CN110917349B - Bowl-shaped ISP (internet service provider) composite functional nano particle as well as preparation method and application thereof - Google Patents

Abstract

_The invention discloses a bowl _- shaped ISP composite functional nanoparticle and a preparation method and application thereof. Polyethylene glycol block polystyrene (PEG‑b‑PS). The bowl-shaped ISP functional composite nanoparticle prepared by the invention has a magnetic targeting function, which can improve the enrichment of ZnPc at the tumor tissue site, and the novel bowl-shaped ISP composite functional nanoparticle of the present invention can magnetically target the tumor tissue site , to enhance the activity of photosensitizers by catalytic oxygen production, and achieve high-efficiency treatment of PDT. The preparation method of the invention is simple and convenient, the raw material sources are wide, and the bioavailability is high, and the prepared nano-particles are used as photosensitizers and carriers in the preparation of photodynamic drugs.

Description

A bowl-shaped ISP composite functional nanoparticle and its preparation method and application

technical field

The invention belongs to the technical field of nanometer systems that can improve photodynamic activity, and in particular relates to a bowl-shaped ISP composite functional nanoparticle and a preparation method and application thereof, in particular to a functional composite nanoparticle with magnetic targeting and its application in Application of photosensitive therapy in tumor.

Background technique

Photodynamic therapy (PDT) is a new type of tumor treatment. The photosensitizer is injected into the human body through intravenous injection, and then the photosensitizer located at the tumor site is excited by light of a specific wavelength, reacts with the surrounding oxygen to generate reactive oxygen species, and oxidizes and damages the biological macromolecules in the tumor cells, killing the tumor cells to achieve the goal of tumor treatment. Effect. PDT has received extensive attention due to its low toxicity, drug resistance, and reusability. Zinc phthalocyanine (ZnPc), as a promising metal complex photosensitizer, has high biosafety (low dark toxicity) and photosensitivity antitumor activity.

The structure formed by the self-assembly of a block polymer with polyethylene glycol at one end has a high application value for drug loading. Because polyethylene glycol has good biocompatibility, it can prolong the loading time of drugs. Circulation time in the blood. Most of these structures have two or more properties, providing more possibilities for loading a variety of drugs. At present, nanotechnology is widely used in drug delivery and functionalization systems, among which magnetic _Fe3O4 nanoparticles have received extensive attention in the field of tumor therapy due to their excellent magnetic targeting _. In photodynamic therapy, the development of photodynamic therapy is greatly limited due to the toxic and side effects on healthy tissues caused by the easy removal of drugs in the blood circulation and the poor targeting of the drugs. In addition, phthalocyanine photosensitizers consume oxygen through illumination, and the insufficient supply of oxygen limits the activity of photosensitizers and reduces their intracellular antitumor effect.

SUMMARY OF THE INVENTION

Purpose of the invention: In view of the problems existing in the prior art, the present invention provides a bowl-shaped ISP composite functional nanoparticle. The new bowl-shaped ISP composite functional nanoparticle can be magnetically targeted to tumor tissue, and enhance photosensitivity through catalytic oxygen production. agent activity to achieve high-efficiency treatment of PDT.

The invention also provides a preparation method of the ISP composite functional nanoparticle and its application in the preparation of photosensitive drugs.

Technical scheme: In order to achieve the above purpose, a bowl-shaped ISP composite functional nanoparticle according to the present invention is characterized in that, after self-assembly of block polymers into a bowl-shaped structure, Fe ₃ O ₄ particles and photosensitizer ZnPc are loaded Formed; the block polymer is polyethylene glycol block polystyrene, abbreviated as PEG-b-PS.

The bowl-shaped ISP composite functional nanoparticles have a bowl-shaped structure, and the Fe ₃ O ₄ nanoparticles are loaded in the grooves of the bowl-shaped structure to form functional nano-carriers with magnetic targeting, and then the ISP is obtained by loading the photosensitizer ZnPc Functional composite nanoparticles.

Further, the bowl-shaped ISP composite functional nanoparticles are organic-inorganic composite nanoparticles suitable for intravenous injection.

The preparation method of bowl-shaped ISP functional composite nanoparticles according to the present invention comprises the following steps:

(1) Preparation of bowl-shaped PEG-b-PS self-assembled structure: After PEG-OH was dissolved in tetrahydrofuran uniformly, 2-bromoisobutyryl bromide was added under _N2 protection and 0 °C ice-water bath to react, and the product After suction filtration, the supernatant was extracted with NaHCO ₃ solution, and vacuum-dried to obtain PEG-Br macromolecular initiator; the PEG-Br macromolecular initiator was dissolved in anisole to dissolve, and styrene was added, CuCl and PMDETA were added to react, and the product Through purification and separation, the obtained solution was concentrated by distillation under reduced pressure and then settled in methanol solution. The precipitate was filtered with suction and then dried in vacuum to obtain a polyethylene glycol block polystyrene polymer, which is PEG-b-PS; PEG-b -PS is dissolved in a mixed solution of 1,4-dioxane and tetrahydrofuran, and injected with double distilled water to obtain a bowl-shaped structure of PEG-b-PS;

(2) Synthesis of superparamagnetic Fe ₃ O ₄ nanoparticles: Fe(acac) ₃ was dissolved in triethylene glycol, and a solution of superparamagnetic Fe ₃ O ₄ nanoparticles was synthesized by thermal decomposition;

(3) Preparation of bowl-shaped ISP functional composite nanoparticles: The Fe ₃ O ₄ nanoparticle solution with triethylene glycol modification was mixed with the bowl-shaped structure PEG-b-PS solution, and the mixture of triethylene glycol and PEG was mixed. The similar compatibility characteristics of the inter-structures make Fe ₃ O ₄ nanoparticles loaded in the bowl-like structure PEG-b-PS, and centrifugation after ultrasonication to obtain the bowl-like structure PEG-b-PS nanoparticles loaded with Fe ₃ O ₄ nanoparticles , and then the ZnPc solution was added to it, mixed, and centrifuged after ultrasonication to obtain bowl-shaped ISP functional composite nanoparticles.

Wherein, the PEG-Br described in step (1) is dissolved in anisole to dissolve, styrene is added, and the reaction between CuCl and PMDETA is that the mixture is reacted overnight at 80-100 °C under anhydrous and oxygen-free conditions; the preferred temperature is 90 °C .

Wherein, the feeding conditions of PEG-Br and styrene in step (1) are argon protection and liquid nitrogen atmosphere.

Specifically, the PEG-Br and styrene are in an argon atmosphere during the feeding of step (1), and the low temperature state of the raw materials is maintained by placing the reaction vessel in an ice-water bath at 0°C.

Wherein, in step (2), the superparamagnetic Fe ₃ O ₄ nanoparticle solution synthesized by thermal decomposition method is that after Fe (acac) ₃ is uniformly dissolved in triethylene glycol, the temperature is gradually increased to ₂₀₀ ° C., 250°C, 280°C, and reflux reaction at 280°C for 0.5-1 h to obtain a superparamagnetic Fe ₃ O ₄ nanoparticle solution.

Preferably, the gradient temperature in step (2) is maintained at 200° C. and 250° C. for 5-10 min, respectively.

Further, the mass ratio of the bowl-shaped structure PEG-b-PS, Fe ₃ O ₄ , and ZnPc described in step (3) is 2-3:1.5-2.5:0.5-1.5, and further, in step (3) The mass ratio of PEG-b-PS, Fe ₃ O ₄ and ZnPc is 2:2:1.

The application of the bowl-shaped ISP functional composite nanoparticles of the present invention in the preparation of photodynamic drugs.

Wherein, the bowl-shaped ISP functional composite nanoparticles are used as photosensitizers and carriers in the preparation of photodynamic drugs.

In the present invention, PEG-b-PS is synthesized by ATRP method, a bowl-shaped structure is obtained by solution self-assembly, superparamagnetic Fe ₃ O ₄ nanoparticles are synthesized by thermal decomposition method, ZnPc is synthesized by DBU catalysis method, and the bowl-shaped structure PEG- Add superparamagnetic Fe ₃ O ₄ nanoparticle solution to b-PS solution, remove unadsorbed Fe ₃ O ₄ by centrifugation, add photosensitizer ZnPc, remove unadsorbed ZnPc by centrifugation, and obtain bowl-shaped ISP functional composite nanoparticle after centrifugal washing of the product particle.

Preferably, after the PEG-b-PS is homogeneously dissolved in tetrahydrofuran by PEG-OH, 2-bromoisobutyryl bromide is added under N ₂ protection and in an ice-water bath to react, and the product is filtered with NaHCO in the supernatant. _3. Solution extraction and vacuum drying to obtain PEG-Br macromolecular initiator. The PEG-Br macromolecular initiator was dissolved in anisole to dissolve, the solution was transferred to a Schlenk bottle, styrene, CuCl and PMDETA were added, the mixture was reacted at 90 °C overnight under anhydrous and oxygen-free conditions, and the product passed through neutral alumina. The chromatographic column removes the complex containing cuprous ion, and the obtained solution is concentrated by distillation under reduced pressure and then settled in methanol solution. The precipitate is filtered with suction and then dried in vacuum to obtain PEG-b-PS polymer. In the mixed solvent of 1,4-dioxane and water, a bowl-like structure is assembled, and its shape is shown in Figure 3, showing a bowl-like structure.

The application of the bowl-shaped ISP functional composite nanoparticles prepared by the invention in the preparation of photosensitive drugs. Aiming at the problem of insufficient targeting of photosensitizers at tumor sites, the invention uses bowl-shaped structure PEG-b-PS as a carrier and the magnetic targeting ability of Fe ₃ O ₄ nanoparticles to construct bowl-shaped ISP functional composite nanoparticles to achieve Efficient tumor-targeted PDT therapy. The bowl-shaped ISP functional composite nanoparticles of the present invention have good biocompatibility and are basically non-toxic in cells. It has excellent magnetic targeting ability to tumor tissue, which can improve the uptake of drugs by cells and enhance the PDT effect of photosensitizers.

Mechanism: Since one end of the self-assembled structure of PEG-b-PS is PEG, it has good biocompatibility. The polymer PEG-b-PS is amphiphilic, which is conducive to the loading of drugs; and it is loaded in the bowl-shaped groove. The Fe ₃ O ₄ nanoparticles were added with the magnetic targeting function, and ZnPc was adsorbed on the surface of the bowl-shaped PEG-b-PS structure, making the whole composite nanoparticles have photodynamic therapy activity. Due to the relatively high concentration of H ₂ O ₂ in tumor tissue microenvironment and cells, H ₂ O ₂ is catalyzed by Fe ₃ O ₄ to generate oxygen, which increases the oxygen content in tumor cells, thereby enhancing the activity of ZnPc. After the composite nanoparticle is injected into the body, it is targeted to the tumor site by an external magnetic field, so as to improve the PDT effect.

The raw materials used in the present invention are all commercially available.

Beneficial effect: Compared with the prior art, the present invention has the following advantages:

(1) The bowl-shaped PEG-b-PS nanostructure of the present invention has a simple assembly method, good dispersibility and uniform size.

(2) The bowl-shaped ISP functional composite nanoparticles prepared by the present invention have a magnetic targeting function, which can improve the enrichment of ZnPc in tumor tissue, and the bowl-shaped ISP composite functional nanoparticles of the present invention can magnetically target tumors to tumors At the tissue site, the activity of photosensitizers can be improved by catalytic oxygen production to achieve efficient treatment of PDT.

(3) The detection by the O ₂ probe shows that the bowl-shaped ISP functional composite nanoparticles prepared by the present invention have good H ₂ O ₂ catalytic ability and can relieve the hypoxia of tumor tissue.

(4) In vivo anti-tumor experiments show that, compared with ZnPc, the bowl-shaped ISP functional composite nanoparticles prepared by the present invention have better tumor growth inhibition ability, and the effect is more obvious after an external magnetic field is applied.

(5) The preparation method of the present invention is simple and convenient, the source of raw materials is wide, and the bioavailability is high, and the prepared nanoparticle is used as a photosensitizer carrier in the preparation of photodynamic drugs.

Description of drawings

Fig. 1 is the structural representation of the bowl-shaped ISP functional composite nanoparticle of the present invention;

Fig. 2 is the synthetic schematic diagram of PEG-b-PS block polymer;

Figure 3 TEM image of the PEG-b-PS block polymer assembled into a bowl-like structure;

Fig. 4 is the transmission electron microscope image of Fe ₃ O ₄ ;

Fig. 5 is the synthetic schematic diagram of ZnPc;

Figure 6 is a zeta potential diagram of water, Fe ₃ O ₄ , bowl-shaped PEG-b-PS and bowl-shaped ISP composite functional nanoparticles;

Figure 7 is a graph showing the production of reactive oxygen species in vitro under ZnPc, bowl-shaped ISP composite functional nanoparticles and an external magnetic field;

Figure 8 is a schematic diagram of the phototoxicity of ZnPc, bowl-shaped ISP functional composite nanoparticles and their tumor cell phototoxicity after the MTT method is applied;

FIG. 9 is a schematic diagram showing the comparison of ZnPc, bowl-shaped ISP composite functional nanoparticles and their ability to inhibit tumor growth after adding external magnetic field targeting in mouse xenograft model animals.

Figure 10 shows the MRI images of the bowl-shaped ISP composite functional nanoparticles in a magnetic field and a non-magnetic field environment for 24 hours in a mouse xenograft model animal.

Detailed ways

The present invention will be further described below with reference to the accompanying drawings and embodiments.

Example 1

Preparation of bowl-shaped structure PEG-b-PS: The PEG-b-PS block polymer was synthesized as shown in Figure 2. Specifically, poly(ethylene glycol) monomethyl ether (6.00 g, 2.00 mmol) with a molecular weight of 3000 was prepared in 20 mL of tetrahydrofuran. After the mixture was uniformly dissolved, triethylamine (1.04 mL, 7.5 mmol) was added, and the mixture was added dropwise 2-bromoisobutyryl bromide (620 μL, 5.00 mmol) in an ice-water bath at 0°C under nitrogen protection for 24 hours. After the reaction, suction filtration to obtain a white precipitate, and vacuum drying to obtain PEG-Br. PEG-Br was dissolved in 1.5ml anisole, and CuCl (45mg, 0.45mmol) and PMDETA (α-bromoisobutyrate, N,N,N',N",N"-Pentamethyldiethylenetriamine, 66μL were added under anhydrous and anoxic conditions. 0.32 mmol), anhydrous and oxygen-free reaction at 90 °C for 12 hours, in an argon atmosphere during the feeding period, and the low temperature state of the raw materials is maintained by placing the reaction vessel in an ice-water bath at 0 °C. The product is separated and removed by neutral alumina chromatography column using dichloromethane as the eluent to remove the complex and impurities containing Cu. The solution is concentrated, precipitated in methanol, and dried in vacuum to obtain a PEG-b-PS block polymer. Dissolve 10 mg of polymer in 1 mL of a mixed solvent of tetrahydrofuran and 1,4-dioxane, the volume ratio of which is tetrahydrofuran: 1,4-dioxane=4:1, add 1 mL of distilled water at a rate of 1 mL/h, The final volume ratio of the mixed organic solution and double distilled water is 1:1, and the amount of polymer feeding and the volume of the mixed solvent can be expanded in equal proportions. The organic solvent is removed by dialysis with distilled water to obtain a bowl-shaped PEG-b with a concentration of 4 mg/mL. -PS solution, the morphology of which is shown in Figure 3.

Example 2

Preparation of superparamagnetic Fe ₃ O ₄ nanoparticles: 1.42 g Fe(acac) ₃ was uniformly dissolved in 50 mL of triethylene glycol, and then under the protection of N ₂ , a gradient temperature was carried out from room temperature to 200 °C, then to 250 °C and finally to 280 °C , each stage was kept stable for 10 min, and the triethylene glycol solution of superparamagnetic Fe ₃ O ₄ nanoparticles was obtained by reacting at 280 °C for 0.5 h. The electron microscope images of the as-prepared _Fe3O4 nanoparticles are shown in Fig. ₄ .

Example 3

ZnPc synthesis: The synthesis of side-chain tetra-substituted benzoic acid sodium salt phthalocyanine derivatives was carried out according to the steps shown in FIG. 5 . p-Hydroxybenzoic acid (500 mg, 3.62 mmol) and 4-nitrophthalonitrile (658 mg, 3.8 mmol) were dissolved in N,N-dimethylformamide (8 mL), potassium carbonate (561.2 mg, 4.06 mmol) In the mixed solvent, under the protection of N ₂ , the reaction generates compound 1; The solution was reacted at 140 °C for 12 h to generate compound 2; compound 2 (200 mg, 0.18 mmol) was reacted with sodium hydroxide (16 mg, 0.4 mmol) in ethanol (10 mL) for 24 h to finally generate a side-chain tetra-substituted benzoic acid sodium salt phthalocyanine derivative (ZnPc).

Example 4

Preparation of bowl-shaped ISP composite functional nanoparticles: The dialyzed 4 mg/mL bowl-shaped PEG-b-PS solution obtained in Example 1 was mixed with 6 mg/mL Fe ₃ O ₄ nanoparticle triethylene glycol solution according to the following method. Mix PEG-b-PS and Fe ₃ O ₄ in a ratio of 2:2, centrifuge at 9600 r/min for 5-10 min to remove unloaded Fe ₃ O ₄ nanoparticles, and remove Fe ₃ outside the groove by ultrasonic _O4 nanoparticles. The prepared nanoparticle solution was diluted with distilled water to a concentration of 1 mg/mL of bowl-shaped structure PEG-b-PS, and mixed with the ZnPc prepared in Example 3 to prepare an aqueous solution of 1 mg/mL according to the bowl-shaped structure of PEG-b-PS and 1 mg/mL. The ZnPc mass ratio was mixed at a ratio of 2:1, and the unloaded ZnPc was removed by centrifugation at a speed of 9600 r/min for 10 min to obtain bowl-shaped ISP composite functional nanoparticles, the morphology of which is shown in Figure 1.

Example 5

Zeta potential changes determine Fe ₃ O ₄ nanoparticles and ZnPc loading. The bowl-shaped PEG-b-PS solution obtained in Example 1, the Fe ₃ O ₄ nanoparticle triethylene glycol solution obtained in Example 2, the ZnPc obtained in Example 3, and the bowl-shaped ISP composite functional nanoparticles obtained in Example 4 were combined. , according to the mass ratio of bowl-shaped structure PEG-b-PS: Fe ₃ O ₄ nanoparticles: ZnPc=100:20:7 to prepare 2mL aqueous solution, in which the concentration of ZnPc is 2.8mg/mL, and its zeta potential value is tested. As shown in Figure 6, the electrical properties of PEG-b-PS, Fe ₃ O ₄ nanoparticles and ZnPc can be obtained by the zeta potential value, and the zeta potential value of the bowl-shaped ISP composite functional nanoparticle solution is basically equal to the potential of the three The sum of the values shows that Fe ₃ O ₄ nanoparticles and ZnPc were successfully loaded on the bowl-like structure PEG-b-PS.

Example 6

ZnPc, bowl-shaped ISP composite functional nanoparticles and their in vitro oxygen detection under magnetic field:

The ZnPc prepared in Example 3 and the bowl-shaped ISP composite functional nanoparticles obtained in Example 4 were irradiated with a 665 nm light source to generate reactive oxygen species and induce apoptosis. Oxygen can react with tris(4,7-biphenyl-1,10-o-phenanthroline) ruthenium dichloride to reduce its fluorescence intensity. The experimental steps are as follows. Hela cells were inserted into the culture plate. After 24 h, DMEM solutions of ZnPc and bowl-shaped ISP composite functional nanoparticles with a concentration of phthalocyanine of 0.7 μg/mL were prepared. (4,7-biphenyl-1,10-o-phenanthroline) ruthenium dichloride, after incubation for 1 h, light was applied to observe the fluorescence intensity.

As shown in Figure 7, tris(4,7-biphenyl-1,10-phenanthroline) ruthenium dichloride is an oxygen detection probe, which itself has fluorescence. After reacting with oxygen, its fluorescence intensity will decrease, The decrease in fluorescence intensity is inversely proportional to the oxygen production capacity. As shown in Fig. 7, under the same experimental conditions, the bowl-shaped ISP composite functional nanoparticles can catalyze the intracellular H ₂ O ₂ to generate oxygen and reduce tris(4,7-biphenyl-1,10-phenanthroline) The fluorescence intensity of ruthenium dichloride, and the bowl-shaped ISP composite functional nanoparticles with a higher magnetic field, the effect of generating oxygen will be better, resulting in tris(4,7-biphenyl-1,10-o-phenanthrene) The fluorescence intensity of ruthenium dichloride was lower. In addition, ZnPc alone is in a hypoxic state due to its consumption of oxygen during illumination, and tris(4,7-biphenyl-1,10-phenanthroline)ruthenium dichloride is the highest. Therefore, after entering the cell, the bowl-shaped ISP composite functional nanoparticle has the effect of improving the activity of the photosensitizer and the targeting ability of the photosensitizer at the same time.

Example 7

In vitro photosensitizing antitumor activity detected by MTT assay:

To compare the photosensitivity antitumor activity of ZnPc and bowl-shaped ISP functional composite nanoparticles and their external magnetic field, the concentration of ZnPc and bowl-shaped ISP functional composite nanoparticles was respectively formulated to be 0.7 μg/mL (calculated as the concentration of phthalocyanine) The DMEM solution was added to the plated Hela cell line, and a group of bowl-shaped ISP functional composite nanoparticles solution was added with magnets under the plate, and the drug was incubated for 4h with a 665nm light source for 10min, and after another 24h of incubation, MTT was used. Cell viability was detected by the method.

As shown in Figure 8, the experimental results show that the anti-tumor activity of the bowl-shaped ISP functional composite nanoparticles is higher than that of ZnPc alone, indicating that the bowl-shaped ISP functional composite nanoparticles of the present invention have the function of improving the activity of photosensitizers. Afterwards, the effect is better and more obvious, indicating that the bowl-shaped ISP functional composite nanoparticles prepared in the example of the present invention have the effect of improving the therapeutic activity of PDT.

Example 8

In vivo anticancer activity assay:

In vivo mouse xenograft model animals, ZnPc and bowl-shaped ISP functional composite nanoparticles and their tumor suppressive ability after external magnetic field were compared. The experimental steps are as follows, with the concentration of phthalocyanine as the standard, the phosphate buffer solution with pH=7.4 was used to prepare a drug solution with a concentration of 3.2 mg/kg, and ZnPc and bowl-shaped ISP functional composite nanoparticles were respectively injected into the charge through the tail vein. In tumor mice, the dose per mouse was 200 μL. When the administration was completed, one group of mice injected with bowl-shaped ISP functional composite nanoparticles was placed in a fixture, and a magnet was attached to the tumor site for targeting. After 6 h of administration, the tumor site was illuminated.

As shown in Figure 9, the results of the anti-tumor activity study in the mouse xenograft model animals showed that the tumor volume change rate of the mice injected with ZnPc and bowl-shaped ISP functional composite nanoparticles was significantly lower than that of the blank control group. It was proved that both ZnPc and bowl-shaped ISP functional composite nanoparticles inhibited tumor growth. By applying an external magnetic field, the tumor volume change of the bowl-shaped ISP functional composite nanoparticles was further inhibited, indicating that the external magnetic field enhanced the enrichment of the bowl-shaped ISP functional composite nanoparticles at the tumor site, thereby improving the treatment of photosensitizers. active.

Example 9

In vivo nuclear magnetic imaging detection

In vivo mouse xenograft model animals, the targeting ability comparison test of bowl-shaped ISP functional composite nanoparticles before and after external magnetic field. The experimental steps are as follows. The bowl-shaped ISP functional composite nanoparticles were prepared into a 0.32 mg/mL drug solution with a pH=7.4 phosphate buffer solution, and administered to the two groups of tumor-bearing nudes by tail vein injection at a dose of 200 μL per animal. In mice, the second group of mice injected with bowl-shaped ISP functional composite nanoparticles was placed in a fixture, and a magnet was attached to the tumor site for targeting and magnetization for 1 h. The MRI images of the two groups of mice were taken at 0h and 24h, respectively. As shown in Figure 10, the results of in vivo T ₂ mode NMR imaging studies in nude mice xenograft model animals showed that the tumor targeting of the bowl-shaped ISP functional composite nanoparticles alone was weaker than that of the bowl-shaped ISP functional composite nanoparticles through an external magnetic field. Nanoparticles, indicating that the bowl-shaped ISP functional composite nanoparticles have good magnetic targeting.

Example 10

The preparation of Example 10 is the same as that of Example 4, except that the mass ratio of the bowl-shaped structure PEG-b-PS, Fe ₃ O ₄ , and ZnPc described in step (3) is 2:1.5:0.5.

Example 11

The preparation of Example 11 is the same as that of Example 4, except that the mass ratio of the bowl-shaped structure PEG-b-PS, Fe ₃ O ₄ , and ZnPc described in step (3) is 3:2.2:1.5.

Claims (10)

1. a bowl-shaped ISP composite functional nano-particle is characterized in that, after being self-assembled into a bowl-shaped structure by a block polymer, loaded Fe ₃ O ₄ particles and photosensitizer ZnPc are formed; the block polymer is polyethylene Diol block polystyrene (PEG- b -PS); The bowl-shaped ISP composite functional nanoparticles include the following steps: (1) Synthesis and self-assembly preparation of bowl-shaped PEG- b -PS: After PEG-OH was uniformly dissolved in tetrahydrofuran, 2-bromoisobutyryl bromide was added to react under _N2 protection and ice-water bath. After suction filtration, the supernatant was extracted with NaHCO ₃ solution, and dried in vacuo to obtain PEG-Br macromolecular initiator; the PEG-Br macromolecular initiator was dissolved in anisole to dissolve, added styrene, CuCl and PMDETA were reacted, and the product passed through Purification and separation, the obtained solution was concentrated by vacuum distillation and then settled in methanol solution, and the precipitate was vacuum-dried after suction filtration to obtain a polyethylene glycol block polystyrene polymer, which was PEG- b -PS; the PEG- b- PS was dissolved in a mixed solution of 1,4-dioxane and tetrahydrofuran, and injected with double distilled water to obtain a bowl-shaped PEG- b -PS solution; (2) Synthesis of superparamagnetic Fe ₃ O ₄ nanoparticles: Fe(acac) ₃ was dissolved in triethylene glycol, and a solution of superparamagnetic Fe ₃ O ₄ nanoparticles was synthesized by thermal decomposition; (3) Preparation of bowl-shaped ISP functional composite nanoparticles: The Fe ₃ O ₄ nanoparticle solution with triethylene glycol modification was mixed with the bowl-shaped structure PEG- b -PS solution, and the solution was mixed with triethylene glycol and PEG. The similar compatibility characteristics of the inter-structures make Fe ₃ O ₄ nanoparticles loaded in the bowl-like structure PEG- b -PS, and centrifugation after ultrasonication obtains the bowl-like structure PEG- b -PS nanoparticles loaded with Fe ₃ O ₄ nanoparticles. , and then the ZnPc solution was added to it, mixed, and centrifuged after ultrasonication to obtain bowl-shaped ISP functional composite nanoparticles. 2 . The bowl-shaped ISP composite functional nanoparticle according to claim 1 , wherein the bowl-shaped ISP composite functional nanoparticle has a bowl-shaped structure, and the Fe ₃ O ₄ nanoparticles are loaded in the concave cavity of the bowl-shaped structure. 3 . A functional nanocarrier with magnetic targeting is formed in the groove, and then ISP functional composite nanoparticles are obtained by loading a photosensitizer ZnPc. 3 . The bowl-shaped ISP composite functional nanoparticle according to claim 1 , wherein the bowl-shaped ISP composite functional nanoparticle is an organic-inorganic composite nanoparticle suitable for intravenous injection. 4 . 4. the preparation method of the bowl-shaped ISP functional composite nano-particle of claim 1, is characterized in that, comprises the steps: (1) Synthesis and self-assembly preparation of bowl-shaped PEG- b -PS: After PEG-OH was uniformly dissolved in tetrahydrofuran, 2-bromoisobutyryl bromide was added to react under _N2 protection and ice-water bath. After suction filtration, the supernatant was extracted with NaHCO ₃ solution, and dried in vacuo to obtain PEG-Br macromolecular initiator; the PEG-Br macromolecular initiator was dissolved in anisole to dissolve, added styrene, CuCl and PMDETA were reacted, and the product passed through Purification and separation, the obtained solution was concentrated by vacuum distillation and then settled in methanol solution, and the precipitate was vacuum-dried after suction filtration to obtain a polyethylene glycol block polystyrene polymer, which was PEG- b -PS; the PEG- b- PS was dissolved in a mixed solution of 1,4-dioxane and tetrahydrofuran, and injected with double distilled water to obtain a bowl-shaped PEG- b -PS solution; (2) Synthesis of superparamagnetic Fe ₃ O ₄ nanoparticles: Fe(acac) ₃ was dissolved in triethylene glycol, and a solution of superparamagnetic Fe ₃ O ₄ nanoparticles was synthesized by thermal decomposition; (3) Preparation of bowl-shaped ISP functional composite nanoparticles: The Fe ₃ O ₄ nanoparticle solution with triethylene glycol modification was mixed with the bowl-shaped structure PEG- b -PS solution, and the solution was mixed with triethylene glycol and PEG. The similar compatibility characteristics of the inter-structures make Fe ₃ O ₄ nanoparticles loaded in the bowl-like structure PEG- b -PS, and centrifugation after ultrasonication obtains the bowl-like structure PEG- b -PS nanoparticles loaded with Fe ₃ O ₄ nanoparticles. , and then the ZnPc solution was added to it, mixed, and centrifuged after ultrasonication to obtain bowl-shaped ISP functional composite nanoparticles. 5. The preparation method according to claim 4, characterized in that, in step (1), the PEG-Br is dissolved in anisole, and styrene is added, and CuCl and PMDETA are reacted in the mixture under anhydrous and anoxic conditions. The reaction was carried out at 80-100 °C overnight; the PEG-Br and styrene in step (1) were in an argon atmosphere during the feeding period, and the low temperature state of the raw materials was maintained by placing the reaction vessel in an ice-water bath. 6 . The preparation method according to claim 4 , wherein in step (2), the synthesis of superparamagnetic Fe ₃ O ₄ nanoparticle solution by thermal decomposition method is Fe(acac) ₃ dissolved in triethylene glycol 6 . After homogenization, the gradient temperature was raised to 200 ℃, 250 ℃, and 280 ℃ under N ₂ protection, respectively, and the reaction was refluxed at 280 ℃ for 0.5-1 h to obtain a superparamagnetic Fe ₃ O ₄ nanoparticle solution. 7 . The preparation method according to claim 6 , wherein the gradient heating in step (2) is maintained at 200° C. and 250° C. for 5-10 min respectively. 8 . 8 . The preparation method according to claim 4 , wherein the mass ratio of PEG- b -PS, Fe ₃ O ₄ , and ZnPc described in step (3) is 2-3:1.5-2.2:0.5-1.5 . . 9 . The application of the bowl-shaped ISP functional composite nanoparticle of claim 1 in the preparation of photodynamic drugs. 10 . 10 . The application according to claim 9 , wherein the bowl-shaped ISP functional composite nanoparticles are used as photosensitizers and carriers in the preparation of photodynamic drugs. 11 .

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