CN112263679B - Targeted oxygen-carrying nano sound-sensitive agent and preparation method thereof - Google Patents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- 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
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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
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Abstract
The invention discloses a targeted oxygen-carrying nano sound sensitizer and a preparation method thereof. The preparation method is simple in preparation process, and the prepared targeting oxygen-carrying nano sound sensitizer is stable in property, high in bioavailability and good in targeting property, and can be used for efficiently and targeted delivery of exogenous oxygen molecules and MnPP into tumors, so that the tumor hypoxia microenvironment is improved, and the sound power curative effect is improved.
Description
Technical Field
The invention relates to the field of nano medicine, in particular to a targeted oxygen-carrying nano sound sensitizer and a preparation method thereof.
Background
In the prior art, optical treatment of tumors has become a research hotspot for cancer treatment due to the non-invasive and space-time controllable advantageous features. Tumour optical treatments mainly include photodynamic therapy (PDT) and photothermal therapy (PTT). However, near infrared light has a limited tissue penetration depth, and the therapeutic effect of deep tumors is poor. In contrast, sonodynamic therapy (SDT) attracts a great deal of attention, and uses the stronger penetrating power of ultrasound to treat tumors by generating Reactive Oxygen Species (ROS) or cavitation effects from sonosensitizers accumulated in deep tumors. Currently, sonodynamic therapy has been used clinically, combining endocrine and immunotherapy to successfully cure 3 cases of advanced breast cancer patients. Common sonosensitizer molecules include: porphyrin, porphyrin derivative, anticancer medicine DOX, acid yellow, methylene blue, polyhydroxy fullerene and other organic molecules. However, these traditional organic sonosensitizer molecules have the problems of low bioavailability, oxygen dependence, lack of tumor targeting and the like, which results in low sonodynamic therapeutic efficiency and seriously hinders the clinical popularization of the method.
In recent years, the rapid development of global nanotechnology brings a brand new revolution to cancer treatment. The novel drug carrier of the nano material can realize specific targeting positioning, and efficiently enrich the drugs to tumor focus; and simultaneously, the size, morphology, surface charge, ligand modification and other physicochemical properties of the nano particles are regulated, so that a high-density interstitial matrix barrier formed by collagen, mucopolysaccharide, proteoglycan and the like in the tumor is broken through, and the loaded medicine is delivered into the tumor, thereby enhancing the anti-tumor curative effect. Aiming at the bottleneck problems of low bioavailability, poor targeting property, oxygen dependence and the like of the traditional sound sensitive agent, the nanotechnology provides a new strategy and a new direction, and brings a new opportunity for the clinical popularization of a novel nano sound dynamic pharmaceutical preparation. Development of novel nano-sonosensitizers with high bioavailability, good targeting property and capability of improving tumor hypoxia microenvironment has become an important research direction in the field of current acoustic power treatment.
However, the existing nano sound sensitive agent has complex preparation process, cannot prepare large volume, has unstable property, is easy to precipitate and flocculate, still has some problems such as sound sensitive agent safety and the like, and prevents the clinical popularization of sound power treatment.
Hybrid systems of human serum albumin and oxyhemoglobin are reported in the prior art, but high-efficiency and low-toxicity sound sensitizer is not added, and high-efficiency treatment of deep tumors cannot be realized. The three major factors of acoustic power are: ultrasound, oxygen and sonophores. Ultrasound can be up to 10cm deep, so that when nanoparticles penetrate deep into the tumor, other means such as light, even two-zone, cannot achieve such deep penetration. Under the condition of deep ultrasonic penetration, the sound-sensitive agent can effectively play a role, and realize the high-efficiency treatment of deep tumors. Nanoparticles of human serum albumin coated manganese porphyrin sonosensitizers have also been reported in the prior art, but are not capable of carrying oxygen efficiently, and therefore do not play a role in efficient sonodynamic therapy.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides the targeted oxygen-carrying nano sound sensitizer which has the advantages of simple preparation process, stable property, high safety, high bioavailability and good targeting property, and can realize high-efficiency sound power treatment. The disulfide bond breaking-reconstructing technology is adopted, the Human Serum Albumin (HSA) and the oxyhemoglobin (Hb) are hybridized by a one-step ultrasonic method, the hydrophobic sound-sensitive agent manganese porphyrin (MnPP) is wrapped, the targeted oxygen-carrying nanometer sound-sensitive agent is prepared, and exogenous oxygen molecules and MnPP are efficiently and targeted and delivered into the tumor, so that the tumor hypoxia microenvironment is improved, and the sound power curative effect is improved.
The invention provides a targeted oxygen-carrying nano sound-sensitive agent, which is characterized in that the exterior is a hybrid protein body, the interior is wrapped with sound-sensitive agent manganese porphyrin, and the hybrid protein body consists of human serum albumin and oxygen-carrying hemoglobin.
The targeting oxygen-carrying nano sound-sensitive agent has a spherical structure, and forms stronger intermolecular force with the manganese porphyrin sound-sensitive agent with a macrocyclic conjugated structure, so that the manganese porphyrin sound-sensitive agent is efficiently wrapped in the hybrid protein body, the water solubility of the manganese porphyrin sound-sensitive agent is improved, and the bioavailability of the manganese porphyrin sound-sensitive agent is improved.
The oxygen-carrying hemoglobin can carry oxygen with high efficiency and can enhance the effect of sound power treatment.
The human serum albumin has a tumor specific targeting function, and can be used for efficiently targeting tumors through gp60 glycoprotein receptor-mediated tumor endothelial cell penetration effect and tumor cell secretion protein SPARC-mediated enhanced uptake mechanism.
Further, the manganese porphyrin is formed by complexing metal manganese ions with a macrocyclic compound with a porphyrin structure. After complexing the metal manganese ion with the macrocyclic compound with the porphyrin structure, the fluorescent resonance energy transfer effect is generated, so that the fluorescence quenching of the porphyrin sound sensitizer is realized, and the phototoxicity of the porphyrin sound sensitizer is reduced.
The oxygen-carrying nano sound sensitizer can target and deliver exogenous oxygen molecules and manganese porphyrin into tumors.
The invention also provides a preparation method of the targeted oxygen-carrying nano sound sensitizer, which comprises the following steps:
(1) Preparation of manganese porphyrin: mixing a macrocyclic compound with a porphyrin structure with a metal manganese salt, filtering the precipitate, and drying;
(2) And (3) preparing the targeted oxygen-carrying nano sound sensitizer by using human serum albumin, oxygen-carrying hemoglobin and manganese porphyrin obtained in the step (1).
Further, the macrocyclic compound of the porphyrin structure and the metal manganese salt in the step (1) are in an equimolar ratio.
Further, the macrocyclic compound of the porphyrin structure is 5,10,15, 20-tetra (4-carboxyphenyl) porphyrin.
Further, the metal manganese salt in the step (1) includes at least one of manganese chloride, manganese sulfate or manganese acetate.
Further, the step (1) includes a step of performing reaction protection by using an inert gas, wherein the inert gas is at least one of nitrogen and argon.
Further, the separation step in the step (1) uses column chromatography with silica gel as a stationary phase and methylene chloride and methanol as mobile phases.
Further, the mass ratio of the human serum albumin to the oxyhemoglobin in the step (2) is 1-5:1. this ratio affects the particle size of the targeted oxygen-carrying nanoacoustic sensitizer.
Further, the step (2) includes a step of sonicating a mixed solution of the human serum albumin, the oxyhemoglobin, and the manganese porphyrin using a cytobreaker.
Further, the ultrasonic treatment time is 5-20min. The ultrasonic time can influence the particle size of the oxygen-carrying nano sound-sensitive agent.
Further, the pH value of the mixed solution is 7-8. The pH value directly influences the particle size of the oxygen-carrying nano sound-sensitive agent, and the particle size directly determines the enrichment amount of the oxygen-carrying nano sound-sensitive agent at the tumor part.
The invention also provides application of the oxygen-carrying nano sound sensitizer in preparing antitumor drugs.
In conclusion, compared with the prior art, the invention achieves the following technical effects:
1. the preparation method can prepare a large volume of targeted oxygen-carrying nano sound sensitizer, can prepare more than a few liters, and the volume of the nano particles obtained by the preparation method in the prior art is hundreds of milliliters at most, so the preparation method provides a foundation for the amplified production and clinical research of the nano particles.
2. The targeted oxygen-carrying nano sound sensitizer prepared by the invention can be stably stored, and does not have sedimentation or flocculation phenomenon in one year.
3. The preparation method is simple and easy to implement, and the targeted oxygen-carrying nano sound-sensitive agent with uniform particle size can be prepared by adding the raw materials in two steps under stirring, does not need any high-temperature and complex equipment or harsh reaction conditions, and is convenient to operate and popularize.
4. After complexing the metal manganese ion and the macrocyclic compound with the porphyrin structure, the phototoxicity of the porphyrin sound-sensitive agent is reduced, and the safety is improved.
5. The invention improves the water solubility of the manganese porphyrin sound-sensitive agent, thereby improving the bioavailability thereof.
6. The human serum albumin has a tumor specific targeting function, so that the oxygen-carrying nano sound sensitizer has good targeting property.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a UV-Vis absorption spectrum of a manganese porphyrin sound-sensitive molecule in example 4.
FIG. 2 is a transmission electron microscope image of the targeted oxygen-carrying nanosonic sensitizer of example 4.
FIG. 3 is a graph showing the results of the targeting oxygen-carrying nanoscopic agents of the present invention in example 5 that effectively carry oxygen molecules into tumors.
Fig. 4 is a graph showing the results of the effective inhibition of tumor growth by the targeted oxygen-carrying nanoacoustic sensitizer of the present invention in example 6.
Detailed Description
In order that those skilled in the art will better understand the present invention, a technical solution in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in which it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, shall fall within the scope of the invention.
The targeted oxygen-carrying nano sound sensitizer can realize safe and efficient targeting of the inside of a tumor, thereby improving the anoxic microenvironment of the tumor and improving the sound power curative effect, and the principle is as follows:
1. after complexing metal manganese ions with a macrocyclic compound with a porphyrin structure, generating a fluorescence resonance energy transfer effect, thereby quenching the fluorescence of the porphyrin sound sensitizer and reducing the phototoxicity of the porphyrin sound sensitizer;
2. after porphyrin molecule metal coordination, the metalloporphyrin triplet state (3 MTTP) generated by ultrasonic action is effectively combined with oxygen molecules, so that the active oxygen yield of metalloporphyrin is remarkably improved, and the metalloporphyrin is an ideal sound sensitizer molecule;
3. the targeted oxygen-carrying nano sound-sensitive agent has a spherical structure, and forms stronger intermolecular force with the manganese porphyrin sound-sensitive agent with a macrocyclic conjugated structure, so that the manganese porphyrin sound-sensitive agent is efficiently wrapped in the hybrid protein body, the water solubility of the manganese porphyrin sound-sensitive agent is improved, and the bioavailability of the manganese porphyrin sound-sensitive agent is improved;
4. the invention adopts the components in the human body: the human serum albumin and the oxyhemoglobin are used as heterozygous carriers, so that the safety is high;
5. human serum albumin has tumor specific targeting function: the tumor is efficiently targeted by a gp60 glycoprotein receptor-mediated tumor endothelial cell penetrating effect and a tumor cell secretion protein SPARC-mediated enhanced uptake mechanism;
6. manganese ions released by degradation of the targeted oxygen-carrying nanosonic sensitizer can be used for magnetic resonance imaging.
The preparation method of the targeted oxygen-carrying nano sound-sensitive agent is characterized in that the targeted oxygen-carrying nano sound-sensitive agent is prepared by adopting a one-step ultrasonic method, and hydrophobic manganese porphyrin is wrapped in a hybrid protein body along with volatilization of a chloroform solvent to form the spherical targeted oxygen-carrying nano sound-sensitive agent. The method comprises the following specific steps:
(1) Preparation of manganese porphyrin
(1) Mixing a macrocyclic compound with porphyrin structure (such as 5,10,15, 20-tetra (4-carboxyphenyl) porphyrin, PP) with metal manganese salt (at least one of manganese chloride, manganese sulfate or manganese acetate), stirring under the protection of inert gas, heating and refluxing, stopping the reaction, and cooling to room temperature;
(2) the precipitate was filtered, washed with deionized water and dried in vacuo. Separating by column chromatography, rotary evaporating at low temperature, drying, and collecting sample to obtain manganese porphyrin (MnPP).
(2) Preparation of targeted oxygen-carrying nano sound sensitizer
(1) Weighing manganese porphyrin, and dissolving the manganese porphyrin in chloroform;
(2) weighing oxyhemoglobin powder, dissolving in ultrapure water, and placing in a shaking table for reaction;
(3) the human serum albumin and the oxyhemoglobin are mixed according to the mass ratio of 1-5:1, mixing, and transferring the manganese porphyrin solution in the step (1) to the bottom of the mixed solution;
(4) and (3) placing the mixed solution in an ice-water bath, performing ultrasonic treatment by using a cell pulverizer to form a suspension, adjusting the pH value to 7-8, and then placing the suspension in an ultrasonic cleaner for ultrasonic treatment until the suspension becomes clear, thus obtaining the targeted oxygen-carrying nano sound sensitizer.
Example 1 preparation method of Targeted oxygen-carrying nanosonic agent
The method specifically comprises the following steps:
(1) Preparation of manganese porphyrin
(1) Mixing 5,10,15, 20-tetra (4-carboxyphenyl) porphyrin (PP) purchased from the technical Co., ltd. Of carbofuran and manganese chloride in anhydrous DMF solution, stirring, heating and refluxing for 2 hours under the protection of nitrogen, monitoring the reaction progress by a UV-Vis absorption spectrometer, and stopping the reaction after the reaction liquid is changed from black red to grass green and the Q band peak is changed from 4 to 2 with a certain degree of red shift, and cooling to room temperature;
(2) the precipitate was filtered, washed with deionized water and dried in vacuo. Separating by column chromatography, and taking silica gel as stationary phase, wherein the volume ratio is 3:1 as mobile phase. And (5) rotary evaporation at low temperature, drying and collecting a sample to obtain manganese porphyrin (MnPP).
(2) Preparation of targeted oxygen-carrying nano sound sensitizer
(1) Weighing 1mg of manganese porphyrin, and dissolving in 100 mu L of chloroform;
(2) 5mg of Hb powder was weighed, dissolved in 1mL of ultrapure water, and placed in a shaker to react for 0.5h under the following reaction conditions: 37 ℃,100rpm;
(3) HSA and Hb are mixed according to the mass ratio of 1:1, uniformly mixing, and transferring 100 mu L of the manganese porphyrin solution in the step (1) to the bottom of the mixed solution;
(4) placing the above mixture in ice water bath, performing ultrasonic treatment with cell pulverizer for 5min to obtain suspension, and treating with Na 2 CO 3 And regulating the pH value of the solution to 7, and then placing the solution in an ultrasonic cleaner for ultrasonic until the suspension becomes clear, thus obtaining the targeted oxygen-carrying nano sound sensitizer.
The zeta potential of the targeted oxygen-carrying nano sound sensitizer is larger than-30 mV, the particle size range is 50-200nm, and the results of potential and particle size can prove that the targeted oxygen-carrying nano sound sensitizer is successfully prepared. However, the particle size range of the targeted oxygen-carrying nano sound sensitizer is slightly larger, and the uniformity of the particle size is not high. This is related to the ratio of human serum albumin to oxyhemoglobin, the pH of the solution, the time of sonication.
Example 2 preparation method of Targeted oxygen-carrying nanosonic agent
In this example, the ratio of human serum albumin to oxygen-carrying hemoglobin, the pH value of the system, and the time of ultrasound are different from those of example 1, the pH value directly affects the particle size of the oxygen-carrying nanoacoustic sensitizer, and the particle size directly determines the enrichment amount of the oxygen-carrying nanoacoustic sensitizer at the tumor site. The ultrasonic time directly affects the particle size of the oxygen-carrying nano-sonosensitizer, and the ratio of human serum albumin to oxygen-carrying hemoglobin can also affect the particle size.
The method specifically comprises the following steps:
(1) Preparation of manganese porphyrin
(1) Mixing 5,10,15, 20-tetra (4-carboxyphenyl) porphyrin (PP) and manganese acetate in an equal molar ratio into anhydrous DMF solution, stirring under the protection of argon, heating and refluxing for 6 hours, monitoring the reaction progress by a UV-Vis absorption spectrometer, stopping the reaction after the reaction liquid changes from black red to grass green and the Q band peak changes from 4 to 2 with a certain degree of red shift, and cooling to room temperature;
(2) the precipitate was filtered, washed with deionized water and dried in vacuo. Separating by column chromatography, and taking silica gel as stationary phase, wherein the volume ratio is 3:1 as mobile phase. And (5) rotary evaporation at low temperature, drying and collecting a sample to obtain manganese porphyrin (MnPP).
(2) Preparation of targeted oxygen-carrying nano sound sensitizer
(1) Weighing 5mg of manganese porphyrin, and dissolving in 500 mu L of chloroform;
(2) 10mg of Hb powder was weighed, dissolved in 5mL of ultrapure water, and placed in a shaker to react for 2 hours under the following conditions: 37 ℃,200rpm;
(3) HSA and Hb are mixed according to the mass ratio of 5:1, uniformly mixing, and transferring 500 mu L of manganese porphyrin solution in the step (1) to the bottom of the mixed solution;
(4) placing the above mixture in ice water bath, performing ultrasonic treatment with cell pulverizer for 20min to obtain suspension, and treating with Na 2 CO 3 And regulating the pH value of the solution to 8, and then placing the solution in an ultrasonic cleaner for ultrasonic until the suspension becomes clear, thus obtaining the targeted oxygen-carrying nano sound sensitizer.
The zeta potential of the targeted oxygen-carrying nano sound sensitizer is larger than-30 mV, and the particle size range is 80-200nm. The results of the potential and the particle size can indicate that the targeted oxygen-carrying nano sound sensitizer is successfully prepared. The particle size range of the targeted oxygen-carrying nano-sonosensitizer is slightly reduced compared with that of the example 1, but the particle size range is still large, and the particle size uniformity degree is not high, which is related to the ratio of the human serum albumin and the oxygen-carrying hemoglobin, the pH value of the solution and the ultrasonic time. The targeted oxygen-carrying nano sound sensitizer with more uniform particle size can be prepared by continuously optimizing the conditions.
Example 3 preparation method of Targeted oxygen-carrying nanosonic agent
In this example, the ratio of human serum albumin to oxygen-carrying hemoglobin, the pH value of the system, and the time of ultrasound are different from those of example 1, the pH value directly affects the particle size of the oxygen-carrying nanoacoustic sensitizer, and the particle size directly determines the enrichment amount of the oxygen-carrying nanoacoustic sensitizer at the tumor site. The ultrasonic time directly affects the particle size of the oxygen-carrying nano-sonosensitizer, and the ratio of human serum albumin to oxygen-carrying hemoglobin can also affect the particle size.
The method specifically comprises the following steps:
(1) Preparation of manganese porphyrin
(1) Mixing 5,10,15, 20-tetra (4-carboxyphenyl) porphyrin (PP) and manganese acetate in an equal molar ratio into anhydrous DMF solution, stirring under the protection of argon, heating and refluxing for 6 hours, monitoring the reaction progress by a UV-Vis absorption spectrometer, stopping the reaction after the reaction liquid changes from black red to grass green and the Q band peak changes from 4 to 2 with a certain degree of red shift, and cooling to room temperature;
(2) the precipitate was filtered, washed with deionized water and dried in vacuo. Separating by column chromatography, and taking silica gel as stationary phase, wherein the volume ratio is 3:1 as mobile phase. And (5) rotary evaporation at low temperature, drying and collecting a sample to obtain manganese porphyrin (MnPP).
(2) Preparation of targeted oxygen-carrying nano sound sensitizer
(1) Weighing 1mg of manganese porphyrin, and dissolving in 200 mu L of chloroform;
(2) 5mg of Hb powder was weighed, dissolved in 1mL of ultrapure water, and placed in a shaker to react for 0.5h under the following reaction conditions: 37 ℃,100rpm;
(3) HSA and Hb are mixed according to the mass ratio of 3:1, uniformly mixing, and transferring 200 mu L of the manganese porphyrin solution in the step (1) to the bottom of the mixed solution;
(4) placing the above mixture in ice water bath, performing ultrasonic treatment with cell pulverizer for 5min to obtain suspension, and treating with Na 2 CO 3 And regulating the pH value of the solution to 8, and then placing the solution in an ultrasonic cleaner for ultrasonic until the suspension becomes clear, thus obtaining the targeted oxygen-carrying nano sound sensitizer.
The zeta potential of the targeted oxygen-carrying nano sound sensitizer is larger than-30 mV, the particle size range is 100-200nm, and the results of potential and particle size can prove that the targeted oxygen-carrying nano sound sensitizer is successfully prepared. The particle size range of the targeted oxygen-carrying nano-sonosensitizer is slightly reduced compared with that of the example 2, but the particle size range is still large, and the particle size uniformity degree is not high, which is related to the ratio of the human serum albumin and the oxygen-carrying hemoglobin, the pH value of the solution and the ultrasonic time. The targeted oxygen-carrying nano sound sensitizer with more uniform particle size can be prepared by continuously optimizing the conditions.
Example 4 preparation method of Targeted oxygen-carrying nanosonic agent
In this example, the ratio of human serum albumin to oxygen-carrying hemoglobin, the pH value of the system, and the time of ultrasound are different from those of example 1, the pH value directly affects the particle size of the oxygen-carrying nanoacoustic sensitizer, and the particle size directly determines the enrichment amount of the oxygen-carrying nanoacoustic sensitizer at the tumor site. The ultrasonic time directly affects the particle size of the oxygen-carrying nano-sonosensitizer, and the ratio of human serum albumin to oxygen-carrying hemoglobin can also affect the particle size.
The method specifically comprises the following steps:
(1) Preparation of manganese porphyrin
(1) Mixing 5,10,15, 20-tetra (4-carboxyphenyl) porphyrin (PP) and manganese sulfate in an equal molar ratio into anhydrous DMF solution, stirring under the protection of argon, heating and refluxing for 4 hours, monitoring the reaction progress by a UV-Vis absorption spectrometer, stopping the reaction after the reaction liquid is changed from black red to grass green and the Q band peak is changed from 4 to 2 with a certain degree of red shift, and cooling to room temperature;
(2) the precipitate was filtered, washed with deionized water and dried in vacuo. Separating by column chromatography, and taking silica gel as stationary phase, wherein the volume ratio is 3:1 as mobile phase. And (5) rotary evaporation at low temperature, drying and collecting a sample to obtain manganese porphyrin (MnPP).
(2) Preparation of targeted oxygen-carrying nano sound sensitizer
(1) Weighing 3mg of manganese porphyrin, and dissolving in 300 mu L of chloroform;
(2) 7.5mg of Hb powder was weighed, dissolved in 3mL of ultrapure water, and placed in a shaker for reaction for 1.5h under the following conditions: 37 ℃,150rpm;
(3) HSA and Hb are mixed according to the mass ratio of 3:1, uniformly mixing, and transferring 300 mu L of manganese porphyrin solution in the step (1) to the bottom of the mixed solution;
(4) placing the above mixture in ice water bath, performing ultrasonic treatment with cell pulverizer for 12.5min to obtain suspension, and treating with Na 2 CO 3 And regulating the pH value of the solution to 7.5, and then placing the solution in an ultrasonic cleaner for ultrasonic until the suspension becomes clear, thus obtaining the targeted oxygen-carrying nano sound sensitizer.
The zeta potential of the targeted oxygen-carrying nano sound sensitizer is larger than-30 mV, the particle size range is 100-150nm, and the results of potential and particle size can prove that the targeted oxygen-carrying nano sound sensitizer is successfully prepared. The oxygen-carrying nano sound sensitizer can be enriched to tumor sites more efficiently in vivo.
The particle size means that the amount of the supported sound sensitive agent is different, so that the oxygen carrying amount is different, but the particle size directly determines the enrichment amount of the nano sound sensitive agent at the tumor part, and in general, the targeted oxygen carrying nano sound sensitive agent is easier to enrich at the tumor part when the particle size is 100-150nm.
In examples 1-4, the particle sizes of the oxygen-carrying nano sound-sensitive agents prepared were different, and the factors influencing the particle sizes were: the ratio of human serum albumin and oxyhemoglobin, the pH value of the system and the ultrasonic time. According to the invention, various preparation conditions are searched, and FIG. 1 is a UV-Vis absorption spectrum diagram of the manganese porphyrin sound-sensitive molecule in the embodiment, and the Q band peaks of the prepared manganese porphyrin are converted from 4 to 2 with a certain degree of red shift (see a dotted line frame of FIG. 1), so that the manganese porphyrin sound-sensitive molecule can be effectively prepared by the preparation method. Fig. 2 is a transmission electron microscope image of the targeted oxygen-carrying nano-acoustic sensitizer in the embodiment, and the shape rule of the prepared targeted oxygen-carrying nano-acoustic sensitizer and the particle size of 100-150nm can be seen, which illustrates that the preparation method of the invention can effectively prepare the targeted oxygen-carrying nano-acoustic sensitizer.
The targeting oxygen-carrying nano sound sensitizer particles prepared by the embodiment are most uniform, have the highest oxygen carrying capacity and can be better targeted and accumulated to tumor sites. The preparation conditions and proportions of this example are most preferred. The results of animal experiments can also be described, see in particular example 5 and example 6.
Example 5 the targeting oxygen-carrying nanosonosensitizer of the present invention effectively carries oxygen molecules into tumors
The targeted oxygen-carrying nano-acoustic sensitizer prepared in example 4 is injected into a tumor-bearing mouse (directly available) through tail vein, and is measured by a small animal photoacoustic instrument before injection and after injection for 3 hours, the result is shown in fig. 3, the control group is a control group only added with phosphate buffer solution, and the result shows that compared with the control group, the targeted oxygen-carrying nano-acoustic sensitizer has obvious photoacoustic signals (as indicated by white arrows), so that the targeted oxygen-carrying nano-acoustic sensitizer can effectively improve the tumor hypoxia microenvironment.
Example 6 the oxygen-carrying nanosonosensitizer of the present invention was effective in inhibiting tumor growth
The targeted oxygen-carrying nano-sized sound-sensitive agent prepared in the embodiment 4 is injected into a tumor-bearing mouse (directly available) by tail vein, after 3 hours, ultrasonic treatment is started for 5 minutes, the mouse is killed, the tumor is taken out to measure the tumor volume, the result is shown in fig. 4, PBS is a control group only added with phosphate buffer solution, US represents ultrasonic, and the result shows that the tumor volume of the targeted oxygen-carrying nano-sized sound-sensitive agent is obviously reduced compared with that of the control group under the action of ultrasonic, so that the targeted oxygen-carrying nano-sized sound-sensitive agent can effectively inhibit the tumor growth.
In conclusion, the targeting oxygen-carrying nano sound sensitizer is prepared by adopting a one-step ultrasonic method to hybridize Human Serum Albumin (HSA) and oxygen-carrying hemoglobin (Hb) and wrapping hydrophobic sound sensitizer manganese porphyrin (MnPP). The preparation process is simple, and the prepared targeting oxygen-carrying nano sound sensitizer has stable property, high bioavailability and good targeting property, can efficiently and targetedly deliver exogenous oxygen molecules and MnPP into the tumor, improves the anoxic microenvironment of the tumor and improves the sound power curative effect.
1. The preparation method can prepare a large volume of targeted oxygen-carrying nano sound sensitizer, can prepare more than a few liters, and the volume of the nano particles obtained by the preparation method in the prior art is hundreds of milliliters at most, so the preparation method provides a foundation for the amplified production and clinical research of the nano particles.
2. The targeted oxygen-carrying nano sound sensitizer prepared by the invention can be stably stored, and does not have sedimentation or flocculation phenomenon in one year.
3. The preparation method is simple and easy to implement, and the targeted oxygen-carrying nano sound-sensitive agent with uniform particle size can be prepared by adding the raw materials in two steps under stirring, does not need any high-temperature and complex equipment or harsh reaction conditions, and is convenient to operate and popularize.
4. After complexing the metal manganese ion and the macrocyclic compound with the porphyrin structure, the phototoxicity of the porphyrin sound-sensitive agent is reduced, and the safety is improved.
5. The invention improves the water solubility of the manganese porphyrin sound-sensitive agent, thereby improving the bioavailability thereof.
6. The human serum albumin has a tumor specific targeting function, so that the oxygen-carrying nano sound sensitizer has good targeting property.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.
Claims (5)
1. The preparation method of the targeted oxygen-carrying nano sound sensitizer is characterized by comprising the following steps of:
(1) Preparation of manganese porphyrin: mixing 5,10,15, 20-tetra (4-carboxyphenyl) porphyrin and metal manganese salt, filtering to precipitate, drying and separating; the 5,10,15, 20-tetra (4-carboxyphenyl) porphyrin and the manganese metal salt are in an equimolar ratio; the metal manganese salt comprises at least one of manganese chloride, manganese sulfate or manganese acetate;
(2) Preparing a targeted oxygen-carrying nano sound sensitizer by using human serum albumin, oxygen-carrying hemoglobin and manganese porphyrin obtained in the step (1);
weighing 3mg of manganese porphyrin, and weighing 7.5mg of oxyhemoglobin-loaded powder, wherein the mass ratio of human serum albumin to the oxyhemoglobin-loaded powder is 3:1, a step of; the step (2) comprises the step of performing ultrasonic treatment on the mixed solution of the human serum albumin, the oxygen-carrying hemoglobin and the manganese porphyrin by using a cytobreaker; the ultrasonic time is 12.5 min; the pH value of the mixed solution is 7.5;
the particle size range of the targeted oxygen-carrying nano sound-sensitive agent obtained by the steps (1) and (2) is 100-150nm.
2. The method according to claim 1, wherein the step (1) comprises a step of performing reaction protection using an inert gas.
3. The method according to claim 1, wherein the separation step in the step (1) uses column chromatography.
4. A targeted oxygen-carrying nano-sonosensitizer, characterized in that it is prepared by the preparation method of any one of claims 1-3; the targeted oxygen-carrying nano sound sensitizer is externally provided with a heterozygous protein body, and the interior of the targeted oxygen-carrying nano sound sensitizer is wrapped with manganese porphyrin; the hybrid protein body consists of human serum albumin and oxyhemoglobin; the manganese porphyrin is formed by complexing metal manganese ions with 5,10,15, 20-tetra (4-carboxyphenyl) porphyrin.
5. The use of the targeted oxygen-carrying nano sound-sensitive agent in the preparation of antitumor drugs.
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