CN112957467B - Nanometer diagnosis and treatment agent, preparation method and application - Google Patents
Nanometer diagnosis and treatment agent, preparation method and application Download PDFInfo
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- CN112957467B CN112957467B CN202110199356.2A CN202110199356A CN112957467B CN 112957467 B CN112957467 B CN 112957467B CN 202110199356 A CN202110199356 A CN 202110199356A CN 112957467 B CN112957467 B CN 112957467B
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- photosensitizer
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- calcium carbonate
- ferroferric oxide
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Abstract
The invention relates to the field of biological medicine, in particular to a nano diagnosis and treatment agent, a preparation method and application, and a nano carrier, wherein the nano carrier comprises superparamagnetic ferroferric oxide nano particles and a calcium carbonate layer coated on the surfaces of the superparamagnetic ferroferric oxide nano particles, the nano probe comprises the nano carrier and a photosensitizer, the mass ratio of the photosensitizer to the nano carrier is 1-2:10, the photosensitizer is coated in the calcium carbonate layer, the diagnosis and treatment agent comprises the nano carrier, the photosensitizer and an anticancer drug, the mass ratio of the photosensitizer to the nano carrier is 1-2:10, the anticancer drug to the nano carrier is 1-2:10, and the photosensitizer and the anticancer drug are coated in the calcium carbonate layer. The diagnosis and treatment agent prepared by the invention has multifunctional diagnosis and treatment effect and cancer targeting.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to a nano diagnosis and treatment agent, a preparation method and application.
Background
Lymphomas, particularly those in which diffuse large B-cells are a relatively common hematological malignancy, are highly invasive and heterogeneous, and the incidence has been on the rise year by year in recent years. At present, a personalized comprehensive treatment strategy is generally adopted for the lymphoma clinically, and different medical intervention means such as chemical drug treatment, radiation treatment, targeted treatment, biological immunotherapy, traditional Chinese medicine treatment and the like are utilized, but no satisfactory method for treating the lymphoma exists so far. Therefore, it is still necessary to continue to explore new lymphoma diagnosis and treatment methods.
Disclosure of Invention
In view of the above drawbacks of the prior art, an object of the present invention is to provide a nano-medical agent, a preparation method and an application thereof, which are used for solving the problems in the prior art.
In a first aspect of the present invention, there is provided a nano-carrier, the nano-carrier comprising superparamagnetic ferroferric oxide nanoparticles and a calcium carbonate layer coated on the surfaces of the superparamagnetic ferroferric oxide nanoparticles.
In a second aspect, the present invention provides a method for preparing the nanocarrier of the first aspect, wherein the method comprises at least the following steps:
1) Mixing ferric chloride, sodium acetate and glycol solution, reacting at 150-250 ℃, and magnetically separating to obtain superparamagnetic ferroferric oxide nano particles.
2) The superparamagnetic ferroferric oxide nano particles and CaCl 2 And Na (Na) 2 CO 3 Mixing, and collecting precipitate after the reaction.
3) Mixing the precipitate obtained in the step 2) with activated hyaluronic acid, and taking the precipitate to obtain the nano-carrier.
According to a third aspect of the invention, there is provided a nanoprobe comprising the nanocarrier of the first aspect and a photosensitizer, wherein the mass ratio of the photosensitizer to the nanocarrier is 1-2:10, and the photosensitizer is coated in the calcium carbonate layer.
According to a fourth aspect of the present invention, there is provided a diagnostic and therapeutic agent comprising the nanocarrier of the first aspect, a photosensitizer and an anticancer drug, wherein the mass ratio of the photosensitizer to the nanocarrier is 1-2:10, the mass ratio of the anticancer drug to the nanocarrier is 1-2:10, and the photosensitizer and the anticancer drug are both coated in the calcium carbonate layer.
In a fifth aspect of the present invention, there is provided a method of preparing a diagnostic agent according to the fourth aspect, the method comprising at least the steps of:
1) The superparamagnetic ferroferric oxide nano particles, photosensitizer, anticancer drug and CaCl 2 And Na (Na) 2 CO 3 Mixing, and centrifuging to remove supernatant after the reaction is completed to obtain a primary diagnosis and treatment agent;
2) And mixing the primary diagnosis and treatment agent with activated hyaluronic acid, and centrifuging to obtain a precipitate to obtain the diagnosis and treatment agent.
In a sixth aspect of the invention there is provided the use of a diagnostic agent according to the fifth aspect for the manufacture of a product for the diagnosis and treatment of lymphoma.
As described above, the diagnosis and treatment agent has the following beneficial effects:
the invention skillfully coats the photosensitizer drug IR820 and the chemotherapeutic drug doxorubicin into the calcium carbonate by a chemical synthesis method, so that the diagnosis and treatment agent can degrade the surface calcium carbonate layer in a responsive way in the microenvironment of tumor bias acid, thereby releasing the antitumor drug in a targeted way. And the activated hyaluronic acid is utilized to carry out biological organic modification on the surface of the calcium carbonate, so that the tumor targeting is increased, the endocytic uptake of the diagnosis and treatment agent by tumor cells is promoted, and the diagnosis and treatment capability of the multifunctional diagnosis and treatment agent is greatly improved.
Drawings
FIG. 1 is a transmission electron microscope photograph of a nano-carrier prepared according to the present invention;
FIG. 2 is a high resolution transmission electron micrograph of a nanocarrier prepared in accordance with the present invention;
FIG. 3 is a UV spectrum of the preparation of a diagnostic agent according to the present invention;
FIG. 4 shows hysteresis curves for preparing a diagnostic agent according to the present invention;
FIG. 5 shows the results of CCK-8 detection for preparing a diagnostic agent according to the present invention;
FIG. 6 is fluorescence intensity of ex vivo organs;
FIG. 7 is a photograph of HE staining.
Detailed Description
Other advantages and effects of the present invention will become apparent to those skilled in the art from the following disclosure, which describes the embodiments of the present invention with reference to specific examples. The invention may be practiced or carried out in other embodiments that depart from the specific details, and the details of the present description may be modified or varied from the spirit and scope of the present invention.
Please refer to fig. 1 to 7. It should be noted that, the illustrations provided in the present embodiment merely illustrate the basic concept of the present invention by way of illustration, and only the components related to the present invention are shown in the drawings and are not drawn according to the number, shape and size of the components in actual implementation, and the form, number and proportion of the components in actual implementation may be arbitrarily changed, and the layout of the components may be more complex.
In a first aspect of the present invention, there is provided a nano-carrier, the nano-carrier comprising superparamagnetic ferroferric oxide nanoparticles and a calcium carbonate layer coated on the surfaces of the superparamagnetic ferroferric oxide nanoparticles.
The calcium carbonate layer positioned on the surface of the superparamagnetic ferroferric oxide nano-particles can be coated with medicament, such as photosensitizer, anticancer agent and the like, the calcium carbonate layer is subjected to responsive degradation in the micro-environment of biased acid, the coated medicament is released, the targeted release can be realized, the superparamagnetic ferroferric oxide nano-particles generate magnetism under the condition of exogenous magnetic substances and are aggregated at the site of the exogenous magnetic substances, and the nano-carrier also has a magnetic targeting function and nuclear magnetic imaging.
In one embodiment, the thickness of the calcium carbonate layer is 1-5 nm.
The thickness of the calcium carbonate layer may be selected by the experimenter according to the agent loading, for example, 1 to 2nm, 2 to 3nm, 3 to 4nm, or 4 to 5nm.
Preferably, the calcium carbonate layer has a thickness of 5nm, at which the calcium carbonate layer can encapsulate more of the agent.
In one embodiment, the superparamagnetic ferroferric oxide nanoparticles have a particle size of 5-10 nm. The ferroferric oxide nano-particles with the particle size have paramagnetism, namely, the ferroferric oxide nano-particles generate magnetism in a magnetic environment, and the magnetism of the ferroferric oxide nano-particles can disappear after the ferroferric oxide nano-particles leave the magnetic environment.
In one embodiment, hyaluronic acid is attached to the surface of the calcium carbonate layer. The design is beneficial to promoting the endocytic uptake of the nano-carrier by tumor cells, and increases the tumor targeting.
In a second aspect, the present invention provides a method for preparing the nanocarrier of the first aspect, wherein the method comprises at least the following steps:
1) Mixing ferric chloride, sodium acetate and glycol solution, reacting at 150-250 ℃, and magnetically separating to obtain superparamagnetic ferroferric oxide nano particles.
2) The superparamagnetic ferroferric oxide nano particles and CaCl 2 And Na (Na) 2 CO 3 Mixing, and collecting precipitate after the reaction.
3) Mixing the precipitate obtained in the step 2) with activated hyaluronic acid, and taking the precipitate to obtain the nano-carrier.
In the step 1), a certain amount of ferric chloride and sodium acetate are weighed and added into glycol solution, then the mixture is put into a reaction kettle, the reaction kettle is placed at 150-250 ℃ for reaction for 6-12 hours, and then magnetic separation is carried out, so that superparamagnetic ferroferric oxide nano particles are obtained.
In step 2), the superparamagnetic ferroferric oxide nano-particles obtained in step 1) and CaCl 2 And Na (Na) 2 CO 3 Stirring and mixing, reacting for a period of time, centrifuging at high speed by a centrifuge after the reaction is completed, and removing supernatant to obtain precipitate.
In step 3), the precipitate obtained in step 2) is mixed with activated hyaluronic acid and stirred for a period of time, and the centrifuged precipitate is obtained by high-speed centrifugation by a centrifuge, so as to obtain the nano-carrier.
In one embodiment, in step 1), the mass ratio of the ferric chloride to the sodium acetate is 0.8-2.5: 1 to 10.
The mass ratio of the ferric chloride to the sodium acetate can be selected by experimenters according to the own needs, and can be 0.8-1: 1-10, 1-2: 1 to 10, 2 to 2.5:1 to 10, 0.8 to 2.5:1 to 5 or 0.8 to 2.5:5 to 10.
In an embodiment, in step 2), the superparamagnetic ferroferric oxide nanoparticles, the CaCl 2 And the Na is 2 The mass ratio of CO is 10:1 to 3:1 to 3.
Experimental personnel select the superparamagnetic ferroferric oxide nano particles and the CaCl according to the thickness requirement of the calcium carbonate layer 2 And the Na is 2 CO 3 For example, the mass ratio of (c) may be 10:1 to 1.5:1 to 1.5, 10:1.5 to 2: 1.5-2, 10:2 to 2.5: 2-2.5, 10:2.5 to 3:2.5 to 3, 10:1: 1. 10:2:2 or 10:3:3.
in one embodiment, in step 2), the reaction time is from 6 to 12 hours.
The experimenter needs to choose the reaction time, which may be, for example, 6-8 hours or 8-12 hours.
In one embodiment, the mass ratio of the precipitate to the activated hyaluronic acid is 1-3: 3.3 to 4.5.
The experimenter needs to choose the mass ratio of the precipitate to the activated hyaluronic acid, which may be, for example, 1-2: 3.3 to 4.5, 2 to 3:3.3 to 4.5, 1 to 3:3.3 to 4 or 1 to 3:4 to 4.5.
In one embodiment, the precipitate is mixed with the activated hyaluronic acid for a period of time ranging from 18 to 36 hours.
The experimenter needs to choose the time for mixing the precipitate with the activated hyaluronic acid, which may be, for example, 18-20 hours, 20-22 hours, 22-24 hours or 24-36 hours.
In one embodiment, the activated hyaluronic acid is obtained by mixing hyaluronic acid, 1-ethyl- (3-dimethylaminopropyl) carbodiimide and hydroxysuccinimide in a phosphate buffer solution.
Preferably, the mass ratio of the hyaluronic acid, the 1-ethyl- (3-dimethylaminopropyl) carbodiimide and the hydroxysuccinimide in the phosphoric acid is 0.8-1: 1.5 to 2:1 to 1.5.
The mass ratio of the hyaluronic acid, the 1-ethyl- (3-dimethylaminopropyl) carbodiimide and the hydroxysuccinimide in the phosphoric acid can be selected by an experimenter according to the needs, and can be 0.8-0.9: 1.5 to 2:1 to 1.5 or 0.9 to 1:1.5 to 2:1 to 1.5.
According to a third aspect of the invention, there is provided a nanoprobe comprising the nanocarrier of the first aspect and a photosensitizer, wherein the mass ratio of the photosensitizer to the nanocarrier is 1-2:10, and the photosensitizer is coated in the calcium carbonate layer.
In this embodiment, the experimenter may select the mass ratio of the photosensitizer to the nanocarrier, which may be, for example, 1-1.5:10 or 1.5-2:10.
In the invention, the photosensitizer is coated in the calcium carbonate layer of the nano-carrier, and the nano-carrier can be oriented to the tumor part to release the photosensitizer, thereby improving the use efficiency of the photosensitizer and reducing the damage of the photosensitizer to normal tissues.
Preferably, the photosensitizer is IR820 with an emission wavelength in a near infrared region, the interference of biological autofluorescence is less, and after the IR820 is ingested by tumor cells, singlet oxygen can be released under the irradiation of specific light rays so as to kill the tumor cells.
According to a fourth aspect of the present invention, there is provided a diagnostic and therapeutic agent comprising the nanocarrier of the first aspect, a photosensitizer and an anticancer drug, wherein the mass ratio of the photosensitizer to the nanocarrier is 1-2:10, the mass ratio of the anticancer drug to the nanocarrier is 1-2:10, and the photosensitizer and the anticancer drug are both coated in the calcium carbonate layer.
In this embodiment, the experimenter may select the mass ratio of the photosensitizer to the nanocarrier, for example, 1-1.5:10 or 1.5-2:10, and may also select the mass ratio of the anticancer drug to the nanocarrier, for example, 1-1.5:10 or 1.5-2:10.
The diagnosis and treatment agent contains superparamagnetism ferroferric oxide nano particles which generate magnetism under the condition of exogenous magnetic substances and gather at the site of the exogenous magnetic substances in a directional manner, and has a magnetic targeting function. Considering that the meta-acidity is an important characteristic of the tumor microenvironment, the photosensitizer and the anticancer drug are skillfully coated in the tumor microenvironment by a chemical synthesis method of calcium carbonate, so that the diagnosis and treatment agent can responsively degrade a surface calcium carbonate layer in the tumor meta-acidity microenvironment to release the photosensitizer and the anticancer drug in a targeted manner. And the activated hyaluronic acid is utilized to carry out biological organic modification on the calcium carbonate layer, so that the tumor targeting is increased, the endocytic uptake of the diagnosis and treatment agent by tumor cells is promoted, and the diagnosis and treatment capability of the diagnosis and treatment agent is greatly improved.
Preferably, the anticancer drug is doxorubicin. Doxorubicin has a broad spectrum of anti-tumor properties and is often used as a chemotherapeutic agent for various hematological tumors and solid malignant tumors in humans.
In the embodiment, because the doxorubicin has side effects such as cardiotoxicity, bone marrow suppression, digestive tract side reaction and the like, the photosensitizer medicine IR820 has poor stability in organisms and is easy to be clear by organisms, the diagnosis and treatment agent can target to tumor positions, the toxicity of the doxorubicin is reduced, and the use efficiency of the photosensitizer medicine IR82 is increased.
In a fifth aspect of the present invention, there is provided a method of preparing a diagnostic agent according to the fourth aspect, the method comprising at least the steps of:
1) The superparamagnetic ferroferric oxide nano particles, photosensitizer, anticancer drug and CaCl 2 And Na (Na) 2 CO 3 Mixing, and centrifuging to remove supernatant after the reaction is completed to obtain a primary diagnosis and treatment agent;
2) And mixing the primary diagnosis and treatment agent with activated hyaluronic acid, and centrifuging to obtain a precipitate to obtain the diagnosis and treatment agent.
In the step 1), a certain amount of superparamagnetic ferroferric oxide nano particles, a photosensitizer and an anticancer drug CaCl are respectively weighed 2 And Na (Na) 2 CO 3 Mixing, stirring for 12-36 h, and centrifuging to remove supernatant by using a centrifuge after the reaction is completed to obtain the primary diagnosis and treatment agent.
In step 2), the primary diagnosis and treatment agent obtained in step 1) is mixed with activated hyaluronic acid, stirred for a period of time, centrifuged at a high speed by a centrifuge, and the centrifuged sediment is taken to obtain the diagnosis and treatment agent.
In a sixth aspect of the invention there is provided the use of a diagnostic agent according to the fifth aspect for the manufacture of a product for the diagnosis and treatment of lymphoma.
The diagnosis and treatment agent contains superparamagnetism ferroferric oxide nano particles, the diagnosis and treatment agent can be magnetically targeted to the lymphoma part, the calcium carbonate layer contained in the diagnosis and treatment agent is coated with the photosensitizer and the anticancer drug, the calcium carbonate layer is degraded in the tumor environment, the photosensitizer and the anticancer drug are released, and then laser irradiation is additionally applied, so that the combined treatment of chemotherapy, photo-thermal imaging and fluorescence imaging on tumors is realized.
Example 1
(1) 5mmol of FeCl 3 Adding the mixture into glycol solution (100 ml), adding 1g of NaAc, uniformly mixing and stirring for 20-40min until the precipitate is completely dissolved, reacting for 6-12 h at 150-250 ℃, magnetically separating, and cleaning to obtain superparamagnetic ferroferric oxide nano particles.
(2) The superparamagnetism ferroferric oxide nano particles are obtained by the steps, caCl containing photosensitizer medicine IR820 (500 mg) is added 2 (10 mg) in the solution, stirring thoroughly for 18-24h; na of doxorubicin (500 mg) was further added 2 CO 3 (10 mgl) in the solution, stirring thoroughly again for 24 hours; after the reaction is completed, a precipitate is obtained by high-speed centrifugation.
(3) 800mg of hyaluronic acid is added into 40ml of phosphate buffer solution, fully mixed and stirred, 1.5g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide and 1g of hydroxysuccinimide are added for activation, fully mixed and stirred for 20-40min, and an activated hyaluronic acid solution is obtained.
(4) And (3) shaking the precipitate obtained in the step (3) with the activated hyaluronic acid solution obtained in the step (4) for 18-24 hours, and centrifuging at high speed (10000-12000 rpm) to obtain the diagnosis and treatment agent.
Example 2
(1) 15mmol of FeCl 3 Adding into glycol solution (200 ml), adding 10g NaAc, mixing, stirring for 20-40min until the precipitate is completely dissolved, reacting at 150-250deg.C for 6-12 hr, magnetically separating, and cleaningAfter washing, superparamagnetic ferroferric oxide nanometer particles can be obtained.
(2) The superparamagnetism ferroferric oxide nano particles are obtained by the steps, caCl containing photosensitizer medicine IR820 (800 mg/ml) is added 2 (20 mg/ml) and fully stirring for 18-24h; na of doxorubicin (800 mg/ml) was further added 2 CO 3 (20 mg/ml) and stirring again for 24h; after the reaction is completed, a precipitate is obtained by high-speed centrifugation.
(3) 1000mg of hyaluronic acid is added into 60ml of phosphate buffer solution, fully mixed and stirred, 2.0g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide and 1.5g of hydroxysuccinimide are added for activation, fully mixed and stirred for 20-40min, and an activated hyaluronic acid solution is obtained.
(4) And (3) shaking the precipitate obtained in the step (3) with the activated hyaluronic acid solution obtained in the step (4) for 18-24 hours, and centrifuging at high speed (10000-12000 rpm) to obtain the diagnosis and treatment agent.
As shown in fig. 1 and 2, the transmission electron microscope shows that the diagnosis and treatment agent has good dispersibility and uniform particle size, and the crystal lattice of the magnetic particles can be clearly seen.
Example 3
And detecting the ultraviolet absorption spectrum of the diagnosis and treatment agent by using a Cary 500 ultraviolet-visible spectrophotometer spectrometer. The experimental result is shown in fig. 3, the IR820 absorption peak is red shifted, and the successful loading of the photosensitizer on the diagnosis and treatment agent is confirmed.
The multifunctional nanoprobe in fig. 3 is a diagnostic agent of the present invention, and the nanoprobe in the following examples is also a diagnostic agent of the present invention. But in a different manner.
Example 4
Magnetic nanoproperties of the diagnostic agent were examined using a vibrating sample magnetometer (Lake Shore 7207) to draw hysteresis curves. The experimental results are shown in FIG. 4, which shows the hysteresis curve of the diagnostic agent.
Example 5
The influence of the diagnosis and treatment agent on the bioactivity of tumor cells under the condition of laser excitation or not is detected by using a CCK-8 experiment, so that the biocompatibility and the therapeutic property of the nano probe are evaluated. The test results are shown in FIG. 5, CCK-8 detection: under no laser excitation, the diagnosis and treatment agent has better biocompatibility and the potential of a diagnosis probe; under the excitation of laser, the diagnosis and treatment agent has better anti-tumor property.
Example 6
And measuring the fluorescence intensity of the isolated main organs of the nude mice by using a Bruker in-vitro fluorescence detection system, so as to evaluate the organ distribution condition of the nano probe in the animal body. The test results are shown in FIG. 6, in vitro organ fluorescence intensity: the fluorescence intensity of the diagnosis and treatment agent in tumor tissues is obviously stronger than that of other tissues and organs.
Example 7
The HE staining detection evaluates the treatment condition of the diagnosis and treatment agent on the tumor, and compared with a control group, the diagnosis and treatment agent can obviously kill tumor cells under the excitation of laser. Test results As shown in FIG. 7, compared with the control group, the diagnosis and treatment agent prepared by the invention can obviously kill tumor cells.
In summary, the present invention effectively overcomes the disadvantages of the prior art and has high industrial utility value.
The above embodiments are merely illustrative of the principles of the present invention and its effectiveness, and are not intended to limit the invention. Modifications and variations may be made to the above-described embodiments by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is intended that all equivalent modifications and variations of the invention be covered by the claims, which are within the ordinary skill of the art, be within the spirit and scope of the present disclosure.
Claims (9)
1. The nano carrier is characterized by comprising superparamagnetic ferroferric oxide nano particles and a calcium carbonate layer coated on the surfaces of the superparamagnetic ferroferric oxide nano particles, wherein the surfaces of the calcium carbonate layer are subjected to biological organic modification by using activated hyaluronic acid, so that the surfaces of the calcium carbonate layer are attached with the hyaluronic acid, and the mass ratio of the superparamagnetic ferroferric oxide nano particles coated with the calcium carbonate layer to the activated hyaluronic acid is (1-3): 3.3-4.5, wherein the time for mixing the superparamagnetic ferroferric oxide nano particles coated with the calcium carbonate layer with the activated hyaluronic acid is 18-36 h.
2. A nanocarrier according to claim 1, wherein: the thickness of the calcium carbonate layer is 1-5 nm.
3. A nanocarrier according to claim 1, wherein: the particle size of the superparamagnetic ferroferric oxide nano particles is 5-10 nm.
4. A method for preparing the nanocarrier of any of claims 1 to 3, comprising at least the steps of:
1) Mixing ferric chloride, sodium acetate and ethylene glycol solution, reacting at 150-250 ℃, and magnetically separating to obtain superparamagnetic ferroferric oxide nano particles;
2) The superparamagnetic ferroferric oxide nano particles and CaCl 2 And Na (Na) 2 CO 3 Mixing, and taking a precipitate after the reaction is completed;
3) Mixing the precipitate obtained in the step 2) with activated hyaluronic acid, and taking the precipitate to obtain the nano-carrier.
5. The method of claim 4, wherein the step of determining the position of the first electrode is performed,
in the step 1), the mass ratio of the ferric chloride to the sodium acetate is 0.8-2.5: 1-10;
in step 2), the superparamagnetic ferroferric oxide nanoparticles, the CaCl 2 And the Na is 2 CO 3 The mass ratio of (2) is 10: 1-3: 1-3;
in the step 3), the mass ratio of the precipitate to the activated hyaluronic acid is 1-3: 3.3 to 4.5.
6. A nanoprobe, characterized in that: the nano probe comprises the nano carrier and a photosensitizer, wherein the mass ratio of the photosensitizer to the nano carrier is 1-2:10, and the photosensitizer is coated in the calcium carbonate layer.
7. A diagnostic agent, characterized in that: the diagnosis and treatment agent comprises the nano-carrier, a photosensitizer and an anticancer drug according to any one of claims 1 to 3, wherein the mass ratio of the photosensitizer to the nano-carrier is 1-2:10, the mass ratio of the anticancer drug to the nano-carrier is 1-2:10, and the photosensitizer and the anticancer drug are both coated in the calcium carbonate layer.
8. A method of preparing a diagnostic agent according to claim 7, comprising at least the steps of:
the superparamagnetic ferroferric oxide nano particles, photosensitizer, anticancer drug and CaCl 2 And Na (Na) 2 CO 3 Mixing, and centrifuging to remove supernatant after the reaction is completed to obtain a primary diagnosis and treatment agent;
and mixing the primary diagnosis and treatment agent with activated hyaluronic acid, and centrifuging to obtain a precipitate to obtain the diagnosis and treatment agent.
9. Use of a diagnostic agent according to claim 7 for the preparation of a product for diagnosis and treatment of lymphomas.
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