CN107496377B - Preparation method and application of hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug loading system - Google Patents
Preparation method and application of hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug loading system Download PDFInfo
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- CN107496377B CN107496377B CN201710962069.6A CN201710962069A CN107496377B CN 107496377 B CN107496377 B CN 107496377B CN 201710962069 A CN201710962069 A CN 201710962069A CN 107496377 B CN107496377 B CN 107496377B
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- 238000011068 loading method Methods 0.000 title claims abstract description 12
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
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- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
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Abstract
The invention relates to a preparation method and application of a hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug-loading system, which can effectively solve the problem of drug use for treating tumors and adopts the technical scheme that hyaluronic acid and Prussian blue nanoparticles are connected through a chemical bond to form a nano layer in an aqueous medium, and a photosensitizer, namely indocyanine green enters a Prussian blue mesoporous structure through physical action; the preparation method is simple, the materials are easy to obtain, the prepared drug-carrying system can convert the TAM phenotype from M2 type assisting in malignant transformation of tumors to M1 type with a tumor killing and inhibiting function, oxygen required by laser-induced ICG to generate active oxygen is efficiently supplemented, and the self-oxygen-generating photodynamic treatment effect is enhanced; the carrier has the functions of gated drug release and active targeting; the HPBs generated at the tumor part can be used for nuclear magnetic resonance imaging and photoacoustic imaging, so that the diagnosis and treatment of the tumor are integrated.
Description
Technical Field
The invention relates to the field of medicines, in particular to a preparation method and application of a hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug loading system.
Background
Tumor-associated macrophages (TAMs) refer to macrophages that are infiltrated in tumor tissue and are an important component of the tumor microenvironment. Under different tumor microenvironment signal regulation, TAM can be polarized to form M1 type macrophage with proinflammatory and antitumor activity or form M2 type macrophage with anti-inflammatory and tumor immunosuppression effects. While different subtypes of TAM have different effects on anti-tumor treatment approaches: the M1 type can enhance the treatment effect of some antitumor therapies, and the M2 type macrophage can inhibit the treatment effect of some antitumor therapies. TAMs usually exhibit M2-type polarization states in malignant tumors. Therefore, the method regulates the polarization direction of macrophages, reverses M2 type macrophages into M1 type macrophages with the effects of inhibiting tumor growth and antigen presentation, and has important significance for inhibiting invasion and metastasis of tumors and improving prognosis of tumor patients.
Photodynamic therapy (PDT) is a novel therapy for selectively treating diseases by combining photosensitizer, light and oxygen molecules and performing photodynamic reaction, and due to the advantages of obvious treatment effect, low toxicity, small side effect on human body and the like, the PDT is more and more concerned, and the development of novel photothermal conversion agent nano-materials which have the advantages of simple preparation, low cost, stable structure, reliable biological safety and certain tumor targeting property has recently become a research hotspot of scholars at home and abroad.
Prussian Blue (PB) is a long-history dye, has excellent photophysical, electrooptical and magnetic properties, and has been widely used in many fields, such as nuclear magnetic resonance contrast agents, photoacoustic imaging contrast agents, photothermal therapy and the like. The Prussian blue has the advantages of simple preparation process, mild reaction conditions, low cost, easy surface modification and stable chemical structure, is a clinical medicine for treating radiation poisoning, and is certified by FDA.
Hyaluronic Acid (HA) molecule is an essential polysaccharide in human body, HA with different molecular weights HAs different effects, wherein the HA with low molecular weight is used as an immune activator, HAs excellent biocompatibility and tumor targeting property, and can cause M2 type macrophages to be converted into M1 macrophages. In addition, the HA modified nanoparticles can improve the hydrophilicity and stability of the nanoparticles, prolong the blood circulation time, achieve the aim of sustained and slow release of the drug, improve the tumor active targeting property of the nanoparticles, and reduce the toxic and side effects of the nanoparticles on normal cells, thereby realizing the targeted therapy of the cancer.
Indocyanine green (ICG), a functional dye with high absorption, fluorescence and high reactivity in the near-infrared wavelength region, has been widely used as a probe in diagnostic and therapeutic applications, and can be used in photodynamic therapy by generating singlet oxygen ions through its photosensitizing properties to destroy cancer cell channels. ICG not only can be used as a tracer for fluorescence imaging, but also can generate heat and active oxygen under near infrared light for carrying out photo-thermal and photodynamic therapy.
The tumor microenvironment has the characteristics of hypoxia, high pressure, acidity and the like, the hypoxia is one of the microenvironment conditions which are necessarily experienced in the occurrence and development processes of numerous malignant tumors, and the hypoxia which is an important microenvironment ubiquitous in solid tumors plays an important role in the infiltration of TAM. Macrophages tend to infiltrate the hypoxic regions of the tumor.
Disclosure of Invention
In view of the above situation, in order to overcome the defects of the prior art, the invention aims to provide a preparation method and application of a hollow mesoporous gated hyaluronic acid modified prussian blue nanoparticle drug-loading system, which can effectively solve the problem of drug use for treating tumors.
The technical scheme includes that the Prussian blue nanoparticle drug carrier system modified by hollow mesoporous gated hyaluronic acid is characterized in that the hyaluronic acid and Prussian blue nanoparticles are connected through a chemical bond to form a nano layer in an aqueous medium, and a photosensitizer indocyanine green enters a Prussian blue mesoporous structure through a physical effect;
the preparation method comprises the following steps:
(1) synthesizing mesoporous Prussian blue nanoparticles: dissolving 1-50g of polyvinylpyrrolidone K30 and 10-200mg of potassium ferricyanide in 30-50ml of hydrochloric acid with the mass concentration of 0.01-0.1M, magnetically stirring the solution into a transparent solution, reacting at 70-90 ℃ for 20-30h, centrifuging at 10000-;
(2) synthesis of hyaluronic acid modified prussian blue nanoparticles: taking 1-5mg mesoporous Prussian blue nanoparticles, adding 5-20ml of ultrapure water, performing ultrafiltration to uniformly disperse the mesoporous Prussian blue nanoparticles, adding 0.1-5mg of polyetherimide under magnetic stirring, continuing stirring for 20-30h, dialyzing, and freeze-drying to obtain polyetherimide modified mesoporous Prussian blue nanoparticles; taking 10-100mg of polyetherimide modified mesoporous Prussian blue nanoparticles, adding 40-60ml of formamide, and dissolving by ultrasonic oscillation to obtain polyetherimide modified mesoporous Prussian blue nanoparticle solution; respectively adding 300-400mg of N-hydroxysuccinimide and 180-250mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride into 3-5ml of formamide for dissolving, adding into the polyetherimide modified mesoporous Prussian blue nanoparticle solution, stirring, and reacting at room temperature for 8-12 h; dissolving 10-100mg of hyaluronic acid in 8-12ml of formamide, adding 150-200 mul of triethylamine, slowly dropwise adding into the polyetherimide modified mesoporous Prussian blue nanoparticle solution, stirring at room temperature for reaction for 20-30h, adding precooled acetone with the volume of 3-4 times of the reaction liquid, cooling in an ice bath, crystallizing, filtering with 0.22 mu m of oil film oil, washing for 3-5 times with acetone, dissolving with 3-4ml of ultrapure water, dialyzing in a dialysis bag with the molecular weight cutoff MWCO =3kDa for 2-3 days, sucking out the dialyzate and freeze-drying to obtain the hyaluronic acid modified Prussian blue nanoparticles;
(3) synthesis of hyaluronic acid modified prussian blue nanoparticles loaded with green indole phthalocyanine: adding 5-20mg of hyaluronic acid modified Prussian blue nanoparticles serving as a carrier into 2-40ml of deionized water, ultrasonically dissolving by using a probe, mixing with 1-5ml of photosensitizer green aqueous solution with the mass concentration of 2mg/ml, ultrasonically treating for 25-35min, stirring at room temperature, putting into a dialysis bag with the molecular weight cut-off of MWCO =3kDa, dialyzing for 2-3 days, and carrying out freeze drying to obtain the hollow mesoporous gated hyaluronic acid modified Prussian blue drug-carrying nanoparticle system.
The particle size of the Prussian blue nanoparticle drug-carrying system modified by the hollow mesoporous gated hyaluronic acid prepared by the method is 150-300 nm.
The hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug carrier system prepared by the method is applied to preparation of antitumor drugs.
The hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug-loaded system prepared by the method is applied to preparation of nuclear magnetic imaging agents and photoacoustic imaging agents.
The preparation method is simple, the materials are easy to obtain, the prepared drug-carrying system can convert TAM phenotype from M2 type assisting in malignant transformation of tumors to M1 type with tumor killing and inhibiting functions, and a large amount of H is generated2O2Reacting with HPBs with catalase activity in tumor hypoxia environment to release a large amount of O2Can be used for relieving tumor hypoxia state and neutralizing H+The acidic environment of the tumor is improved, the oxygen required by the laser-induced ICG to generate active oxygen is efficiently supplemented, and the self-oxygen-generating photodynamic treatment effect is enhanced; the carrier has the functions of gated drug release and active targeting; the HPBs generated at the tumor part can be used for nuclear magnetic resonance imaging and photoacoustic imaging, so that the diagnosis and treatment of the tumor are integrated.
Detailed Description
The following examples further illustrate embodiments of the present invention in detail.
Example 1
The preparation method of the hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug-loading system comprises the following steps:
(1) synthesizing mesoporous Prussian blue nanoparticles: dissolving 1g of polyvinylpyrrolidone K30 and 10mg of potassium ferricyanide in 30ml of hydrochloric acid with the mass concentration of 0.01M, magnetically stirring to form a transparent solution, reacting at 70 ℃ for 30h, centrifuging at 10000rpm for 12min, washing with distilled water for 2 times, drying at 70 ℃ to obtain Prussian blue nanoparticles, dissolving 0.1mg of Prussian blue nanoparticles in 0.5ml of hydrochloric acid solution with the mass concentration of 1M, adding 0.1mg of polyvinylpyrrolidone under magnetic stirring, magnetically stirring for 2h, reacting at 130 ℃ for 5h, centrifuging at 10000rpm for 12min, washing with distilled water for 2 times, and freeze-drying to obtain mesoporous Prussian blue nanoparticles;
(2) synthesis of hyaluronic acid modified prussian blue nanoparticles: taking 1mg mesoporous Prussian blue nanoparticles, adding 5ml of ultrapure water, carrying out ultrafiltration to uniformly disperse the mesoporous Prussian blue nanoparticles, adding 0.1mg of polyetherimide under magnetic stirring, continuing stirring for 20 hours, dialyzing, and carrying out freeze drying to obtain polyetherimide modified mesoporous Prussian blue nanoparticles; taking 10mg of polyetherimide modified mesoporous Prussian blue nanoparticles, adding 40ml of formamide, and dissolving by ultrasonic oscillation to obtain polyetherimide modified mesoporous Prussian blue nanoparticle solution; respectively adding 3ml of formamide into 300mg of N-hydroxysuccinimide and 180mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to dissolve, adding the formamide into the polyetherimide modified mesoporous Prussian blue nanoparticle solution, stirring, and reacting at room temperature for 12 hours; dissolving 10mg of hyaluronic acid in 8ml of formamide, adding 150 mul of triethylamine, slowly dropwise adding the dissolved hyaluronic acid into the polyetherimide modified mesoporous Prussian blue nanoparticle solution, stirring and reacting for 20 hours at room temperature, adding precooled acetone with the volume of 3 times of the reaction solution, cooling in an ice bath, crystallizing, filtering with 0.22 mu m of oil film oil, washing with 3 times of acetone, dissolving with 3ml of ultrapure water, dialyzing in a dialysis bag with the molecular weight cutoff MWCO =3kDa for 2 days, sucking out the dialyzate and freeze-drying to obtain the hyaluronic acid modified Prussian blue nanoparticles;
(3) synthesis of hyaluronic acid modified prussian blue nanoparticles loaded with green indole phthalocyanine: adding 5mg of prussian blue nano-particles modified by hyaluronic acid as a carrier into 2ml of deionized water, ultrasonically dissolving by using a probe, mixing with 1ml of green aqueous solution of photosensitizer indole phthalocyanine with the mass concentration of 2mg/ml, ultrasonically treating for 25min, stirring at room temperature, dialyzing in a dialysis bag with the molecular weight cutoff MWCO =3kDa for 2 days, and freeze-drying to obtain the hollow mesoporous gated hyaluronic acid modified prussian blue nano-particle drug-carrying system.
Example 2
The preparation method of the hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug-loading system comprises the following steps:
(1) synthesizing mesoporous Prussian blue nanoparticles: dissolving 30g of polyvinylpyrrolidone K30 and 132mg of potassium ferricyanide in 40ml of hydrochloric acid with the mass concentration of 0.05M, magnetically stirring the solution into a transparent solution, reacting at 80 ℃ for 24 hours, centrifuging at 12000rpm for 10 minutes, washing with distilled water for 3 times, drying at 80 ℃ to obtain Prussian blue nanoparticles, dissolving 1.0mg of Prussian blue nanoparticles in 1.0ml of hydrochloric acid solution with the mass concentration of 1.0M, adding 5mg of polyvinylpyrrolidone under magnetic stirring, magnetically stirring for 3 hours, reacting at 140 ℃ for 4 hours, centrifuging at 12000rpm for 10 minutes, washing with distilled water for 3 times, and freeze-drying to obtain mesoporous Prussian blue nanoparticles;
(2) synthesis of hyaluronic acid modified prussian blue nanoparticles: taking 3mg mesoporous Prussian blue nanoparticles, adding 10ml of ultrapure water, carrying out ultrafiltration to uniformly disperse the mesoporous Prussian blue nanoparticles, adding 3mg of polyetherimide under magnetic stirring, continuing stirring for 24 hours, dialyzing, and carrying out freeze drying to obtain polyetherimide modified mesoporous Prussian blue nanoparticles; taking 45mg of polyetherimide modified mesoporous Prussian blue nanoparticles, adding 50ml of formamide, and dissolving by ultrasonic oscillation to obtain polyetherimide modified mesoporous Prussian blue nanoparticle solution; respectively adding 346mg of N-hydroxysuccinimide and 206mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride into 4ml of formamide for dissolving, adding the formamide solution into the polyetherimide modified mesoporous Prussian blue nanoparticle solution, stirring, and reacting at room temperature for 10 hours; dissolving 50mg of hyaluronic acid in 10ml of formamide, adding 180 mul of triethylamine, slowly dropwise adding the dissolved hyaluronic acid into the polyetherimide modified mesoporous Prussian blue nanoparticle solution, stirring and reacting for 24 hours at room temperature, adding precooled acetone with 4 times volume of reaction liquid, cooling in an ice bath, crystallizing, filtering with 0.22 mu m of oil film oil, washing with acetone for 4 times, dissolving with 3ml of ultrapure water, dialyzing in a dialysis bag with MWCO =3kDa for 2 days, sucking out dialysate and freeze-drying to obtain the hyaluronic acid modified Prussian blue nanoparticles;
(3) synthesis of hyaluronic acid modified prussian blue nanoparticles loaded with green indole phthalocyanine: adding 10mg of hyaluronic acid modified Prussian blue nanoparticles serving as a carrier into 10ml of deionized water, ultrasonically dissolving by using a probe, mixing with 3ml of photosensitizer green aqueous solution with the mass concentration of 2mg/ml, ultrasonically treating for 30min, stirring at room temperature, dialyzing in a dialysis bag with the molecular weight cutoff (MWCO =3kDa) for 2 days, and freeze-drying to obtain the hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug-carrying system.
Example 3
The preparation method of the hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug-loading system comprises the following steps:
(1) synthesizing mesoporous Prussian blue nanoparticles: dissolving 50g of polyvinylpyrrolidone K30 and 200mg of potassium ferricyanide in 50ml of hydrochloric acid with the mass concentration of 0.1M, magnetically stirring the solution into a transparent solution, reacting at 90 ℃ for 20 hours, centrifuging at 14000rpm for 8 minutes, washing with distilled water for 3 times, drying at 90 ℃ to obtain Prussian blue nanoparticles, dissolving 10mg of Prussian blue nanoparticles in 1.5ml of hydrochloric acid solution with the mass concentration of 1M, adding 10mg of polyvinylpyrrolidone under magnetic stirring, magnetically stirring for 3 hours, reacting at 150 ℃ for 3 hours, centrifuging at 14000rpm for 8 minutes, washing with distilled water for 3 times, and freeze-drying to obtain mesoporous Prussian blue nanoparticles;
(2) synthesis of hyaluronic acid modified prussian blue nanoparticles: taking 5mg mesoporous Prussian blue nanoparticles, adding 20ml of ultrapure water, carrying out ultrafiltration to uniformly disperse the mesoporous Prussian blue nanoparticles, adding 5mg of polyetherimide under magnetic stirring, continuing stirring for 30h, dialyzing, and carrying out freeze drying to obtain polyetherimide modified mesoporous Prussian blue nanoparticles; taking 100mg of polyetherimide modified mesoporous Prussian blue nanoparticles, adding 60ml of formamide, and dissolving by ultrasonic oscillation to obtain polyetherimide modified mesoporous Prussian blue nanoparticle solution; respectively adding 400mg of N-hydroxysuccinimide and 250mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride into 5ml of formamide for dissolving, adding the formamide solution into the polyetherimide modified mesoporous Prussian blue nanoparticle solution, stirring, and reacting at room temperature for 12 hours; dissolving 100mg of hyaluronic acid in 12ml of formamide, adding 200 mul of triethylamine, slowly dropwise adding the dissolved hyaluronic acid into a polyetherimide modified mesoporous Prussian blue nanoparticle solution, stirring and reacting for 30 hours at room temperature, adding precooled acetone with 4 times volume of reaction liquid, cooling in an ice bath, crystallizing, filtering with 0.22 mu m of oil film oil, washing for 5 times with acetone, dissolving in 4ml of ultrapure water, dialyzing in a dialysis bag with MWCO =3kDa for 3 days, sucking out dialysate and freeze-drying to obtain hyaluronic acid modified Prussian blue nanoparticles;
(3) synthesis of hyaluronic acid modified prussian blue nanoparticles loaded with green indole phthalocyanine: adding 20mg of hyaluronic acid modified Prussian blue nanoparticles serving as a carrier into 40ml of deionized water, ultrasonically dissolving by using a probe, mixing with 5ml of photosensitizer green aqueous solution with the mass concentration of 2mg/ml, ultrasonically treating for 35min, stirring at room temperature, dialyzing in a dialysis bag with the molecular weight cutoff (MWCO =3kDa) for 3 days, and freeze-drying to obtain the hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug-carrying system.
The invention provides a mesoporous gated hyaluronic acid modified Prussian blue nano particle (HA-HPBs) self-generating oxygen and drug loading system; the invention adopts hollow mesoporous Prussian blue nano-particles (HPBs) with high drug loading capacity and biocompatibility as a base material, indole green pigments (ICG) as a model drug and low molecular weight Hyaluronic Acid (HA) for modification to construct accurate multi-mechanism tumor treatment with photothermal and photodynamic self-oxygen production functions under the mediation of nuclear magnetic imaging and photoacoustic imaging dual-mode imaging. The particle size of the nano system is 150-300nm, the size is uniform, and the dispersibility is good; the system mainly has the following characteristics: 1) the HA of the carrier is disconnected from the HPBs under the weak acid condition of the tumor, so that the medicament in the mesopores is released at fixed points at the tumor part, and the characteristic of mesoporous gating type medicament release is achieved; 2) the hollow mesoporous structure of the drug delivery system has high drug capacity, and can make the drug slowly release at the target site; 3) the drug delivery system can convert tumor-associated macrophage (TAM) phenotype from M2 type for assisting tumor malignant transformation to M1 type with tumor killing and inhibiting effects, and generate large amount of H2O2Reacting with HPBs with catalase activity in tumor hypoxia environment to release a large amount of O2Thereby realizing the self-oxygen generation function of the drug delivery system; 4) the carrier has the functions of gated drug release and active targeting; the HA is low molecular weight HA with the molecular weight of 6276 kd; 5) the HPBs of the targeted tumor part can be used for carrying out nuclear magnetic resonance imaging and photoacoustic imaging so as to realize the diagnosis and treatment integration of the tumor;
the hyaluronic acid modified mesoporous Prussian blue nanoparticles (HA-HPBs) are self-generating oxygen delivery system. The preparation method comprises the following steps of (1) preparing a photosensitive agent, namely a photosensitive agent, wherein the photosensitive agent consists of hollow mesoporous Prussian blue nano particles (HPBs) and a photosensitizer indocyanine green (ICG), and is modified by Hyaluronic Acid (HA); by utilizing the function of HA on phenotypic transformation of tumor-associated macrophages (TAM), the TAM phenotype is transformed from M2 type assisting in malignant transformation of tumors to M1 type with a tumor killing and inhibiting function, and the tumor precise multi-mechanism treatment with photothermal and photodynamic self-oxygenation functions under the dual-mode imaging mediation of ultrasonic imaging and photoacoustic imaging is constructed.
HA is chemically modified on the surface of HPBs; HA is connected to the surface of HPBs to block the mesoporous structure of the HPBs, and after the HA reaches a tumor part, the HA is decomposed and removed by the acidic environment of the tumor part and HA enzyme, ICG is released, and a gating effect is realized. The release of the medicine before reaching the tumor target action part is reduced, the fixed-point delivery of the medicine is realized, and the curative effect of the medicine is improved to the maximum extent. Finally, the aims of improving the dispersibility and the biocompatibility, increasing the circulation time of a medicine carrying system in vivo, improving the targeting capability to the tumor and realizing the fixed-point aggregation and release of the medicine are achieved.
The invention utilizes low molecular weight HA to convert TAM phenotype from M2 type assisting malignant transformation of tumor to M1 type with tumor killing and inhibiting functions, and M1 macrophage releases a large amount of H2O2Not only has the function of killing tumors, but also releases a large amount of O in the acidic environment of tumor ischemia and hypoxia after reacting with HPBs containing catalase activity2Can be used for relieving tumor hypoxia state and neutralizing H+Improves the acidic environment of the tumor and enhances the self-oxygen-generating photodynamic treatment effect. Meanwhile, the HPBs accumulated at the tumor part can obviously enhance the functions of nuclear magnetic imaging and photoacoustic imaging, and the diagnosis and treatment of the tumor under the dual-mode mediation are integrated.
The invention utilizes the characteristic that tumor-related macrophages are enriched in tumor ischemia hypoxic regions to synthesize and target-deliver multifunctional HA modified mesoporous Prussian blue nanoparticles (HA-HPBs) to the tumor ischemia hypoxic regions, utilizes the function of hyaluronic acid to phenotypically convert TAM, so that the TAM phenotype is converted from M2 type which assists malignant transformation of tumor to M1 type with tumor killing and inhibiting functions, and the macrophages converted into M1 type release a large amount of H2O2 which not only HAs killing effect on tumor, but also release a large amount of O2 when the acidic environment of tumor ischemia hypoxic and the HPBs containing catalase activity react, so that the acidic environment of tumor is improved by neutralizing H + while the tumor hypoxia state is relieved, and the self-generating oxygen photodynamic treatment effect is enhanced. Meanwhile, the functions of photoacoustic imaging and photothermal therapy of HPBs and the photothermal and photodynamic effects of ICG are utilized to realize the accurate multi-mechanism tumor diagnosis and treatment under the mediation of dual-mode imaging (photoacoustic imaging and nuclear magnetic resonance imaging).
The HA-HPBs are self-oxygen-generating drug-loading systems and can be used for injection, oral administration or implantation administration. Wherein the injection is preferably injection or lyophilized powder for injection, the oral administration is preferably selected from tablet, capsule, pill, syrup, and granule, and the implantation is preferably selected from gel and solution.
The HA-HPBs self-oxygen-generating drug-carrying system can be used for targeted drug delivery of tumor parts, tumor PH response type drug release, dual-mode imaging-mediated tumor chemotherapy and precise multi-mechanism treatment of self-oxygen-generating photodynamic therapy.
The invention relates to a hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle self-generating oxygen photodynamic therapy system. The method is characterized in that multifunctional mesoporous Prussian blue nanoparticles (HPBs) are synthesized by a hydrothermal coprecipitation method, the material is used as a matrix (large in specific surface area, large in capacity, uniform in particle size, and HAs nuclear magnetic imaging and photoacoustic imaging functions), a photosensitizer indolizine green (ICG) is used as a drug model, and low-molecular-weight Hyaluronic Acid (HA) molecules (immune activator) are connected through chemical bonds, so that the tumor targeting and the gating effect of drug release are realized. The system can convert tumor-associated macrophage phenotype from M2 type for assisting tumor malignant transformation into M1 type with tumor killing and inhibiting functions, and generate a large amount of H2O2Reacting with HPBs with catalase activity in tumor hypoxia environment to release a large amount of O2And the photodynamic treatment effect is enhanced while the tumor hypoxia state is relieved. And nuclear magnetic imaging and photoacoustic imaging diagnosis are carried out simultaneously, so that the aim of accurate multi-mechanism tumor treatment with photothermal and photodynamic self-oxygen generation functions under the dual-mode imaging mediation is fulfilled.
The invention obtains consistent results through repeated experiments, and the related experimental data are as follows
Experiment 1: preparation of hyaluronic acid modified Prussian blue nano-particles (HA-HPBs) drug-carrying system
(1) Synthesis of mesoporous prussian blue nanoparticles (HPBs): 3.0g of polyvinylpyrrolidone K30 (PVP) and 132mg of potassium ferricyanide (K)3[Fe(CN)6]) Dissolved in 40ml of 0.01M hydrochloric acid, magnetically stirred to form a transparent solution, and then placed in an electric furnace for reaction at 80 ℃ for 24 hours. Centrifuging (12000 rpm, 30 min), washing with distilled water for 3 times, and vacuum drying at 80 deg.C for 24 hr to obtain Prussian blue nanoparticles (PBs). 1mg of PBs was weighed and dissolved in 1ml of 1M hydrochloric acid solution, 5mg of PVP was added to the solution under magnetic stirring, and after three hours of magnetic stirring, the solution was placed in an autoclave and reacted for 4 hours in an electric furnace at 140 ℃. Centrifuging (12000 rpm, 10 min), washing with distilled water for 3 times, and freeze-drying to obtain HPBs.
(2) Synthesis of HA-HPBs: precisely weighing 5mgHPBs, adding 20ml of ultrapure water, performing ultrafiltration to uniformly disperse the HPBs, adding 5mgPEI under magnetic stirring, continuing stirring for 24h, dialyzing, and freeze-drying to obtain PEI modified HPBs (HPBs-PEI). 45mg of HPBs-PEI was precisely weighed in a 100ml flask, 50ml of formamide was added thereto, and dissolved by shaking under ultrasonic waves. 346mgEDC and 206mgNHS are weighed into a penicillin bottle respectively, and are dissolved by adding 4ml of formamide respectively. EDC and NHS were added to the HPBs-PEI formamide solution, stirred in a beaker and reacted overnight at room temperature. Precisely weighing 50mg of HA in a penicillin bottle, adding 10ml of formamide for dissolving, then adding 180 mu l of triethylamine, sealing by using a sealing film, slowly dropwise adding the mixture into activated HPBs-PEI by using a rubber head dropper, and stirring and reacting for 24 hours at room temperature. And after the reaction is stopped, adding 3-4 times of precooled acetone into the reaction solution, cooling in an ice bath, crystallizing, filtering with oil (filtering with a 0.22 mu m microporous filter membrane), and washing the product with acetone for 3-5 times. Dissolving the precipitate with 3-4ml of ultrapure water, dialyzing (MWCO =3kDa) for 48h, changing the solution every 8h, removing formamide and redundant HA, freeze-drying to obtain HA-HPBs, and storing in a refrigerator at 4 ℃ for later use.
The prepared HPBs have uniform particle size, the average particle size is within the range of 100-300 nm, and the potential is-24.4 mv; HA-modified HA-HPBs (hydroxyapatite) have uniform particle size, average particle size of about 150nm, good dispersibility and potential of-17.6 mv.
Experiment 2: preparation of HA-HPBs loaded with ICG:
10mg of HA-HPBs were weighed, added to 10ml of ultrapure water, and subjected to 250W probing for 10min to disperse uniformly in water for use. Then weighing 10mg of ICG and dissolving in ultrapure water to obtain ICG mother liquor, slowly dripping the ICG mother liquor into the HA-HPBs solution under the action of 400W ultrasound and ice water bath, continuing to perform ultrasound for 0.5h after dripping is finished, enabling the ICG to fully diffuse into mesoporous channels and hollow structures of the HA-HPBs under the condition of violent movement, then performing ultrasound (300W, 10 times and 6s each time) on the solution probe, centrifuging (7500 r/min, 5 min), dialyzing to remove free drugs, freeze-drying for 48h to obtain the ICG-loaded HA-HPBs (HA-HPBs/ICG), and storing in dark at 4 ℃ for later use.
Experiment 3: controlled drug release of HA-HPBs/ICG in acidic environment
HA-HPBs/ICG were placed in dialysis bags (MW =3500Da cut-off), immersed in phosphate PBS buffers of different pH values (7.4: mock normal body fluid, 5.5: mock tumor tissue and 4.0: mock lysosome) and PBS buffers of different concentrations of HA enzyme (1. mu.g/ml and 10. mu.g/ml), shaken at 37 ℃ at intervals, fractions were removed, ICG was measured by UV method, concentration was measured and release rate was calculated. The result shows that the preparation HAs obvious acidity sensitivity and HA enzyme sensitivity when releasing the medicine, and the medicine releasing speed is as follows: pH4.0> pH5.5> pH7.4, HA enzyme 10 μ g/ml >1 μ g/ml.
Experiment 4: HA-HPBs induce the transformation of M2 phenotype macrophages into M1 phenotype macrophages
Under in vitro culture conditions, RAW264.7 macrophages are respectively induced into M1 type macrophages and M2 type macrophages by reference to a classical method with LPS at the concentration of 1000ng/ml and IL-4 at the concentration of 40ng/ml, and then the conversion amount of the M2 type macrophages to M1 type macrophages is induced by the HA-HPBs through the difference of M1 type macrophage surface receptors and M2 type macrophages (M1 type macrophages: CD86/PE, M2 type macrophages: CD 206/FITC) after 200 mug/ml HA, 100 mug/ml HPBs are respectively acted on the M2 type macrophages for 1h and 3 h. The results show that the conversion effect is: HA > HA-PB > PB, conversion time: 3h >1 h.
Experiment 5: determination of antitumor Activity of HA-HPBs/ICG drug-loaded System
In vitro antitumor activity (mouse breast cancer cell line 4T-1 is taken as a research object): time effect: the cells were treated once with HA-HPBs/ICG + M2 and HA-HPBs/ICG, respectively, and their inhibition of tumor cell growth was examined at different time points (SRB or other measurements); dose effect: cells were treated with different doses of HA-HPBs/ICG + M2, HA-HPBs/ICG and examined for inhibition of tumor cell growth (SRB or other assay).
Different experimental groups are set for the above experiments: HA-HPBs, HA-HPBs + M1, HA-HPBs + M2, M1, M2, ICG +808nm laser, HA-HPBs/ICG + M1, HA-HPBs/ICG + M2, HA-HPBs/ICG + M1+808nm laser, HA-HPBs/ICG + M2+808nm laser, etc. The result shows that the inhibition effect of HA-HPBs/ICG + M2+808nm laser on cells HAs obvious time dependence and concentration dependence, and compared with HA-HPBs, HA-HPBs + M2 can obviously inhibit the proliferation of 4T1 tumor cells;
in vivo antitumor activity: 4T-1 cells were inoculated subcutaneously into the flank of nude mice, tumor growth was monitored every other day, and the general condition of nude mice was recorded. When the tumor volume reaches 100-300 mm3At that time, animals were randomly grouped and treatment (intravenous injection) was started- ① saline group, ② HPBs group, ③ HA-HPBs group, ④ HPBs +808nm laser group, ⑤ HA-HPBs +808nm laser group, ⑥ ICG +808nm laser group, ⑦ HPBs/ICG +808nm laser group ⑧ HA-HPBs/ICG +808nm laser group-tumor volume was continuously monitored until animals were sacrificed until the seventh week.
The test results show that compared with other groups, the HA-HPBs/ICG +808nm laser group achieves obvious tumor inhibition effect in vivo and the relative tumor proliferation rate is minimum.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the administration system can make TAM phenotype transformed from M2 type which is auxiliary for malignant transformation of tumorTransforming into M1 type with tumor killing and inhibiting effects, and generating large amount of H2O2Reacting with HPBs with catalase activity in tumor hypoxia environment to release a large amount of O2Can be used for relieving tumor hypoxia state and neutralizing H+The acidic environment of the tumor is improved, the oxygen required by the laser-induced ICG to generate active oxygen is efficiently supplemented, and the self-oxygen-generating photodynamic treatment effect is enhanced;
(2) the carrier has the functions of gated drug release and active targeting; the HA is low molecular weight HA with the molecular weight of 6276 kd;
(3) the HPBs generated at the tumor part can be used for nuclear magnetic resonance imaging and photoacoustic imaging, so that the diagnosis and treatment of the tumor are integrated.
Claims (7)
1. A preparation method of a Prussian blue nanoparticle drug-loading system modified by hollow mesoporous gated hyaluronic acid is characterized in that the hyaluronic acid and Prussian blue nanoparticles are connected through a chemical bond to form a nano layer in an aqueous medium, and a photosensitizer indocyanine green enters a Prussian blue mesoporous structure through a physical effect;
the preparation method comprises the following steps:
(1) synthesizing mesoporous Prussian blue nanoparticles: dissolving 1-50g of polyvinylpyrrolidone K30 and 10-200mg of potassium ferricyanide in 30-50ml of hydrochloric acid with the mass concentration of 0.01-0.1M, magnetically stirring the solution into a transparent solution, reacting at 70-90 ℃ for 20-30h, centrifuging at 10000-;
(2) synthesis of hyaluronic acid modified prussian blue nanoparticles: taking 1-5mg mesoporous Prussian blue nanoparticles, adding 5-20ml of ultrapure water, performing ultrafiltration to uniformly disperse the mesoporous Prussian blue nanoparticles, adding 0.1-5mg of polyetherimide under magnetic stirring, continuing stirring for 20-30h, dialyzing, and freeze-drying to obtain polyetherimide modified mesoporous Prussian blue nanoparticles; taking 10-100mg of polyetherimide modified mesoporous Prussian blue nanoparticles, adding 40-60ml of formamide, and dissolving by ultrasonic oscillation to obtain polyetherimide modified mesoporous Prussian blue nanoparticle solution; respectively adding 300-400mg of N-hydroxysuccinimide and 180-250mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride into 3-5ml of formamide for dissolving, adding into the polyetherimide modified mesoporous Prussian blue nanoparticle solution, stirring, and reacting at room temperature for 8-12 h; dissolving 10-100mg of hyaluronic acid in 8-12ml of formamide, adding 150-200 mul of triethylamine, slowly dropwise adding into the polyetherimide modified mesoporous Prussian blue nanoparticle solution, stirring at room temperature for reaction for 20-30h, adding precooled acetone with the volume of 3-4 times of the reaction liquid, cooling in an ice bath, crystallizing, filtering with 0.22 mu m of oil film oil, washing for 3-5 times with acetone, dissolving with 3-4ml of ultrapure water, dialyzing in a dialysis bag with the molecular weight cutoff MWCO =3kDa for 2-3 days, sucking out the dialyzate and freeze-drying to obtain the hyaluronic acid modified Prussian blue nanoparticles;
(3) synthesizing indocyanine green-loaded hyaluronic acid-modified prussian blue nanoparticles: adding 5-20mg of hyaluronic acid modified Prussian blue nanoparticles serving as a carrier into 2-40ml of deionized water, ultrasonically dissolving by using a probe, mixing with 1-5ml of photosensitizer indocyanine green water solution with the mass concentration of 2mg/ml, ultrasonically treating for 25-35min, stirring at room temperature, putting into a dialysis bag with the molecular weight cutoff MWCO =3kDa, dialyzing for 2-3 days, and freeze-drying to obtain the hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug-carrying system.
2. The preparation method of the hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug carrier system according to claim 1, is characterized by comprising the following steps:
(1) synthesizing mesoporous Prussian blue nanoparticles: dissolving 1g of polyvinylpyrrolidone K30 and 10mg of potassium ferricyanide in 30ml of hydrochloric acid with the mass concentration of 0.01M, magnetically stirring to form a transparent solution, reacting at 70 ℃ for 30h, centrifuging at 10000rpm for 12min, washing with distilled water for 2 times, drying at 70 ℃ to obtain Prussian blue nanoparticles, dissolving 0.1mg of Prussian blue nanoparticles in 0.5ml of hydrochloric acid solution with the mass concentration of 1M, adding 0.1mg of polyvinylpyrrolidone under magnetic stirring, magnetically stirring for 2h, reacting at 130 ℃ for 5h, centrifuging at 10000rpm for 12min, washing with distilled water for 2 times, and freeze-drying to obtain mesoporous Prussian blue nanoparticles;
(2) synthesis of hyaluronic acid modified prussian blue nanoparticles: taking 1mg mesoporous Prussian blue nanoparticles, adding 5ml of ultrapure water, carrying out ultrafiltration to uniformly disperse the mesoporous Prussian blue nanoparticles, adding 0.1mg of polyetherimide under magnetic stirring, continuing stirring for 20 hours, dialyzing, and carrying out freeze drying to obtain polyetherimide modified mesoporous Prussian blue nanoparticles; taking 10mg of polyetherimide modified mesoporous Prussian blue nanoparticles, adding 40ml of formamide, and dissolving by ultrasonic oscillation to obtain polyetherimide modified mesoporous Prussian blue nanoparticle solution; respectively adding 3ml of formamide into 300mg of N-hydroxysuccinimide and 180mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to dissolve, adding the dissolved formamide into the polyetherimide modified mesoporous Prussian blue nanoparticle solution, stirring, and reacting at room temperature for 12 hours; dissolving 10mg of hyaluronic acid in 8ml of formamide, adding 150 mul of triethylamine, slowly dropwise adding the dissolved hyaluronic acid into the polyetherimide modified mesoporous Prussian blue nanoparticle solution, stirring and reacting for 20 hours at room temperature, adding precooled acetone with the volume of 3 times of the reaction solution, cooling in an ice bath, crystallizing, filtering with 0.22 mu m of oil film oil, washing with 3 times of acetone, dissolving with 3ml of ultrapure water, dialyzing in a dialysis bag with the molecular weight cutoff MWCO =3kDa for 2 days, sucking out the dialyzate and freeze-drying to obtain the hyaluronic acid modified Prussian blue nanoparticles;
(3) synthesizing indocyanine green-loaded hyaluronic acid-modified prussian blue nanoparticles: adding 5mg of hyaluronic acid modified Prussian blue nanoparticles serving as a carrier into 2ml of deionized water, ultrasonically dissolving by using a probe, mixing with 1ml of photosensitizer indocyanine green water solution with the mass concentration of 2mg/ml, ultrasonically treating for 25min, stirring at room temperature, then putting into a dialysis bag with the molecular weight cutoff MWCO =3kDa for dialysis for 2 days, and freeze-drying to obtain the hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug-carrying system.
3. The preparation method of the hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug carrier system according to claim 1, is characterized by comprising the following steps:
(1) synthesizing mesoporous Prussian blue nanoparticles: dissolving 30g of polyvinylpyrrolidone K30 and 132mg of potassium ferricyanide in 40ml of hydrochloric acid with the mass concentration of 0.05M, magnetically stirring the solution into a transparent solution, reacting at 80 ℃ for 24 hours, centrifuging at 12000rpm for 10 minutes, washing with distilled water for 3 times, drying at 80 ℃ to obtain Prussian blue nanoparticles, dissolving 1.0mg of Prussian blue nanoparticles in 1.0ml of hydrochloric acid solution with the mass concentration of 1.0M, adding 5mg of polyvinylpyrrolidone under magnetic stirring, magnetically stirring for 3 hours, reacting at 140 ℃ for 4 hours, centrifuging at 12000rpm for 10 minutes, washing with distilled water for 3 times, and freeze-drying to obtain mesoporous Prussian blue nanoparticles;
(2) synthesis of hyaluronic acid modified prussian blue nanoparticles: taking 3mg mesoporous Prussian blue nanoparticles, adding 10ml of ultrapure water, carrying out ultrafiltration to uniformly disperse the mesoporous Prussian blue nanoparticles, adding 3mg of polyetherimide under magnetic stirring, continuing stirring for 24 hours, dialyzing, and carrying out freeze drying to obtain polyetherimide modified mesoporous Prussian blue nanoparticles; taking 45mg of polyetherimide modified mesoporous Prussian blue nanoparticles, adding 50ml of formamide, and dissolving by ultrasonic oscillation to obtain polyetherimide modified mesoporous Prussian blue nanoparticle solution; respectively adding 346mg of N-hydroxysuccinimide and 206mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride into 4ml of formamide for dissolving, adding the formamide solution into the polyetherimide modified mesoporous Prussian blue nanoparticle solution, stirring, and reacting at room temperature for 10 hours; dissolving 50mg of hyaluronic acid in 10ml of formamide, adding 180 mul of triethylamine, slowly dropwise adding the dissolved hyaluronic acid into the polyetherimide modified mesoporous Prussian blue nanoparticle solution, stirring and reacting for 24 hours at room temperature, adding precooled acetone with 4 times volume of reaction liquid, cooling in an ice bath, crystallizing, filtering with 0.22 mu m of oil film oil, washing with acetone for 4 times, dissolving with 3ml of ultrapure water, dialyzing in a dialysis bag with MWCO =3kDa for 2 days, sucking out dialysate and freeze-drying to obtain the hyaluronic acid modified Prussian blue nanoparticles;
(3) synthesizing indocyanine green-loaded hyaluronic acid-modified prussian blue nanoparticles: adding 10mg of hyaluronic acid modified Prussian blue nanoparticles serving as a carrier into 10ml of deionized water, ultrasonically dissolving by using a probe, mixing with 3ml of photosensitizer indocyanine green water solution with the mass concentration of 2mg/ml, ultrasonically treating for 30min, stirring at room temperature, then putting into a dialysis bag with the molecular weight cutoff MWCO =3kDa for dialysis for 2 days, and freeze-drying to obtain the hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug-carrying system.
4. The preparation method of the hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug carrier system according to claim 1, is characterized by comprising the following steps:
(1) synthesizing mesoporous Prussian blue nanoparticles: dissolving 50g of polyvinylpyrrolidone K30 and 200mg of potassium ferricyanide in 50ml of hydrochloric acid with the mass concentration of 0.1M, magnetically stirring the solution into a transparent solution, reacting at 90 ℃ for 20 hours, centrifuging at 14000rpm for 8 minutes, washing with distilled water for 3 times, drying at 90 ℃ to obtain Prussian blue nanoparticles, dissolving 10mg of Prussian blue nanoparticles in 1.5ml of hydrochloric acid solution with the mass concentration of 1M, adding 10mg of polyvinylpyrrolidone under magnetic stirring, magnetically stirring for 3 hours, reacting at 150 ℃ for 3 hours, centrifuging at 14000rpm for 8 minutes, washing with distilled water for 3 times, and freeze-drying to obtain mesoporous Prussian blue nanoparticles;
(2) synthesis of hyaluronic acid modified prussian blue nanoparticles: taking 5mg mesoporous Prussian blue nanoparticles, adding 20ml of ultrapure water, carrying out ultrafiltration to uniformly disperse the mesoporous Prussian blue nanoparticles, adding 5mg of polyetherimide under magnetic stirring, continuing stirring for 30h, dialyzing, and carrying out freeze drying to obtain polyetherimide modified mesoporous Prussian blue nanoparticles; taking 100mg of polyetherimide modified mesoporous Prussian blue nanoparticles, adding 60ml of formamide, and dissolving by ultrasonic oscillation to obtain polyetherimide modified mesoporous Prussian blue nanoparticle solution; respectively adding 400mg of N-hydroxysuccinimide and 250mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride into 5ml of formamide for dissolving, adding the formamide solution into the polyetherimide modified mesoporous Prussian blue nanoparticle solution, stirring, and reacting at room temperature for 12 hours; dissolving 100mg of hyaluronic acid in 12ml of formamide, adding 200 mul of triethylamine, slowly dropwise adding the dissolved hyaluronic acid into a polyetherimide modified mesoporous Prussian blue nanoparticle solution, stirring and reacting for 30 hours at room temperature, adding precooled acetone with 4 times volume of reaction liquid, cooling in an ice bath, crystallizing, filtering with 0.22 mu m of oil film oil, washing for 5 times with acetone, dissolving in 4ml of ultrapure water, dialyzing in a dialysis bag with MWCO =3kDa for 3 days, sucking out dialysate and freeze-drying to obtain hyaluronic acid modified Prussian blue nanoparticles;
(3) synthesizing indocyanine green-loaded hyaluronic acid-modified prussian blue nanoparticles: adding 20mg of hyaluronic acid modified Prussian blue nanoparticles serving as a carrier into 40ml of deionized water, ultrasonically dissolving by using a probe, mixing with 5ml of photosensitizer indocyanine green water solution with the mass concentration of 2mg/ml, ultrasonically treating for 35min, stirring at room temperature, then putting into a dialysis bag with the molecular weight cutoff MWCO =3kDa for dialysis for 3 days, and freeze-drying to obtain the hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug-carrying system.
5. The method for preparing the prussian blue nanoparticle drug-carrying system modified by the hollow mesoporous gated hyaluronic acid as claimed in claim 1, wherein the particle size of the prussian blue nanoparticle drug-carrying system modified by the hollow mesoporous gated hyaluronic acid is 150-300 nm.
6. The application of the hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug carrier system prepared by the method of any one of claims 1 or 2-4 in preparing antitumor drugs.
7. The use of the hollow mesoporous gated hyaluronic acid modified Prussian blue nanoparticle drug-loaded system prepared by the method of any one of claims 1 or 2-4 in the preparation of nuclear magnetic imaging agents and photoacoustic imaging agents.
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