CN112755183A - Organic metal framework nano material, preparation and application thereof - Google Patents
Organic metal framework nano material, preparation and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of nano biomaterials, and particularly relates to an organic metal framework nanoprobe with high-loading non-uniform loading of photosensitive molecules for photodynamic response and photothermal response, and preparation and application thereof. In the process of synthesizing the organic metal framework, photosensitive molecules are added, so that the photosensitive molecules are loaded in the organic metal framework MOFs material in a high-efficiency and high-loading manner and are distributed non-uniformly. Experiments prove that the nano probe obtained by the preparation method has excellent photodynamic response and photothermal response due to the participation of photosensitive molecules in the synthesis process of MOFs materials. The nano probe prepared by the invention has both photodynamic response and photothermal response, and can also be used for preparing a probe for treating tumors, and the probe for treating tumors is a probe for treating tumors by combining photothermal and photodynamic.
Description
Technical Field
The invention belongs to the technical field of nano biomaterials, relates to an organic metal framework nano probe, and preparation and application thereof, and more particularly relates to an organic metal framework nano material which is loaded with a high-load non-uniform photosensitive molecule and has photodynamic response and photothermal response, and preparation and application thereof.
Background
Diagnosis and treatment of tumors have been the mainstay of life science research. At present, the diagnosis and treatment of tumors based on nanomaterials mainly comprise surgical resection, light treatment (mainly comprising photodynamic treatment and photothermal treatment), chemotherapy and radiotherapy, latest biological immunotherapy and the like. Among them, the development of light-sensitive reagents and light-heat reagents in light therapy is mature, and the selectivity of light irradiation in light therapy is one of the most popular treatment methods at present.
Traditional photodynamic and photothermal therapy are two independent treatment therapies, if the two are combined for use, a nano material or a drug-loaded platform needs to be loaded with photosensitive molecules and photothermal response molecules at the same time, and when the nano material or the drug-loaded platform reaches a focus part, the focus part is irradiated. It should be noted that most of the currently developed photosensitive molecules use laser with 660nm wavelength, and most of the photo-thermal response molecules use near infrared region, such as 808nm and 980 nm. This results in the need for secondary illumination if simultaneous photothermal and photodynamic therapy is desired, which increases the workload and avoids the effects of cross illumination. Therefore, the invention of the nano material or the probe can realize photothermal treatment and photodynamic treatment under the laser irradiation with the same wavelength, and has great significance for treating tumors.
Disclosure of Invention
The invention provides an organometallic framework nano material with both photodynamic response and photothermal response and carrying a high-load heterogeneous photosensitive molecule, and preparation and application thereof, aiming at adding the photosensitive molecule in the synthesis process of an organometallic framework, so that the photosensitive molecule is loaded in the organometallic framework MOFs material with high efficiency and high load, and the nano material with excellent photodynamic response and photothermal response is obtained, thereby solving the technical problems that the conventional light combination therapy needs to add the photosensitive molecule and the thermosensitive molecule at the same time and needs to carry out secondary illumination.
In order to achieve the above object, according to one aspect of the present invention, there is provided a method for preparing an organometallic framework nanomaterial having both photodynamic response and photothermal response, in which an aqueous solution of a metal salt and an aqueous solution of a photosensitive molecule are added dropwise to an aqueous solution of an organic framework ligand, so that the photosensitive molecule is supported in the organometallic framework material during the formation of the organometallic framework by the organic framework ligand and metal salt ions, and the obtained organometallic framework nanomaterial has both photodynamic response and photothermal response.
Preferably, the specific dropping manner is as follows:
firstly, dripping aqueous solution of metal salt into aqueous solution of organic framework ligand, and then dripping aqueous solution of photosensitive molecule; or
And dripping the mixed aqueous solution of the metal salt and the photosensitive molecules into the aqueous solution of the organic framework ligand.
Preferably, the organic framework ligand is 2-methylimidazole, and the metal salt contains a metal salt of cerium.
Preferably, the photosensitive molecule is chlorin e 6; the mass ratio of the addition amount of the photosensitive molecules to the metal salt is (0.5-5): 100.
preferably, the molar ratio of the metal salt to the organic framework ligand is from 1:12 to 85.
Preferably, in the synthesis process, an aqueous solution of a chemotherapeutic drug is also dripped into the aqueous solution of the organic framework ligand, and the mass ratio of the addition amount of the chemotherapeutic drug to the metal salt is (0.5-5): 100, respectively; when an aqueous solution of metal salt ions, an aqueous solution of photosensitive molecules and an aqueous solution of chemotherapeutic drugs are dripped into an aqueous solution of organic framework ligands, the photosensitive molecules and the chemotherapeutic drugs are loaded in the organic metal framework material in the process of forming the organic metal framework by the organic ligands and the metal salt ions.
Preferably, the chemotherapeutic agent is doxorubicin.
According to another aspect of the invention, the organometallic framework nano-material prepared by the preparation method and having both photodynamic response and photothermal response is provided.
Preferably, the nano material comprises a plurality of nano material units, each nano material unit is composed of more than ten to twenty cubes, the side length of each cube is 8-10nm, and the length of the longest side of each nano material unit is 20-50 nm.
Preferably, the photosensitive molecule is Ce6, the organic framework ligand is 2-methylimidazole, the metal salt contains cerium ions, and the photosensitive molecule in the nanomaterial enables the nanomaterial to have photodynamic response; the photosensitive molecules loaded in the nanomaterial cause vibrational relaxation during de-excitation upon absorption of a photon, the vibrational relaxation being accompanied by heat release, thereby causing the nanomaterial to have a thermal response.
According to another aspect of the invention, the application of the nano material is provided, and the nano material is used as an ultrasonic photoacoustic imaging probe or a tomography imaging probe, or is used for preparing a probe for treating tumors, and the probe for treating tumors is a probe for treating tumors by combining photothermal and photodynamic.
Preferably, the nano material is a nano material modified by thiol-polyethylene glycol.
In general, compared with the prior art, the above technical solution contemplated by the present invention can achieve the following beneficial effects:
(1) the invention synthesizes the organic metal framework nano material by a one-pot method, and photosensitive molecules are added in the synthesis process of the organic metal framework, so that the photosensitive molecules are loaded in the organic metal framework MOFs material in high efficiency and high loading and are in non-uniform distribution. Experiments prove that the nano probe obtained by the preparation method has excellent photodynamic response and photothermal response because photosensitive molecules are non-uniformly distributed in the synthesis process of the MOFs material.
(2) According to the invention, in the synthesis process of the MOFs material, photosensitive molecules are added, so that the photosensitive molecules are loaded in a high-load manner and dispersed in a cubic structure of the MOFs material, and under the irradiation of a laser with a specific wavelength of 660nm, the MOFs material loaded with the photosensitive molecules has photodynamic response and generates singlet oxygen, and the material generates a strong vibration relaxation process and is accompanied with heat release in a de-excited state process due to the dense high-load distribution of the photosensitive molecules in the MOFs material, so that the material shows good photothermal response.
(3) The invention preferably loads small molecules during synthesis rather than after synthesis, greatly improving the loading efficiency, and the loading efficiency of the added small molecules is close to 100%.
(4) The nano material prepared by the invention has a photo-thermal effect, so that pressure waves generated by the photo-thermal effect can be used for photo-acoustic imaging; the preferred metal ions in the MOFs are cerium ions, which are rare earth element ions with high atomic number and can be used for tomography. In addition, the nano probe prepared by the invention has both photodynamic response and photothermal response, and can also be used for preparing a probe for treating tumors, and the probe for treating tumors is a probe for treating tumors by combining photothermal and photodynamic.
(5) The MOF has peroxidase catalytic activity, and when the MOF is used as a carrier for cancer treatment, surrounding hydrogen peroxide can be catalyzed into oxygen, so that the oxygen content in tumor cells is improved, the photodynamic efficiency is further increased, and the tumor cells are killed more effectively.
(6) The MOF material synthesized by the invention can be well applied to a mouse xenograft model, and well inhibits the growth of mouse tumors through the combined treatment of light treatment and chemotherapy.
Drawings
FIG. 1 is a transmission electron microscope image characterizing the morphology of a material. FIG. 1a is a synthesized organometallic framework Ce-MOF without the addition of Ce6 and DOX. FIG. 1b is an organometallic framework MOF/C & D with Ce6 and DOX added.
FIG. 2 examines the characterization of the synthesized MOF/C & D for catalytic hydrogen peroxide.
FIG. 3 is a graph of the detection of singlet oxygen generation at different illumination times using DPBF.
FIG. 4 shows the change in MOF temperature with varying amounts of Ce6 at different times under 660nm illumination. 0.5%, 1%, 1.5% and 3% represent different amounts of Ce6 added in the synthesis of MOF.
FIG. 5 is a schematic representation of the proposed Ce6 loading into MOF to generate singlet oxygen and increase temperature.
FIG. 6a is the ultrasonic/photoacoustic imaging result after mouse tail vein MOF/C & D-PEG injection, and FIG. 6b is the tomography imaging result after mouse tail vein MOF/C & D-PEG injection.
FIG. 7 is a graph showing the therapeutic effect of the synthesized MOF material of the present invention on tumors in a mouse xenograft model.
FIG. 8 is a graph comparing the results of the characterization of the photo-thermal stability of MOF/C, ZIF-8/C and Ce6 in comparative example 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and 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. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
The invention provides a preparation method of an organic metal framework nano material with high-load heterogeneous loaded photosensitive molecules and both photodynamic response and photothermal response.
Dropping an aqueous solution of metal salt ions and an aqueous solution of photosensitive molecules into an aqueous solution of the organic framework ligand, wherein the aqueous solution of metal salt ions and the aqueous solution of photosensitive molecules are specifically used in some embodiments: firstly, dripping the aqueous solution of metal salt ions into the aqueous solution of the organic framework ligand, and then dripping the aqueous solution of photosensitive molecules into the aqueous solution after the dripping is finished.
And dropwise adding an aqueous solution of metal salt ions and an aqueous solution of photosensitive molecules into an aqueous solution of the organic framework ligand, wherein the specific examples of the other examples are as follows: and dropwise adding a mixed solution of an aqueous solution of metal salt ions and an aqueous solution of photosensitive molecules into an aqueous solution of the organic framework ligand.
The invention preferably loads photosensitive molecules in the synthesis of MOFs, but not after the synthesis, greatly improves the loading efficiency, and the loading efficiency of the added small molecules is close to 100 percent.
In some embodiments, the organic framework ligand is 2-Methylimidazole (2-Methylimidazole,2-MIM) and the metal salt is cerium nitrate hexahydrate (Ce (NO)3)3·6H20)。
In some embodiments, the photosensitive molecule is Chlorin e6(Chlorin e6, Ce 6).
In some embodiments, a chemotherapeutic agent is also added dropwise to the aqueous solution of the organic framework ligand. And dropwise adding an aqueous solution of metal salt, an aqueous solution of photosensitive molecules and an aqueous solution of chemotherapeutic drugs into an aqueous solution of the organic framework ligand, so that the photosensitive molecules and the chemotherapeutic drugs are loaded in the organic metal framework material in the process of forming the organic metal framework by the organic ligand and metal salt ions.
Dropping an aqueous solution of metal salt, an aqueous solution of photosensitive molecules and an aqueous solution of chemotherapeutic drugs into an aqueous solution of the organic framework ligand, wherein the aqueous solution of metal salt, the aqueous solution of photosensitive molecules and the aqueous solution of chemotherapeutic drugs are specifically used in some embodiments: firstly, dripping aqueous solution of metal salt into aqueous solution of organic framework ligand, and then dripping aqueous solution of photosensitive molecule and aqueous solution of chemotherapeutic drug into the aqueous solution of organic framework ligand.
Dropping an aqueous solution of metal salt ions, an aqueous solution of photosensitive molecules and an aqueous solution of chemotherapeutic drugs into an aqueous solution of the organic framework ligand, wherein the other embodiments are as follows: and (3) dropwise adding a mixed solution of an aqueous solution of metal salt ions, an aqueous solution of photosensitive molecules and an aqueous solution of chemotherapeutic drugs into an aqueous solution of the organic framework ligand.
The chemotherapy medicament can be a plurality of common chemotherapy medicaments. In some embodiments, the chemotherapeutic agent is Doxorubicin (DOX), paclitaxel (paclitaxel), or cisplatin (cissplatin).
In the preparation process of the nano probe, photosensitive molecules with different amounts or mixed solution of the photosensitive molecules and chemotherapeutic drug molecules are dripped into the aqueous solution of the organic framework ligand, so that the photosensitive molecules or the photosensitive molecules and the chemotherapeutic drug molecules are loaded into the MOFs nano probe.
In some embodiments of the invention, the molar ratio of the metal salt to the organic framework ligand is from 1:12 to 85. The mass ratio of the addition amount of the photosensitive molecules to the metal salt is (0.5-5): 100, the mass ratio of the addition amount of the chemotherapeutic drug to the metal salt is (0.5-5): 100. the mass range of the organic framework ligand 2-methylimidazole added in a reaction system is 3g-7g, and the mass range of substances in the cerium nitrate hexahydrate aqueous solution is 1-3 mmol.
Experiments show that when the mass of the photosensitive molecule Ce6 added in the synthesis process of the MOF is higher in a certain range, the relaxation effect of the corresponding obtained organic metal framework material under the illumination condition is more obvious, and the temperature rise degree caused by the corresponding generated heat effect is larger.
In the process of synthesizing the MOFs material, the aqueous solution of metal salt, the aqueous solution of photosensitive molecules and chemotherapeutic drug molecules are added dropwise into the aqueous solution of the organic framework ligand, so that the MOFs material with the complete morphology is synthesized by dropwise adding under the stirring condition.
The invention also provides the organometallic framework nano-material which is prepared by the preparation method and has high-load heterogeneous loaded photosensitive molecules and photodynamic response and photothermal response.
In some embodiments, the nanomaterial prepared by the method comprises a plurality of nanomaterial units, each nanomaterial unit is composed of more than ten to twenty cubes, the side length of each cube is 8-10nm, and the length of the longest side of each nanomaterial unit is about 20-50 nm.
According to the invention, through selecting proper MOF material types including proper organic framework materials and metal salt types, matching proper photosensitive molecules, and loading the photosensitive molecules in the process of synthesizing the MOF, the obtained organic metal framework materials have both photodynamic response and photothermal response, so that the photosensitive molecules in the prepared organic metal framework materials are inferred to be in non-uniform distribution. The photosensitive molecule Ce6 forms a place with very concentrated aggregation, namely high-compression Ce6, and a relatively loose distribution, namely sparse Ce6 in the MOF, the sparse Ce6 can maintain the own photodynamic property and continuously generate active oxygen under the irradiation of a near infrared wavelength of 660nm, and the high-compression Ce6 releases a large amount of heat energy due to frequent and continuous occurrence of enhanced non-resonant energy transfer, so that the high-compression Ce6 can be used for non-traditional photothermal therapy.
When the photosensitive molecule is Ce6, the organic framework ligand is 2-methylimidazole, and the metal salt ion is cerium nitrate hexahydrate, the photosensitive molecule Ce6 loaded in the nanoprobe makes the nanoprobe have photodynamic response; the photosensitive molecules loaded in the probe or the photosensitive molecules loaded simultaneously with the chemotherapeutic drugs enable the probe to generate strong vibration relaxation in the de-excitation process after the probe absorbs photons, and the vibration relaxation is accompanied with heat dissipation, so that the nano probe has thermal response.
According to the organometallic framework nanoprobe, a photosensitive molecule is Ce6, an organic framework ligand is 2-methylimidazole, metal salt ions are cerium nitrate hexahydrate, the photosensitive molecule loaded in the nanoprobe enables the probe to have strong absorption in a near infrared region of 660nm, and after the photosensitive molecule in the probe absorbs 660nm photons, photochemical reaction occurs and a large number of free radicals are generated, so that photodynamic response is achieved.
Meanwhile, the closely packed Ce6 wrapped in the organic metal frame in the nanoprobe undergoes strong vibrational relaxation during de-excitation after absorbing near-infrared light of 660nm, which is accompanied by heat dissipation, thereby allowing the probe to have thermal response. Specifically, since the tightly packed Ce6 in MOF undergoes vibration relaxation during de-excitation after absorbing near infrared light 660nm, a non-radiative mechanism that enables the Ce6 molecule to collide with surrounding molecules including organic framework ligands, metal ions and the surrounding adjacent Ce6 molecule, the vibration relaxation process is enhanced due to the tight distribution of Ce6, which is accompanied by heat dissipation, thus making the material photo-thermal effect.
When the nanoprobe is also loaded with a chemotherapeutic drug, the Ce6 molecule can not only collide with surrounding molecules including organic framework ligands, metal ions and surrounding adjacent Ce6 molecules, but also collide with the chemotherapeutic drug molecules so as to strengthen the vibration relaxation process.
The nano probe prepared by the invention has a photothermal effect, so that pressure waves generated by the photothermal effect can be used for photoacoustic imaging; the preferred metal ions in the MOFs are cerium ions, which are rare earth element ions with high atomic number and can be used for tomography.
In addition, the prepared nano probe is a high-load MOFs nano material loaded with photosensitive molecules non-uniformly, has both photodynamic response and photothermal response, can also be used for preparing a probe for treating tumors, and is a probe for treating tumors by combining photothermal and photodynamic. In order to make the probe have good water solubility and biocompatibility, in some embodiments, the nanoprobe is modified by covalent bond with thiol-polyethylene glycol before application to improve the water solubility and biocompatibility of the probe in cell application or in vivo application.
In some embodiments of the invention, the organometallic framework (MOFs) probe is prepared by a one-pot method, and a certain amount of photosensitive molecular Chlorin e6(Chlorin e6, Ce6) and chemotherapeutic drug Doxorubicin (Doxorubicin, DOX) are added during preparation, the prepared probe not only has the photodynamic property of Ce6, but also has strong absorption in the near infrared region 660nm due to the high-loading Ce6 in the MOF, and the photosensitive molecular generates a large amount of free radicals through photochemical reaction after absorbing 660nm photons, so that effective photodynamic therapy is performed; due to the vibrational relaxation of the tightly encapsulated Ce6 in the MOF during de-excitation after absorbing near infrared light up to 660nm, a non-radiative mechanism that enables the Ce6 molecule to collide with surrounding molecules including organic framework ligands, metal ions and the surrounding adjacent Ce6 molecule, the vibrational relaxation process is enhanced due to the tight distribution of Ce6, which is accompanied by heat dissipation, and thus the material can be used for photothermal therapy. In addition, the chemotherapy drug DOX is loaded at the same time, so that the combined chemotherapy and light treatment is carried out, and the better treatment effect is realized. Preferably, modification of polyethylene glycol PEG on synthetic MOFs imparts better water solubility and biocompatibility to the probes, allowing the probes to circulate in vivo for an extended period of time.
The invention provides synthesis of an organic metal framework material with high-loading capacity and non-uniform loading of photosensitive molecules, and the organic metal framework material is applied to imaging and treatment of tumors. The invention realizes that the photosensitive molecules are used for photodynamic therapy and photothermal therapy at the same time for the first time, and provides a non-traditional means for photothermal therapy. Meanwhile, the organic metal framework has peroxidase catalysis effect, so that hydrogen peroxide in the surrounding environment can be catalyzed to generate a large amount of oxygen, and the photodynamic therapy effect is enhanced. When the nano-scale particle is used together with chemotherapeutic drugs, the nano-scale particle becomes a multifunctional nano-scale platform and can be well applied to living body treatment.
The invention synthesizes an organic metal framework material with high-loading capacity and non-uniform photosensitive molecule loading. The loaded small molecules are photosensitive molecules or chemotherapeutic drug molecules, the loaded photosensitive molecules can generate active oxygen under illumination of certain wavelength to endow the material with the possibility of photodynamic therapy, and the chemotherapeutic drug molecules can be used for carrying out chemotherapy on cancer cells to endow the material with the possibility of chemotherapy. Preferably, the photoactive molecule is Ce6 and the chemotherapeutic agent is DOX.
In the drawing, Ce-MOF represents a synthesized cerium organometallic framework material, MOF/Ce6 represents a synthesized cerium organometallic framework material loaded with Ce6, MOF/DOX represents a synthesized cerium organometallic framework loaded with DOX, MOF-PEG represents an organometallic framework material of cerium modified with polyethylene glycol, MOF/C & D-PEG represents an organometallic framework material of cerium modified with polyethylene glycol. The percentage charged after Ce6, which represents the mass of Ce6 added when synthesizing MOF, was obtained by dividing the mass of Ce6 added by the mass of cerium salt used in the reaction system. The laser wavelength used for the experiment was 660 nm.
The synthesis of the metal organic framework ligand with high-loading non-uniform loading of photosensitive molecules provided by the invention is characterized in that photosensitive molecules and chemotherapeutic drugs are added in the synthesis, the loaded photosensitive molecules can generate singlet oxygen to kill tumor cells under continuous illumination for photodynamic therapy, and the Ce6 loaded in the material is in non-uniform distribution, so that the non-radiative vibration relaxation process is intensified after heat absorption to generate a large amount of heat, thereby being applied to photothermal therapy. Meanwhile, the loaded chemotherapeutic drug can be released continuously in cell therapy and tumor therapy to achieve the tumor inhibition effect. Combined with the light treatment of Ce6, the composition can kill tumor efficiently. The MOF synthesized by the invention takes cerium as a metal ion source, and the cerium with high atomic number endows the MOF with a very good X-ray attenuation signal, so that the MOF can be well applied to tomography imaging, and the MOF material can have a very good tumor inhibition effect on living bodies by combining the imaging.
In some embodiments of the present invention, the method for preparing the MOF material comprises the following steps:
(1) cerium nitrate hexahydrate is used as metal ions, 2-methylimidazole is used as an organic framework ligand, and Ce-MOF is synthesized by a one-pot method.
(2) If the small molecules need to be loaded, in the synthesis process of (1), after a cerous nitrate hexahydrate solution is dripped into a 2-methylimidazole solution, a certain amount of small molecules are added immediately and continuously stirred.
(3) The MOFs or MOF/C & D described above were modified with thiol-group-bearing polyethylene glycols.
Specifically, in step (1), in some embodiments, the organometallic framework of cerium is prepared by:
1) respectively preparing solutions of cerium nitrate hexahydrate and 2-methylimidazole for later use: dissolving 1.55mmol of cerium nitrate hexahydrate in 3mL of ultrapure water, and uniformly dispersing by ultrasonic to obtain an aqueous solution of the cerium nitrate hexahydrate; 5.5g of 2-methylimidazole is dissolved in 20mL of water and uniformly dispersed by ultrasonic to obtain an aqueous solution of imidazole for later use.
2) Adding 3mL of cerous nitrate hexahydrate solution into 20mL of 1) under vigorous stirring, continuously stirring at room temperature for 6h until the color is changed into light yellow from colorless, centrifuging and washing away unreacted cerium ions and imidazole to obtain light yellow precipitate, namely the organic metal framework.
In step (2), if the small molecule is required to be loaded, the preferable molecules Ce6 and DOX are respectively prepared into 1mg/mL solution, and after the cerium nitrate aqueous solution is added dropwise, the small molecule solution is added dropwise, and other steps are kept unchanged. The color change of the loaded different small molecule solutions is different, if only Ce6 is dripped, the solution is changed from colorless to dark green, and the finally obtained precipitation product is dark green; if only DOX is dripped, the color is finally changed into mauve; when both are added dropwise, the color finally turns into black.
In the step (3), 10mg of the MOF powder prepared in the step (1) or (2) is weighed and dissolved in 20mL of ultrapure water, then 20mg of SH-PEG solution dissolved in 10mL of ultrapure water is added dropwise under continuous stirring, and after continuous stirring for 12h, the mixture is centrifuged to obtain the polyethylene glycol modified MOF, namely MOF-PEG or MOF/C & D-PEG. The effect of the modified PEG here is mainly to give the synthesized MOF better water solubility and biocompatibility.
The invention also provides application of the material in ultrasonic photoacoustic and tomography imaging during tumor enrichment.
The following are examples:
example 1
The embodiment provides a synthesis method of an organic metal framework material with both photodynamic response and photothermal response, and the material is prepared by the following preparation method:
(1) preparation of MOF
In a vigorously stirred 20mL water reaction system containing 5.5g 2-mIm, dropwise adding 3mL cerium nitrate hexahydrate solution dissolved with 1.55mmol, continuously stirring at room temperature for 6h to change the color from colorless to light yellow, and centrifuging at 6000rpm for 10min to wash away unreacted metal ions and imidazole to obtain light yellow precipitate, namely MOF.
As shown in FIG. 1a, the transmission electron micrograph of the obtained MOF shows that the longest side of the obtained MOF is about 50nm and has better dispersibility.
(2) Preparation of MOF/C & D
In a vigorously stirred 20mL aqueous reaction system containing 5.5g of 2-mIm, 3mL of a cerium nitrate hexahydrate solution dissolved with 1.55mmol of cerium nitrate is added dropwise, and after the addition is finished, a mixed aqueous solution of 2mLCe6 and DOX is added dropwise, wherein the mixed aqueous solution contains Ce 620 mg and contains DOX20 mg; continuously stirring at room temperature for 6h to change the color from colorless to black, centrifuging at 6000rpm for 10min to remove unreacted metal ions, and obtaining a light yellow precipitate, namely MOF/C & D3%, from imidazole. During the washing process, the supernatant was found to be essentially clear in color, consistent with the near 100% loading of small molecules such as Ce6 as described above.
As shown in FIG. 1b, the transmission electron microscopy morphology of the obtained MOF/C & D is not much different from that of MOF.
Example 2
The organometallic framework is used for the material characterization of the photo-thermal and photodynamic properties of catalysis, and the steps are as follows:
when the catalytic performance of the prepared organic metal framework is characterized, the synthesized MOF/C & D is dissolved in water and reacts with hydrogen peroxide, and the amount of dissolved oxygen generated by decomposition of the hydrogen peroxide in a reaction system is detected within 5 min.
FIG. 2 shows the capacity of MOF/C & D to catalyze hydrogen peroxide, and the results show that the MOF/C & D can well and continuously catalyze the decomposition of hydrogen peroxide in a reaction system to generate oxygen.
When the capacity of generating active oxygen after the prepared organic metal framework is loaded with photosensitive molecule Ce6 is characterized, a DPBF probe is selected as a measuring probe of the level of the active oxygen in a reaction system, 1mg/mL of DPBF is dissolved in ethanol, 50 mu g/mL of the probe or hydrogen peroxide is added into the reaction system, illumination treatment of 660nm laser is carried out, and the level of the active oxygen generated in the reaction system is obtained by calculating the absorption peak of the DPBF within 5 min.
FIG. 3 shows the strength change of MOF/Ce6 in the presence of light or hydrogen peroxide in the reaction system DPBF, and the result shows that the MOF/Ce6 prepared by the invention can generate a large amount of active oxygen in light, and can generate more active oxygen when the light is added with hydrogen peroxide and then the light is applied.
The photothermal properties of the prepared organometallic frameworks were characterized and the temperature change in the light was recorded for synthetic organometallic framework MOF/Ce6, MOF loaded with different percentages of Ce6, at a concentration of 100 μ g/mL, and ultrapure water. The laser conditions used were: 660nm,1.2W/cm2。
Fig. 4 is the results of photothermal characterization showing that the temperature gets higher as the concentration of loaded Ce6 increases. The temperature rise from room temperature to 55 ℃ can be well realized in a short time (5 min).
Example 3
In vivo ultrasound photoacoustic imaging and tomography imaging
The in vivo ultrasonic photoacoustic imaging and tomography imaging are completed in molecular imaging and transformation medical research center of Xiamen university.
(1) Ultrasonic-photoacoustic integrated multi-mode imaging
A Balb/c mouse subcutaneous tumor was used as a model and the equipment used was Endra's Nexus 128F μ Lly 3-D Photoacustic CT Scanner. The specific operation steps are as follows:
1) preparation of Balb/c mice subcutaneous tumor model: mouse breast cancer cells 4T1 at 37 deg.C with 5% CO2Culturing in DMEM medium under the condition, and collecting 5 × 10 when growth state is good6Inoculating the cells into Balb/c mice subcutaneously until the subcutaneous tumor grows to 200mm3Left and right for standby.
2) Injecting MOF/C & D-PEG with a certain concentration into tail vein, and observing the enrichment of the probe in the tumor.
Fig. 6a is an ultrasonic photoacoustic signal diagram of a mouse injected with a probe at different times, wherein the left US is an ultrasonic signal, and the right PA is a photoacoustic signal, so that the material can be clearly seen that the material has a good enrichment effect in the tumor after being injected for 12 hours, and the photoacoustic signal can be clearly seen.
(2) Tomographic imaging
A Balb/c white mouse subcutaneous tumor was used as a model, and the equipment used was Siemens (Siemens) Inveon PET/CT. The specific operation steps are as follows:
1) preparation of Balb/c mice subcutaneous tumor model: mouse breast cancer cells 4T1 at 37 deg.C with 5% CO2Culturing in DMEM medium under the condition, and collecting 5 × 10 when growth state is good6Inoculating the cells into Balb/c mice subcutaneously until the subcutaneous tumor grows to 200mm3Left and right for standby.
2) MOF/C & D-PEG material with certain concentration is injected into the tumor, and CT signals of the material in the tumor are observed.
FIG. 6b is a signal diagram of a tomography scan of the mouse before and after probe injection, which clearly shows that the material has a strong signal in the tumor after injection.
Example 4
The heterogeneous organic metal framework material loaded with small molecules is used for inhibiting tumor growth in the catalyzed photothermal and photodynamic combined treatment, and the method comprises the following steps:
(1) preparation of Balb/c mice subcutaneous tumor model: mouse breast cancer cells 4T1 at 37 deg.C with 5% CO2Culturing in DMEM complete medium under the condition, and collecting 5 × 10 when growth state is good6Inoculating the cells into Balb/c mice subcutaneously until the subcutaneous tumor grows to 200mm3Left and right for standby.
(2) Experimental grouping and nanoprobe dose selection: toxicity test was performed on Balb/C mice with 500. mu.g/MOF/C & D-PEG, and the mice normally moved without death. The experimental injection of 200. mu.g/body of probe and injection volume of 100. mu.L was selected with reference to the relevant literature and the above results. Mice were then randomly grouped. A probe control group and a light control group are respectively set up.
(3) Combination therapy: tail vein MOF/C injection&D-PEG with the dosage of 200 mu g/mouse, and after 12 hours, the mixture is irradiated by light (660nm, 1.2W/cm)2,5min)。
(4) The body weight and tumor volume of the mice were recorded daily, and as shown in fig. 7, it was found that the tumor volume was greatly suppressed in the experimental group, and no significant suppression was observed in the other groups. The probe can be used for the combined treatment of mouse subcutaneous tumors.
Illustration of the drawings:
FIG. 1 is a transmission electron micrograph of synthetic MOF and MOF/C & D with scale bars at 50 nm.
FIG. 2 is a representation of the use of the synthesized MOF/C & D for catalyzing the decomposition of hydrogen peroxide in a system using a probe concentration of 50. mu.g/mL and a hydrogen peroxide concentration of 100mM, with the amount of dissolved oxygen in the system being mg/L as measured using an oxygen dissolution meter.
FIG. 3 shows DPBF detection of active oxygen generated from synthesized MOF/Ce6, with a probe concentration of 50. mu.g/mL, a hydrogen peroxide concentration of 100mM, and light conditions of 660nm and 1.2W/cm2. The intensity of DPBF was measured spectroscopically by an ultraviolet-visible absorptiometer and then normalized based on the original DPBF absorption intensity.
FIG. 4 is a log of the temperature rise of MOF, MOF and ultrapure water loaded with various amounts of Ce6, using a material concentration of 100. mu.g/mL, laser conditions: 660nm,1.2W/cm2。
FIG. 5 is a schematic view of the present invention providing that loaded heterogeneous Ce6 can generate active oxygen and thermal energy simultaneously, assuming that loosely loaded Ce6 can absorb photons of 660nm, transit from a ground state to an excited state, and then fluoresce back to the ground state or enter a triplet state, which is particularly unstable and generates radicals through a series of photoreactions in a very short time; when the triplet state is in a relatively close state, Ce6 is very rapidly exchanged with surrounding molecules due to the close distance between molecules, and when the triplet state returns to the ground state and undergoes vibrational relaxation, thermal energy is generated in the very short time.
FIG. 6 is a MOF/C & D-PEG for photoacoustic imaging and tomography imaging. US for ultrasound, PA for photoacoustic, Pre for Pre-injection and Post for Post-injection.
FIG. 7 is the results of MOF/C & D-PEG for tumor growth inhibition in a tumor model of mouse xenografts. (1) - (8) respectively represent: PBS group, PBS plus light group, MOF/PEG plus light group, solution plus light group of Ce6 and DOX, MOF/D-PEG plus light group, MOF/C & D-PEG group, MOF/C-PEG plus light group, MOF/C & D-PEG plus light group.
Example 5
In a vigorously stirred 20mL water reaction system containing 5.5g 2-mIm, 1.55mmol of cerium nitrate hexahydrate solution and 5mL of a mixed solution of Ce 620 mg and DOX20 mg are added dropwise, the dropwise adding volume can be increased or decreased correspondingly according to the dissolved amount of Ce6 and DOX, the stirring is continued for 6h at room temperature, the color is changed from colorless to black, unreacted metal ions are washed off by 6000rpm and 10min centrifugation, and the imidazole obtains a light yellow precipitate, namely MOF/C & D3%. If we want to synthesize MOFs containing different percentages of Ce6 and DOX, we can change the amount of Ce6 or DOX according to the percentages. During the washing process, the supernatant was found to be essentially clear in color, consistent with the near 100% loading of small molecules such as Ce6 as described above.
Comparative example 1
In the invention, the property of photo-thermal property after loading small molecules in the cerium MOF is not necessarily applicable to other MOFs, and taking ZIF8 as an example, the ZIF8 loaded with Ce6 is synthesized by the method, and the specific steps are as follows: in a vigorously stirred 1mL aqueous reaction system containing 33mg of 2-mIm, 15mg of zinc nitrate solution was added dropwise, and then 620 μ g of Ce was added dropwise to obtain ZIF8, which was then resuspended so that the concentration of Ce6 was close to that of Ce6 in the MOF/C solution, at which time characterization of photothermal stability was performed under the same conditions, and it was found that the photothermal response in ZIF8 was poor, and that photothermal stability was extremely poor, and thus it was not suitable as a material for photothermal therapy. Furthermore, it can be seen that the free Ce6 solution has a very slight temperature rise upon illumination compared to a similar concentration of free Ce6 solution, and the photo-thermal responsiveness is lost by the photo-bleaching action in the second round of illumination, so this result is a good indication that the material proposed by us is a very suitable carrier for the cerium MOF.
FIG. 8 is a result of photothermal stability characterization, showing that MOF/C has very good photothermal stability, while ZIF-8/C and Ce6 have very poor photothermal stability.
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A preparation method of an organic metal framework nano material with both photodynamic response and photothermal response is characterized in that an aqueous solution of metal salt and an aqueous solution of photosensitive molecules are dripped into an aqueous solution of organic framework ligands, so that the photosensitive molecules are loaded in the organic metal framework material in the process of forming organic metal frameworks by the organic framework ligands and metal salt ions, and the obtained organic metal framework nano material has both photodynamic response and photothermal response.
2. The preparation method according to claim 1, wherein the specific dropping manner is as follows:
firstly, dripping aqueous solution of metal salt into aqueous solution of organic framework ligand, and then dripping aqueous solution of photosensitive molecule; or
And dripping the mixed aqueous solution of the metal salt and the photosensitive molecules into the aqueous solution of the organic framework ligand.
3. The method of claim 1, wherein the organic framework ligand is 2-methylimidazole and the metal salt comprises a metal salt of cerium.
4. The method of claim 1, wherein the photosensitive molecule is chlorin e 6; the mass ratio of the addition amount of the photosensitive molecules to the metal salt is (0.5-5): 100.
5. the method of claim 1, wherein the molar ratio of the metal salt to the organic framework ligand is from 1:12 to 85.
6. The method according to claim 1 or 2, wherein during the synthesis, an aqueous solution of a chemotherapeutic agent is further added dropwise to the aqueous solution of the organic framework ligand, and the mass ratio of the addition amount of the chemotherapeutic agent to the metal salt is (0.5-5): 100, respectively; when an aqueous solution of metal salt ions, an aqueous solution of photosensitive molecules and an aqueous solution of chemotherapeutic drugs are dripped into an aqueous solution of organic framework ligands, the photosensitive molecules and the chemotherapeutic drugs are loaded in the organic metal framework material in the process of forming the organic metal framework by the organic ligands and the metal salt ions.
7. The organometallic framework nanomaterial with both photodynamic response and photothermal response prepared by the preparation method of any one of claims 1 to 6.
8. The organo-metallic framework nanomaterial of claim 7, wherein the photoactive molecule is Ce6, the organo-framework ligand is 2-methylimidazole, the metal salt contains cerium ions, and the photoactive molecule in the nanomaterial is such that it has a photodynamic response; the photosensitive molecules loaded in the nanomaterial cause vibrational relaxation during de-excitation upon absorption of a photon, the vibrational relaxation being accompanied by heat release, thereby causing the nanomaterial to have a thermal response.
9. Use of the nanomaterial of claim 7 as an ultrasound photoacoustic imaging probe or a tomography imaging probe, or for the preparation of a tumor treatment probe, which is a photothermal photodynamic combined tumor treatment probe.
10. The use of claim 9, wherein the nanomaterial is a nanomaterial modified with a thiol-polyethylene glycol.
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