaminetetraacetic acid disodium salt; most preferably, the deferoxamine and the disodium salt of ethylenediaminetetraacetic acid are present in a mass ratio of 1: 1 and mixing.
In the present invention, the mass ratio of the iron-coordination polymer nanoparticles to the dissociating agent is preferably 1: (0.01 to 100); more preferably 1: (0.1 to 10), most preferably 1: (0.1-5).
The concentration of the dissociation agent is preferably 10-50 mg/mL;
according to the invention, after the iron coordination polymer nanoparticles play a therapeutic role, the dissociation agent is added for dissociation, so that the iron coordination polymer nanoparticles in vivo can be rapidly eliminated. Mainly, after a dissociation agent is added, the iron coordination polymer nanoparticles in vivo can be rapidly dissociated into small nanoparticles or small molecule solutions, particularly, the iron coordination polymer nanoparticles in liver can be rapidly removed, and potential damage of the nanoparticles to the liver is reduced.
According to the dissociation method of the iron coordination polymer nano-particles, the dissociation agent is injected into a human body mainly by means of tail vein injection or intramuscular injection.
According to the invention, the dosage of deferoxamine injected into the body is preferably 20-80 mg/kg, and more preferably 20-60 mg/kg.
According to the invention, after the addition of the dissociation agent, the in vivo dissociation condition is detected by using photoacoustic imaging and magnetic resonance imaging. After addition of the dissociating agent, ICP-MS can be used to follow the metabolic profile in vivo.
The iron coordination polymer nano-particle provided by the invention is a coordination polymer prepared from polyphenol, ferric salt and a high molecular polymer.
In the present invention, the polyphenol is preferably selected from one or more of epigallocatechin gallate, epigallocatechin, epicatechin gallate, pelargonidin, cyanidin, delphinidin, peoniflorin, morning glory, malvidin, danshenin, luteolin, tannic acid, catechol, and dopamine; more preferably one or more selected from epigallocatechin gallate, cyanidin, delphinidin, tanshinol, luteolin, tannic acid and dopamine; most preferably one or more selected from epigallocatechin gallate, cyanidin, tannic acid and dopamine.
In the present invention, the ferric salt is a ferric salt well known to those skilled in the art, and is not particularly limited, and the ferric salt is preferably ferric chloride.
The high molecular polymer is selected from one or more of polyvinylpyrrolidone, hyaluronic acid, dextran, chitosan and polyethylene glycol modified polyglutamic acid.
In the present invention, the sources of polyvinylpyrrolidone, hyaluronic acid, dextran, and chitosan are not limited, and commercially available ones may be used.
The polyethylene glycol-modified polyglutamic acid of the present invention is not limited in its origin, and may be commercially available, or may be modified according to the method of the present invention, and preferably specifically: polyethylene glycol was grafted onto the polyglutamic acid backbone.
Wherein the molar ratio of polyethylene glycol to polyglutamic acid in the polyethylene glycol modified polyglutamic acid is preferably (1-20): 1; more preferably (1-15): 1, most preferably (1-10): 1.
the molecular weight of the polyethylene glycol is preferably 1000-10000 Da; more preferably 2000-10000 Da, and most preferably 5000-10000 Da; the molecular weight of the polyglutamic acid is 10000-70000 Da; more preferably 20000 to 70000Da, most preferably 20000 to 50000 Da.
The coordination polymer nano-particles prepared by the invention have long circulation function; the particle size range is 80-110 nm, the particle size is proper, the EPR effect can be realized, and accumulation in a tumor area can be realized; the dual-mode imaging function of photoacoustic imaging and magnetic resonance imaging is realized; under the guidance of imaging, precise photothermal therapy can be performed.
The invention provides a preparation method of iron coordination polymer nanoparticles, which comprises the following steps:
and reacting and coordinating the high molecular polymer, the ferric salt and the polyphenol to obtain the coordination polymer nano-particles.
The preparation method of the iron coordination polymer nano-particles comprises the steps of reacting and coordinating a high molecular polymer, a ferric salt and polyphenol to obtain coordination polymer nano-particles; the preferable concrete is as follows:
mixing and stirring a high molecular polymer and a ferric salt, adding polyphenol, stirring, centrifuging, and performing ultrasonic dispersion to obtain the polymer nanoparticles.
The high molecular weight polymer is first provided or prepared, as already clearly described above, and will not be described again.
The invention firstly mixes and stirs the high molecular polymer and the ferric salt. Preferably, the polyethylene glycol modified polyglutamic acid is dissolved in water, and trivalent ferric salt is added for mixing and stirring.
In the present invention, the ferric salt is a ferric salt well known to those skilled in the art, and is not particularly limited, and the ferric salt is preferably ferric chloride.
The mixing and stirring method of the present invention is not limited, and those skilled in the art will be familiar with the method. The stirring is preferably rapid stirring; the stirring speed is preferably 5000-15000 rpm.
In the invention, the mixing and stirring time is preferably 1-6 h, and more preferably 1-4 h.
After stirring, adding polyphenol, stirring, centrifuging, and performing ultrasonic dispersion to obtain the polymer nanoparticles.
In the present invention, the polyphenol is preferably selected from one or more of epigallocatechin gallate, epigallocatechin, epicatechin gallate, pelargonidin, cyanidin, delphinidin, peoniflorin, morning glory, malvidin, danshenin, luteolin, tannic acid, catechol, and dopamine; more preferably one or more selected from epigallocatechin gallate, cyanidin, delphinidin, tanshinol, luteolin, tannic acid and dopamine; most preferably one or more selected from epigallocatechin gallate, cyanidin, tannic acid and dopamine.
The mode of adding polyphenol is preferably dropwise adding, and the dropwise adding speed is preferably 0.1-1 mL/min. More preferably 0.5 to 1 mL/min.
The mixing and stirring time after the polyphenol is added is preferably 4-24 hours, and more preferably 12-24 hours. The mixing and stirring of the present invention is not limited and is well known to those skilled in the art.
And centrifuging after the mixing and stirring are finished, wherein the centrifuging speed is preferably 6000 to 8000rpm, more preferably 7000 to 8000rpm, and most preferably 8000 rpm. The centrifugation time is preferably 5-15 min, and more preferably 10-13 min; most preferably 10 min. The ultrasonic time is preferably 5-30 min; more preferably 10-25 min; most preferably 10-20 min.
The present invention is not limited to the specific operation and mode of centrifugation and ultrasound, and those skilled in the art are familiar with the present invention.
The reaction temperature of the invention is preferably room temperature; can be 25 to 35 ℃.
According to the present invention, the molar ratio of the high molecular polymer, the ferric salt and the polyphenol is preferably 1: (1-100): (1-100); more preferably 1: (1-50): (1 to 80), most preferably 1: (1-40): (1-50).
The invention provides an application of the iron coordination polymer nanoparticles in the technical scheme or the iron coordination polymer nanoparticles prepared by the preparation method in the technical scheme in the preparation of a therapeutic agent, wherein the therapeutic agent comprises a photothermal therapeutic agent.
The invention provides an application of the iron coordination polymer nanoparticles described in the technical scheme or the iron coordination polymer nanoparticles prepared by the preparation method described in the technical scheme in preparation of an imaging agent, wherein the imaging agent comprises a photoacoustic imaging agent and a magnetic resonance imaging agent.
The invention provides the use of a compound in dissociative photothermal therapy, photoacoustic imaging or magnetic resonance imaging; the compound is one or more of deferoxamine, deferiprone, ethylene diamine tetraacetic acid and ethylene diamine tetraacetic acid disodium salt.
In the present invention, the photothermal therapeutic agent, photoacoustic imaging agent, or magnetic resonance imaging agent is an iron-coordination polymer nanoparticle.
In the invention, the application dosage of the dissociation agent is 20-80 mg/kg.
The above description of the iron coordination polymer nanoparticles of the present invention is clear and will not be repeated herein.
According to the invention, after the addition of the dissociating agent, the metabolism in vivo is followed by ICP-MS.
The invention is preferably carried out as follows:
1) dissociation of iron coordination polymer nanoparticles
Firstly, adding a dissociating agent into dispersed iron coordination polymer nano-particles, uniformly mixing by vortex, and then carrying out magnetic stirring, so that the iron coordination polymer nano-particles can be rapidly dissociated into small nano-particles or small molecule solutions.
2) Photoacoustic imaging detection of in vivo and in vitro dissociation condition of iron coordination polymer nanoparticles
The in vitro photoacoustic imaging experiment is carried out by adopting the prosthesis, and the material for preparing the prosthesis mainly adopts the mixture of agar and fat emulsion. The method for preparing the prosthesis is not particularly limited as long as it is a method known to those skilled in the art. The iron coordination polymer nanoparticles are placed in the prosthesis for testing, and the iron coordination polymer nanoparticles are added with deferoxamine for testing, and the testing method is a method well known to those skilled in the art and is not limited in particular. The test conditions set a wavelength range of 680nm to 850nm and the background absorption set at 900 nm.
The in vivo photoacoustic imaging of the invention adopts about 20g of Balb/C nude mice, and because the change condition of liver parts before and after dissociation is only detected, the nude mice do not need to be inoculated with tumors. Injecting coordination polymer nanoparticles into a mouse body through a tail vein, and detecting liver aggregation conditions at 0h (before material injection) and 24h respectively; and after 24h, injecting deferoxamine into tail veins or muscles, detecting the dissociation conditions of the liver for 30h, 48h, 72h, 96h and 168h by adopting a photoacoustic imaging instrument respectively, and comparing the dissociation conditions with the content change of the liver iron of a deferoxamine injection group.
3) Magnetic resonance imaging detection of in vivo and in vitro dissociation condition of iron coordination polymer nanoparticles
The in-vivo and external magnetic resonance imaging mode selects T1 imaging. Firstly, preparing iron coordination polymer nano particles with different concentrations, measuring the intensity of a magnetic resonance signal, then adding deferoxamine for dissociation, and measuring the intensity of the magnetic resonance signal after dissociation. The in vivo magnetic resonance imaging adopts about 20g of Balb/C nude mice to detect the liver aggregation condition in 0h (before injecting materials) and 24h respectively; and after 24h, injecting deferoxamine into tail veins or muscles, detecting the dissociation conditions of the liver for 30h, 48h, 72h, 96h and 168h by adopting a magnetic resonance imaging instrument respectively, and comparing the change of the iron content of the liver of a group which is not injected with deferoxamine.
4) Iron metabolism tracking:
injecting coordination polymer nanoparticles into a mouse body through a tail vein, collecting liver and kidney at 0h (before material injection) and 24h respectively, and collecting feces and urine; after 24h, deferoxamine is injected into tail vein or intramuscular injection, liver and kidney are collected at 30h, 48h, 72h, 96h and 168h respectively, and corresponding feces and urine are collected. After the experiment, the iron content in the collected sample was measured by ICP-MS.
The dissociation method and application of the iron coordination polymer nano-particles provided by the invention have the advantages of simplicity, rapidness, low toxicity and the like. The dissociation method is mainly applied to the dissociation by adding a dissociation agent after the iron coordination polymer nano-particles play a therapeutic role. The photoacoustic imaging and magnetic resonance imaging detection shows that after the dissociating agent is added, the iron coordination polymer nanoparticles in the body can be rapidly removed, particularly the iron coordination polymer nanoparticles at the liver can be rapidly removed, and the potential damage to the liver is reduced. The metabolic situation of the polymer is further tracked, and the result shows that the iron content discharged by urine is obviously increased and the iron content discharged by feces is obviously reduced when the deferoxamine is added compared with the iron content discharged without the deferoxamine, so that the main metabolic pathway of the undissociated iron coordination polymer nanoparticle is the hepatobiliary-intestinal metabolic pathway, and the metabolic pathway of the nanoparticle is mainly changed into the renal clearance pathway after the deferoxamine is dissociated. The dissociation method is expected to be clinically applied.
In order to further illustrate the present invention, the dissociation method of the iron coordination polymer nanoparticles provided by the present invention is described in detail below with reference to examples.
Among them, the reagents used in the following examples are all commercially available.
Examples 1 to 16
Respectively selecting the molecular weights of the polyethylene glycol and the polyglutamic acid to be 5000Da and 21600Da, wherein the molar ratio is 5: 1. dissolving polyethylene glycol modified polyglutamic acid in water, adding ferric chloride solution, mixing and stirring for 4h, slowly dripping polyphenol under the condition of rapid stirring, wherein the dripping speed is 0.5mL/min, and the mixing and stirring time after adding polyphenol is 12 h. And after the mixing and stirring are finished, centrifuging at 8000rpm for 10 min. And (4) preparing the coordination polymer nanoparticles after ultrasonic dispersion. Wherein the types and the dosage of the polyethylene glycol, the polyglutamic acid, the ferric chloride and the polyphenol are shown in a table 1.
TABLE 1 dosage of different raw materials of examples 1-16
The coordination polymer nanoparticles prepared in example 6 are analyzed, and the result shows that the average size of the iron coordination polymer nanoparticles prepared in example 6 is 80-110 nm.
Examples 17 to 29
1.2mL of iron coordination polymer nanoparticles with the concentration of 2mg/mL are added with deferoxamine with the concentration of 50mg/mL in different volumes respectively and stirred for a certain time. And observing the color change of the mixture, and tracking the ultraviolet and particle size change of the mixture. Wherein, the concentration and the stirring time of adding the deferoxamine are as follows:
TABLE 2 examples 17-29 concentration of added ferrioxamine and stirring time
Example 25 color change of iron coordination polymer nanoparticles before and after dissociation is shown in fig. 1. The results show that the iron coordination polymer nanoparticles gradually lighten from original black with the increase of the volume of the deferoxamine, and gradually change into brown-yellow with the increase of time. The ultraviolet change before and after dissociation is further detected, and the result shows that the absorption of the ultraviolet ray after the dissociation of the iron coordination polymer nanoparticles in a visible light region is obviously reduced or does not exist, so that the dissociation of the nanoparticles is performed. Example 25 TEM image of iron coordination polymer nanoparticles before and after dissociation is shown in FIG. 2, and as can be seen from FIG. 2A, the size of iron coordination polymer nanoparticles before dissociation is between 40-80 nm, and after dissociation, no obvious nanoparticles are found (FIG. 2B), indicating that the iron coordination polymer nanoparticles have been completely dissociated.
Example 30
First, in the iron coordination polymer nanoparticles prepared in example 6 at a concentration of 2mg/mL, the dissociation agent was added according to the kind, amount and time of the dissociation agent added obtained in example 25 and example 29, and placed in the prosthesis, and the photoacoustic signal results thereof were tested.
Fig. 3 is a graph of in vitro photoacoustic imaging detection before and after dissociation of the iron coordination polymer nanoparticles obtained in example 30, and the results show that the photoacoustic signal intensity is significantly reduced after the amount of deferoxamine obtained in example 25 is added, and the photoacoustic signal intensity is further reduced or even disappears after the amount of deferoxamine and disodium ethylenediaminetetraacetate obtained in example 29 is added, which indicates that the photoacoustic signal of the dissociated iron coordination polymer nanoparticles disappears after the deferoxamine and disodium ethylenediaminetetraacetate are added, and may be related to the ultraviolet absorption change of the dissociated iron coordination polymer nanoparticles. Further, the two dissociation agents act in combination to dissociate the nanoparticles more fully. This phenomenon can be used to track the dissociation of iron coordination polymer nanoparticles in vivo.
Example 31
About 20g of Balb/C nude mice are adopted for in vivo photoacoustic imaging. Injecting 100 mu L of iron coordination polymer nanoparticles with the concentration of 2mg/mL into a mouse body through a tail vein, and detecting liver aggregation conditions at 0h (before material injection) and 24h respectively; after 24h, the dissociation agent is injected into tail vein according to the amount of the dissociation agent obtained in example 25 and example 29, and the liver dissociation conditions of 30h, 48h, 72h, 96h and 168h are detected by using a photoacoustic imaging instrument and compared with the liver iron content change of the dissociation agent injection group.
Fig. 4 is a graph of photoacoustic imaging detection of liver tissue in vivo before and after dissociation of iron coordination polymer nanoparticles obtained in example 31, and the results show that at 30h, the photoacoustic signal of liver in mice is significantly decreased after addition of a dissociation agent compared to when no dissociation agent is added, and further, the photoacoustic signal of liver in mice is further decreased after both dissociation agents are added, which indicates that iron coordination polymer nanoparticles accumulated in liver tissue can be rapidly dissociated after addition of a dissociation agent, and thus the photoacoustic signal is decreased.
Example 32
The in-vivo and external magnetic resonance imaging mode selects T1 imaging. Firstly, preparing iron coordination polymer nano particles with the concentration of 2mg/mL, and measuring the intensity of a magnetic resonance signal. Then, a dissociation agent was added in an amount corresponding to the dissociation agent obtained in example 25 and example 29 to dissociate the mixture, and the magnetic resonance signal intensity was measured after dissociation.
Fig. 5 is a graph of the detection condition of magnetic resonance imaging before and after dissociation of the iron coordination polymer nanoparticles obtained in example 32, and the result shows that the magnetic resonance signal intensity of the iron coordination polymer nanoparticles is significantly reduced after one dissociation agent is added, and the magnetic resonance signal of the iron coordination polymer nanoparticles is further reduced or even disappears after two dissociation agents are added, which indicates that the magnetic resonance signal of the dissociated iron coordination polymer nanoparticles disappears after the two dissociation agents are added. This phenomenon can be followed by magnetic resonance imaging of the dissociation of iron-coordination polymer nanoparticles in vivo.
Example 33
The in-vivo magnetic resonance imaging adopts about 20g of Balb/C nude mice. Injecting 100 mu L of iron coordination polymer nanoparticles with the concentration of 2mg/mL into a mouse body through tail veins, and detecting the liver aggregation condition by adopting magnetic resonance imaging at 0h (before material injection) and 24h respectively; after 24h, the dissociation agent is injected into tail vein according to the amount of the dissociation agent obtained in example 20 and example 24, and the liver dissociation conditions of 30h, 48h, 72h, 96h and 168h are detected by a magnetic resonance instrument respectively and compared with the liver iron content change of the dissociation agent injection group.
Fig. 6 is a graph of magnetic resonance imaging examination of liver tissues before and after dissociation of the iron coordination polymer nanoparticles obtained in example 33, and the results show that at 30 hours, the magnetic resonance signal of liver in mice was significantly decreased by adding deferoxamine as compared to the case where no dissociation agent was added, and further, the magnetic resonance signal was further decreased by adding two dissociation agents, which indicates that the iron coordination polymer nanoparticles accumulated in liver tissues were rapidly dissociated by adding dissociation agents, and thus the magnetic resonance signal was decreased.
Example 34
Injecting 100 μ L of the iron coordination polymer nanoparticles prepared in example 6 at a concentration of 2mg/mL into a mouse through the tail vein, harvesting the liver and kidney at 0h (before material injection) and 24h, respectively, and collecting feces and urine; after 24h, the amount of the dissociation agent obtained in example 25 and example 29 was tail vein injected with the dissociation agent, and liver and kidney were collected at 30h, 48h, 72h, 96h, and 168h, respectively, and corresponding feces and urine were collected. After the experiment, the iron content in the collected sample was measured by ICP-MS.
FIG. 7 is a graph showing in vivo metabolism before and after dissociation of the iron-coordination polymer nanoparticles obtained in example 34. The result shows that at 30h, compared with the condition that the dissociating agent is not added, the iron content discharged by the urine is obviously increased, the iron content discharged by the excrement is obviously reduced, and further, after the two dissociating agents are added, the iron content discharged by the urine is further increased, and the iron content discharged by the excrement is further obviously reduced. The main metabolic pathway of the undissociated iron coordination polymer nanoparticles is shown to be a hepatobiliary-intestinal metabolic pathway, and after dissociation of deferoxamine, the metabolic pathway of the iron coordination polymer nanoparticles is mainly changed into a renal clearance pathway.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (6)
1. Use of a compound in a dissociative photothermal therapy agent, photoacoustic imaging agent, or magnetic resonance imaging agent; the compound is deferoxamine or a combination of deferoxamine and disodium ethylenediamine tetraacetate;
the dissociation is that the iron coordination polymer nano particles are dissociated into small nano particles or small molecule solution;
the photothermal therapeutic agent, photoacoustic imaging agent, or magnetic resonance imaging agent is an iron-coordination polymer nanoparticle;
the iron coordination polymer nanoparticles are prepared from polyphenol, ferric salt and high molecular polymer;
the polyphenol is selected from one or more of epigallocatechin gallate, epigallocatechin, epicatechin gallate, pelargonidin, cyanidin, delphinidin, peoniflorin, morning glory extract, malvidin, tanshinol, luteolin, tannic acid, catechol and dopamine; the ferric iron salt is ferric chloride;
the high molecular polymer is selected from one or more of polyvinylpyrrolidone, hyaluronic acid, dextran, chitosan and polyethylene glycol modified polyglutamic acid;
the molar ratio of the high molecular polymer to the trivalent ferric salt to the polyphenol is 1: (1-100): (1-100).
2. The use according to claim 1, wherein the compound is administered in a dose of 20-80 mg/kg.
3. A method for dissociating iron-coordination polymer nanoparticles, comprising:
dissociating the iron coordination polymer nanoparticles by adopting a dissociating agent, wherein the dissociating agent is selected from deferoxamine or a combination of deferoxamine and ethylenediamine tetraacetic acid disodium salt; the iron coordination polymer nanoparticles are prepared from polyphenol, ferric salt and high molecular polymer;
the polyphenol is selected from one or more of epigallocatechin gallate, epigallocatechin, epicatechin gallate, pelargonidin, cyanidin, delphinidin, peoniflorin, morning glory extract, malvidin, tanshinol, luteolin, tannic acid, catechol and dopamine; the ferric iron salt is ferric chloride;
the high molecular polymer is one or more selected from polyvinylpyrrolidone, hyaluronic acid, dextran, chitosan and polyethylene glycol modified polyglutamic acid
The molar ratio of the high molecular polymer to the trivalent ferric salt to the polyphenol is 1: (1-100): (1-100).
4. The dissociation method according to claim 3, wherein the mass ratio of the iron coordination polymer nanoparticles to the dissociation agent is 1: (0.01-100).
5. The dissociation method according to claim 3, wherein the dissociation method is specifically:
dispersing iron coordination polymer nanoparticles, adding a dissociating agent, uniformly mixing by vortex, and magnetically stirring.
6. The dissociation method according to claim 5, wherein the stirring time is 30s to 10 min.
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