CN112245580A - Targeted oxygen-carrying nano enzyme preparation and preparation method thereof - Google Patents
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Images
Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
- A61K41/0033—Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K9/5169—Proteins, e.g. albumin, gelatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a targeting oxygen-carrying nano enzyme preparation and a preparation method thereof. The targeting oxygen-carrying nano enzyme preparation structurally takes hybrid targeting protein Human Serum Albumin (HSA) and enzyme preparation (collagenase or hyaluronidase) as carriers, and loads synthesized ferrous porphyrin Fe (II) TP enhanced sonosensitive molecules as oxygen donors. The targeted oxygen-carrying nano enzyme preparation is prepared by an alcohol compression method, can be used for preparing a large amount of targeted oxygen-carrying nano enzyme preparations at one time, and is a preparation method with simple preparation process, uniform product particle size and stable property.
Description
Technical Field
The invention relates to the field of nano medicine, in particular to a targeted oxygen-carrying nano enzyme preparation and a preparation method thereof.
Background
The tumor extracellular matrix (ECM) is composed of cross-linked fibrin (elastin, collagen, thin-layer protein, and fibronectin), associated large glycoproteins, and proteoglycans (hyaluronic acid, chondroitin sulfate, and keratin sulfate), which promote the growth and progression of tumors. ECM, an important component of the Tumor Microenvironment (TME), is highly correlated with the hypoxia of TME, together leading to therapeutic resistance of the Tumor. Hypoxia increases the expression of collagen and collagen modifying enzymes, promotes ECM remodeling, and thus tumor cell metastasis. On the other hand, because of the high Interstitial Flow Pressure (IFP) inside tumors, collagen-containing ECM acts as a natural barrier, preventing the effective diffusion of therapeutic agents and oxygen into large solid tumors. Thus, the outcome of many types of cancer treatment can be limited due to blockage of the coagulated tumor ECM.
It has been proposed that the structure of the ECM can be controlled to modulate the characteristics of the TME to achieve different types of anti-tumor therapy. Since ECM is highly sensitive to the action of proteases, the major components of ECM can be selectively degraded to increase the diffusion of nano-therapeutic drugs and enhance the therapeutic effect. However, when these enzymes are applied locally to tumors, the clinical value of injecting exogenous enzymes is not significant because of the side effects of limited tumor uptake, potential immunogenicity, etc. Therefore, the development of intelligent nanocarriers for the delivery and tumor-specific release of ECM lytic enzymes is an attractive approach to tumor microenvironment regulation and enhanced cancer therapy.
Ferrous complexes derived from "picket fence" porphyrins, such as ferrous porphyrin Fe (II) TP, can simulate the combination of oxygen-carrying hemoglobin and oxygen to form reversible oxygen adducts, but such ferrous porphyrins are usually rapidly irreversibly oxidized to oxygen-bridged dimers (L-Fe III-O)2-Fe iii-L) and thereby deprives the oxygen-carrying function, whereas hypoxia promotes the restructuring of the tumor extracellular matrix and thereby promotes tumor cell metastasis.
It has been reported that Human Serum Albumin (HSA) nanoparticles have tumor-specific targeting function, and efficiently target tumors through gp60 glycoprotein receptor-mediated tumor endothelial cell penetration effect and tumor cell secretory protein SPARC-mediated enhanced uptake mechanism. However, the pure HSA nanoparticles cannot penetrate the natural barrier of the tumor extracellular matrix, which results in poor effect of the nano-therapeutic drugs.
In conclusion, the prior art lacks of nanoparticles which can destroy tumor extracellular matrix and have high-efficiency oxygen carrying function to transfer oxygen into a tumor microenvironment.
In addition, the existing targeted oxygen-carrying nanoparticles have complex preparation process, the prepared nanoparticles have nonuniform particle size and unstable properties, and the nanoparticles with large volume cannot be prepared. Liposome-based oxygen-carrying microbubbles, the hollow structure of which is filled with oxygen; the outer layer is formed by wrapping oxygen gas with a phospholipid monomolecular layer to form microbubbles, and the targeted oxygen-carrying nanoparticles have a complex preparation process and can only be stored for 2 weeks. The industry needs a preparation method with simple preparation process, uniform product particle size and stable property.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a targeting oxygen-carrying nano enzyme preparation which can simultaneously destroy tumor extracellular matrix and has a high-efficiency oxygen-carrying function and a preparation method thereof. The targeted oxygen-carrying nano enzyme preparation structurally takes hybrid targeted protein Human Serum Albumin (HSA) and an enzyme preparation as carriers, the enzyme preparation is collagenase or hyaluronidase, and synthesized Fe (II) TP enhanced sonosensitive molecules are loaded to serve as oxygen donors. The targeted oxygen-carrying nano enzyme preparation is prepared by an alcohol compression method. The one-step alcohol compression method can prepare a large amount of targeted oxygen-carrying nano-enzyme preparations at one time, and is a preparation method with simple preparation process, uniform product particle size and stable property.
The invention provides a targeted oxygen-carrying nano enzyme preparation, which takes hybridized human serum albumin and enzyme preparation as carriers and internally wraps ferriporphyrin.
Further, the enzyme preparation is collagenase or hyaluronidase.
The invention provides a preparation method of a targeted oxygen-carrying nano enzyme preparation, which comprises the following steps:
(1) preparing ferriporphyrin;
(2) preparing reduced human serum albumin;
(3) mixing reduced human serum albumin and an enzyme preparation in water, and adjusting the pH value of the solution;
(4) taking reduced ferriporphyrin, stirring in water, and adding into the step (3);
(5) adding alcohol solution, stirring, and dialyzing;
(6) and (5) concentrating.
Further, the ferriporphyrin in the step (1) is prepared by reacting ferriporphyrin and ascorbic acid at room temperature under the protection of argon or nitrogen.
Further, the reduced human serum albumin in the step (2) is specifically prepared by dissolving human serum albumin and reduced glutathione in water, reacting in a shaking table at room temperature, and then placing in a dialysis bag for dialysis.
Further, the molar ratio of the human serum albumin to the reduced glutathione is 1-5: 1. this ratio will affect the particle size of the targeted oxygen-carrying nanoenzyme formulation.
Further, the pH value in the step (3) is 7-8. The pH value directly influences the particle size of the oxygen-carrying nano enzyme preparation, and the particle size directly determines the enrichment amount of the oxygen-carrying nano enzyme preparation at tumor parts.
Further, the enzyme preparation in the step (3) is collagenase or hyaluronidase.
Further, in the step (5), the alcohol solution is methanol or ethanol. After adding the alcohol solution, vigorously stirring, and dialyzing with a dialysis bag.
Further, the adding amount of the alcohol solution in the step (5) is 1-3 times of the volume of the solution obtained in the step (4). The addition amount of the alcoholic solution directly influences the particle size of the oxygen-carrying nano-enzyme preparation.
The invention also provides application of the targeted oxygen-carrying nano enzyme preparation in preparation of antitumor drugs.
In summary, compared with the prior art, the invention achieves the following technical effects:
1. the targeted oxygen-carrying nano enzyme preparation can effectively realize tumor penetration, and the effect is realized by supported collagenase or hyaluronidase.
2. The ferriporphyrin provided by the invention has an oxygen carrying function, can input oxygen into a tumor microenvironment, has the effect of a sound-sensitive agent, and can be used for sonodynamic therapy.
3. The method can prepare large-volume targeted oxygen-carrying nano enzyme preparation, can prepare more than several liters of nano enzyme preparation, and has the volume of at most hundreds of milliliters prepared by the prior art, so the method provides a foundation for the amplified production and clinical research of nano particles.
4. The nano enzyme preparation prepared by the method can be stably stored, and does not have the phenomena of sedimentation and flocculation in one year, while the nano particles prepared by the preparation method in the prior art can be stored for more than two months at most.
5. The preparation method is simple and easy to implement, the components are added step by step under stirring to obtain the uniform nano enzyme preparation, no high-temperature and complex equipment or harsh reaction conditions are needed, and the preparation method is convenient to operate and popularize.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a transmission electron micrograph of the targeted oxygen-carrying nanoenzyme preparation of example 4.
FIG. 2 is the oxygen release profile of the targeted oxygen-carrying nanoenzyme preparation of example 4.
FIG. 3 is a graph showing the results of the efficient cleavage of tumor stroma by the targeted oxygenase preparation of example 5.
FIG. 4 is a graph showing the results of the highly effective improvement of tumor hypoxia by the targeted oxygen-carrying nanoenzyme preparation in example 6.
Detailed Description
In order to make the technical solutions of the present invention better understood, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, shall fall within the scope of protection of the present invention.
The principle that the targeted oxygen-carrying nano enzyme preparation improves the tumor hypoxia microenvironment and improves the acoustic dynamic curative effect is as follows:
mixing ferriporphyrin Fe (II) TP and Human Serum Albumin (HSA) solution to obtain HSA-Fe (II) TP and binding constant (k) of oxygen moleculeon) And dissociation constant (k)off) The oxygen content of the tumor is increased, and oxygen transferring and storing effects are achieved.
HAS (human serum albumin) nanoparticles have a tumor specific targeting function, and efficiently target tumors through a tumor endothelial cell penetration effect mediated by gp60 glycoprotein receptor and an enhanced uptake mechanism mediated by tumor cell secretory protein SPARC. The targeted oxygen-carrying nano enzyme preparation not only retains the tumor targeting property of HSA, but also has the function of destroying tumor extracellular matrix by collagenase (or hyaluronidase), can deliver collagenase or hyaluronidase to a tumor part in a targeted manner, has reducibility in a tumor microenvironment, releases collagenase or hyaluronidase so as to decompose tumor extracellular matrix, effectively diffuses oxygen or other therapeutic agents stored on ferriporphyrin into a large solid tumor, improves the tumor hypoxia microenvironment and improves the acoustodynamic curative effect.
The preparation method of the protease hybrid nano enzyme preparation coated with the oxygen-carrying ferriporphyrin comprises the following specific steps:
(1) preparing ferriporphyrin; the ferriporphyrin is prepared by reacting ferriporphyrin and ascorbic acid at room temperature under the protection of argon or nitrogen.
(2) Preparing reduced human serum albumin; the reduced human serum albumin is specifically prepared by dissolving human serum albumin and reduced glutathione in water, reacting in a shaking table at room temperature, and dialyzing in a dialysis bag.
(3) Mixing reduced human serum albumin and enzyme preparation in water, adjusting pH value of the solution to 7-8, wherein the enzyme preparation is collagenase or hyaluronidase.
(4) Taking reduced ferriporphyrin, stirring in water, and adding into the mixture obtained in the step (3).
(5) Adding methanol or ethanol solution, stirring vigorously, and dialyzing with dialysis bag. The addition amount of the methanol or ethanol solution is 1-3 times of the volume of the solution obtained in the step (4).
(6) Concentrating with ultrafiltration tube.
The method realizes the disconnection-reconstruction of the disulfide bond in two steps, and realizes the disconnection of the disulfide bond when reducing glutathione is added to reduce HSA; when compression is performed with the addition of methanol or ethanol, the reconstitution of the disulfide bonds (SH-HSA and SH-collagenase (or SH-hyaluronidase)) is achieved.
EXAMPLE 1 preparation of ferrous porphyrin
The preparation method comprises the following steps: mixing porphyrin (purchased from Sigma-Aldrich, CAS: 69458-20-4) and metal ferrous salt in equal molar ratio in an anhydrous DMF solution, carrying out ferrous ion coordination under the protection of argon, monitoring the reaction progress by an UV-Vis absorption spectrometer, stopping the reaction after the reaction solution changes from yellow to dark red and the Q band peak changes from 4 to 2 with a certain degree of red shift, cooling to room temperature, placing in an ice water bath, and keeping out of the sun overnight; the collected filter cake was washed with deionized water and dried under vacuum. And then separating and purifying by column chromatography, taking silica gel as a stationary phase, wherein the volume ratio is 3: 1, taking dichloromethane and methanol as mobile phases for separation and purification. And (3) performing low-temperature rotary evaporation and drying to obtain a purified ferriporphyrin (Fe (II) TP) sample. Redissolving the purified ferriporphyrin in Dimethylformamide (DMF), adding a small amount of Ascorbic Acid (AA), and stirring at room temperature for 5h under the protection of argon to obtain deoxyferriporphyrin (Deoxy-Fe (II) TP). Then the gas in the reaction bottle is replaced by oxygen, and the stirring is continued for 30min to obtain oxygenated ferriporphyrin (Oxy-Fe (II) TP).
Example 2 preparation of Targeted oxygen-carrying Nanolase formulations
The method specifically comprises the following steps:
(1) dissolving ferriporphyrin in DMSO at the concentration of 5mg/mL, dissolving ascorbic acid as a reducing agent in DMSO at the concentration of 2.5mg/mL, and reacting at room temperature for 5h under the protection of argon to obtain ferriporphyrin (Fe (II) TP) for later use;
(2) human serum albumin and reduced glutathione were mixed at a ratio of 1: dissolving 1 mol ratio in 2mL deionized water, reacting in a shaking table at room temperature for 30min at the speed of 100rpm, placing in a dialysis bag of 3.5KDa after the reaction is finished, and dialyzing overnight to obtain reduced human serum albumin (SH-HSA) for later use;
(3) 100mg reduced human serum albumin and 10mg collagenase were weighed into 10mL deionized water and added with NaHCO3Adjusting the pH value of the solution to 7;
(4) transferring 1mL of reduced Fe (II) TP, dispersing in 1mL of deionized water, stirring at room temperature, and adding into the solution obtained in the step (3);
(5) quickly adding 1 volume of alcohol solution, stirring vigorously for 30min, and dialyzing overnight with 3.5KDa dialysis bag;
(6) concentrating with 50mL 100KDa ultrafiltration tube to obtain 50-100mL 20-150nm targeting oxygen-carrying nano-enzyme preparation.
The zeta potential of the targeted oxygen-carrying nano-enzyme preparation detected by a particle size analyzer is larger than-30 mV, the particle size range is 20-150nm, and the results of the potential and the particle size can indicate that the targeted oxygen-carrying nano-enzyme preparation is successfully prepared. However, the particle size range of the targeted oxygen-carrying nano enzyme preparation is slightly larger, and the particle size uniformity is not high. This is related to the ratio of human serum albumin to reduced glutathione, the pH of the solution, and the volume of alcohol solution added.
EXAMPLE 3 preparation of Targeted oxygen-Carrier nanoenzyme formulations
In this example, the ratio of human serum albumin and reduced glutathione, the pH value of the system, and the volume of the added alcohol solution are different from those in example 2, the pH value directly affects the particle size of the oxygen-carrying nanoenzyme preparation, and the particle size directly determines the enrichment amount of the oxygen-carrying nanoenzyme preparation at the tumor site. The addition amount of the methanol or ethanol solution directly influences the particle size of the oxygen-carrying nano-enzyme preparation, and the proportion of the human serum albumin and the reduced glutathione also influences the particle size.
The preparation method specifically comprises the following steps:
(1) dissolving ferriporphyrin in DMSO at the concentration of 5mg/mL, dissolving ascorbic acid as a reducing agent in DMSO at the concentration of 2.5mg/mL, and reacting at room temperature for 5h under the protection of argon to obtain ferriporphyrin (Fe (II) TP) for later use;
(2) human serum albumin and reduced glutathione were mixed at 5: dissolving 1 mol ratio in 2mL deionized water, reacting in a shaking table at room temperature for 30min at the speed of 100rpm, placing in a dialysis bag of 3.5KDa after the reaction is finished, and dialyzing overnight to obtain reduced human serum albumin (SH-HSA) for later use;
(3) 100mg reduced human serum albumin and 10mg collagenase were weighed into 10mL deionized water and added with NaHCO3Adjusting the pH value of the solution to 8;
(4) transferring 1mL of reduced Fe (II) TP, dispersing in 1mL of deionized water, stirring at room temperature, and adding into the solution obtained in the step (3);
(5) quickly adding 3 times volume of alcohol solution, stirring vigorously for 30min, and dialyzing overnight with 3.5KDa dialysis bag;
(6) concentrating with 50mL 100KDa ultrafiltration tube to obtain 50-100mL 20-100nm targeting oxygen-carrying nano-enzyme preparation.
The zeta potential of the targeted oxygen-carrying nano enzyme preparation is detected by a particle size analyzer to be more than-30 mV, and the particle size range is 20-100 nm. The results of potential and particle size can indicate that the targeted oxygen-carrying nano-enzyme preparation is successfully prepared. The particle size range of the targeted oxygen-carrying nano enzyme preparation is slightly reduced compared with that of example 2, but the particle size range is still slightly large, and the particle size uniformity is not high, which is related to the proportion of the human serum albumin and the reduced glutathione, the pH value of the system and the volume of the added alcohol solution. The targeting oxygen-carrying nano enzyme preparation with more uniform particle size can be prepared by continuously optimizing the conditions.
Example 4 preparation of Targeted oxygen-Carrier nanoenzyme formulations
In this example, the ratio of human serum albumin and reduced glutathione, the pH value of the system, and the volume of the added alcohol solution are different from those in example 2, the pH value directly affects the particle size of the oxygen-carrying nanoenzyme preparation, and the particle size directly determines the enrichment amount of the oxygen-carrying nanoenzyme preparation at the tumor site. The addition amount of the methanol or ethanol solution directly influences the particle size of the oxygen-carrying nano-enzyme preparation. The ratio of human serum albumin to reduced glutathione will also have an effect on the particle size.
The preparation method specifically comprises the following steps:
(1) dissolving ferriporphyrin in DMSO at the concentration of 5mg/mL, dissolving ascorbic acid as a reducing agent in DMSO at the concentration of 2.5mg/mL, and reacting at room temperature for 5h under the protection of argon to obtain ferriporphyrin (Fe (II) TP) for later use;
(2) human serum albumin and reduced glutathione were mixed at 3: dissolving 1 mol ratio in 2mL deionized water, reacting in a shaking table at room temperature for 30min at the speed of 100rpm, placing in a dialysis bag of 3.5KDa after the reaction is finished, and dialyzing overnight to obtain reduced human serum albumin (SH-HSA) for later use;
(3) 100mg reduced human serum albumin and 10mg collagenase were weighed into 10mL deionized water and added with NaHCO3Adjusting the pH value of the solution to 8;
(4) transferring 1mL of reduced Fe (II) TP, dispersing in 1mL of deionized water, stirring at room temperature, and adding into the solution obtained in the step (3);
(5) quickly adding 1.5 times volume of alcohol solution, stirring vigorously for 30min, and dialyzing overnight with 3.5KDa dialysis bag;
(6) concentrating with 50mL of 100KDa ultrafiltration tube to obtain 50-100mL of 30-60nm oxygen-carrying ferriporphyrin-protease hybrid nano enzyme preparation. The zeta potential of the targeted oxygen-carrying nano-enzyme preparation is detected to be more than-30 mV and the particle size range is 30-60nm by a particle size analyzer, which indicates that the targeted oxygen-carrying nano-enzyme preparation is successfully prepared.
The particle size means that the amount of the supported ferriporphyrin is different, which causes the difference of the oxygen carrying amount, but the particle size directly determines the enrichment amount of the targeted oxygen-carrying nanoenzyme preparation at the tumor site, generally, when the particle size is 30-60nm, the targeted oxygen-carrying nanoenzyme preparation is more easily enriched at the tumor site, fig. 1 is a transmission electron microscope image of the targeted oxygen-carrying nanoenzyme preparation in the embodiment, it can be seen that the shape of the prepared targeted oxygen-carrying nanoenzyme preparation is regular, the particle size is 30-60nm, fig. 2 is the oxygen release condition of the targeted oxygen-carrying nanoenzyme preparation in the embodiment, PBS is a control group only added with phosphate buffer, the oxygen release amount of the targeted oxygen-carrying nanoenzyme preparation experimental group is significantly higher than that of the control group, and the above results show that the targeted oxygen-carrying nanoenzyme preparation prepared by the preparation method of the embodiment is more easily enriched at the tumor site due to the proper particle size, and release oxygen into the tumor microenvironment to ameliorate tumor hypoxia.
In examples 2-4, the prepared oxygen-carrying nanoenzyme preparations varied in particle size, and factors affecting the particle size were: the proportion of human serum albumin and reduced glutathione, the pH value of the system and the adding amount of the alcoholic solution. The invention searches various preparation conditions, and the particles prepared by the embodiment have the advantages of most uniformity, highest oxygen carrying capacity and better targeting accumulation to tumor parts. The preparation conditions and ratios of this example are most preferred. Animal experimental results can also be shown, and are specifically shown in example 5 and example 6.
Example 5 the targeted oxygen-carrying nanoenzyme preparation of the invention can effectively shear tumor stroma
The targeted oxygen-carrying nanoenzyme preparation prepared in example 4 was injected into tumor-bearing mice (which could be purchased directly) via tail vein, after 3 hours, the targeted oxygen-carrying nanoenzyme preparation was enriched in a large amount in tumor sites, the mice were killed, tumors were removed, and fixed with paraformaldehyde at room temperature for 24 hours, and then paraffin was embedded and sliced, and then HE staining and immunohistochemical analysis were performed, with the results shown in fig. 3, PBS being a control group injected with phosphate buffer only, and an experimental group being a group injected with the targeted oxygen-carrying nanoenzyme preparation via tail vein, since the tumor sites were enriched with reductive glutathione, the targeted oxygen-carrying nanoenzyme preparation was cleaved, and collagenase was released to cut dense and continuous fibrous matrix in the tumor into pieces (regions indicated by black arrows), thereby loosening the tumor matrix. Therefore, the targeting oxygen-carrying nano enzyme preparation can effectively shear tumor matrixes, thereby being beneficial to deep penetration and enrichment of the targeting oxygen-carrying nano enzyme preparation.
Example 6 the targeting oxygen-carrying nanoenzyme preparation of the invention can efficiently improve tumor hypoxia
The targeted oxygen-carrying nano-enzyme preparation prepared in the embodiment 4 is injected into a tumor-bearing mouse (which can be purchased directly) through tail vein, after 3 hours, the condition that the tumor hypoxia microenvironment is improved by the targeted oxygen-carrying nano-enzyme preparation is monitored by a lighting small animal photoacoustic imager, and the result is shown in fig. 4, PBS is a control group only injected with phosphate buffer, an experimental group is a group only injected with the targeted oxygen-carrying nano-enzyme preparation, and the result shows that after collagenase released by the targeted oxygen-carrying nano-enzyme preparation under the tumor microenvironment response effectively shears a tumor matrix, oxygen molecules can be effectively carried into the tumor part to form oxygenated hemoglobin, and the photoacoustic signal value is enhanced (white scattering point signals indicated by white arrows in fig. 4), so that the tumor hypoxia is effectively improved. Therefore, the targeted oxygen-carrying nano enzyme preparation can effectively increase the deep penetration and enrichment amount of the tumor with the effective assistance of an enzyme shearing matrix, and the carried oxygen molecules can effectively improve the tumor hypoxia.
In conclusion, the invention provides a targeting oxygen-carrying nano enzyme preparation which can simultaneously destroy tumor extracellular matrix and has a high-efficiency oxygen-carrying function and a preparation method thereof. The targeted oxygen-carrying nano enzyme preparation structurally takes hybrid targeted protein Human Serum Albumin (HSA) and an enzyme preparation as carriers, the enzyme preparation is collagenase or hyaluronidase, and synthesized Fe (II) TP enhanced sonosensitive molecules are loaded to serve as oxygen donors.
1. The targeted oxygen-carrying nano enzyme preparation can effectively realize tumor penetration, and the effect is realized by supported collagenase or hyaluronidase.
2. The ferriporphyrin provided by the invention has an oxygen carrying function, can input oxygen into a tumor microenvironment, has the effect of a sound-sensitive agent, and can be used for sonodynamic therapy.
3. The method can prepare large-volume targeted oxygen-carrying nano enzyme preparation, can prepare targeted oxygen-carrying nano enzyme preparation with the volume of more than several liters, and the volume prepared by the prior art is at most hundreds of milliliters, so the method provides a foundation for the amplified production and clinical research of nano particles.
4. The targeted oxygen-carrying nano enzyme preparation prepared by the method can be stably stored, the phenomena of sedimentation and flocculation do not occur in one year, and the storage time of nano particles prepared by the preparation method in the prior art is more than two months at most.
5. The preparation method is simple and easy to implement, the components are added step by step under stirring, the uniform targeted oxygen-carrying nano enzyme preparation can be obtained, no high-temperature and complex equipment or harsh reaction conditions are required, and the preparation method is convenient to operate and popularize.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (11)
1. A targeted oxygen-carrying nano enzyme preparation is characterized in that hybridized human serum albumin and an enzyme preparation are used as carriers, and ferrous porphyrin is wrapped inside the carrier.
2. The targeted oxygen-carrying nanoenzyme formulation of claim 1, wherein the enzyme formulation is a collagenase or hyaluronidase.
3. A preparation method of a targeted oxygen-carrying nano enzyme preparation is characterized by comprising the following steps:
(1) preparing ferriporphyrin;
(2) preparing reduced human serum albumin;
(3) mixing reduced human serum albumin and an enzyme preparation in water, and adjusting the pH value of the solution;
(4) taking reduced ferriporphyrin, stirring in water, and adding into the step (3);
(5) adding alcohol solution, stirring, and dialyzing;
(6) and (5) concentrating.
4. The method according to claim 3, wherein the ferrous porphyrin in step (1) is prepared by using ferric porphyrin and ascorbic acid.
5. The method according to claim 3, wherein the reduced human serum albumin in step (2) is produced by using human serum albumin and reduced glutathione.
6. The method according to claim 5, wherein the molar ratio of the human serum albumin to the reduced glutathione is 1 to 5: 1.
7. the method according to claim 3, wherein the pH in the step (3) is 7 to 8.
8. The method according to claim 3, wherein the enzyme preparation in the step (3) is collagenase or hyaluronidase.
9. The method according to claim 3, wherein the alcohol solution in the step (5) is methanol or ethanol.
10. The method according to claim 3, wherein the alcohol solution in the step (5) is added in an amount of 1 to 3 times the volume of the solution obtained in the step (4).
11. Use of the targeted oxygen-carrying nanoenzyme preparation of any one of claims 1-2 in the preparation of an anti-tumor medicament.
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