CN114344476B - Preparation and application of polymer prodrug modified coordination nano chemical power carrier - Google Patents
Preparation and application of polymer prodrug modified coordination nano chemical power carrier Download PDFInfo
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 19
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of design of nano-medical antitumor prodrugs and drug delivery carriers, and mainly relates to preparation of a polymer prodrug modified coordination nano-chemical power carrier and application of the polymer prodrug modified coordination nano-chemical power carrier in preparation of antitumor drugs. The construction mode of the polymer prodrug modified coordination chemical power carrier is that the polymer prodrug is modified on the surface of a nano coordination carrier by physical or coordination action, and in-vivo and in-vitro efficacy experiments prove that the hydrogen peroxide source and the iron source in tumor tissues can be synchronously increased, and high-activity active oxygen is generated through Fenton reaction to realize the synergy of chemotherapy-chemical dynamic treatment.
Description
Technical Field
The invention belongs to the field of design of nano-medical antitumor prodrugs and drug delivery carriers, and mainly relates to preparation of a polymer prodrug modified coordination nano-chemical power carrier and application of the polymer prodrug modified coordination nano-chemical power carrier in preparation of antitumor drugs.
Background
With the progress of science and technology, many fatal diseases have been effectively treated in the past, but malignant tumors remain one of the main causes of death in humans. Today, people pay more attention to life health and the treatment demands on cancer patients are urgent. The main treatment methods of cancer patients clinically include operation treatment, radiotherapy and chemotherapy, immunotherapy and the like. The early tumor surgical treatment can achieve good effect, but because the early detection rate of domestic cancer patients is low, the surgical treatment has the problems of high recurrence and poor curative effect for most domestic advanced cancer patients, and only a small number of patients can benefit from immunotherapy. Therefore, chemotherapy is still the main means of tumor treatment, but the problems of high systemic toxic and side effects and poor curative effect still exist. Development of novel high-efficiency low-toxicity tumor treatment means is a clinical urgent need.
Chemical kinetics therapy (CDT) is a treatment method for transforming low-activity hydrogen peroxide into hydroxyl free radicals with high cytotoxicity through Fenton reaction mainly through ferrous ion and other catalysts so as to kill tumor cells, and is proved to be a practical and effective tumor specific oxidation treatment mode. Compared with photodynamic therapy and sonodynamic therapy which need to be triggered by exogenous energy, CDT therapy utilizes the high hydrogen peroxide environment endogenous to tumor cells, has congenital tumor selectivity, is not limited by tumor positions, and has great potential in the field of tumor treatment. However, how to increase the hydrogen peroxide concentration and the ferrous ion concentration in cells and how to increase the accumulation of drugs at tumor sites is a difficulty in CDT therapy treatment.
There are studies reporting that ferroferric oxide nano-particles are delivered to tumor sites for CDT treatment of tumors, but the iron-containing inorganic nano-carrier needs to release free iron ions under the acidic condition of pH 2-4, so that the effect of increasing the concentration of the free iron ions in tumor tissues is very limited, fenton reaction can only be generated on the surface of the carrier, and the application of the iron-containing inorganic nano-carrier in CDT treatment of tumors is greatly influenced. There are also studies on the purpose of treating tumors by delivering glucose oxidase directly as a hydrogen peroxide source, but delivering glucose oxidase directly has problems of poor stability and poor tumor targeting effect. To enhance the therapeutic effects of chemo-kinetic therapy, researchers have focused on delivering hydrogen peroxide sources and ferrous sources simultaneously via pharmaceutical carriers in an effort to achieve potent CDT therapeutic effects. However, the above carriers inevitably introduce organic solvents during the preparation process, the process is complex, and since ferrous ions are easily oxidized, it is difficult to stably deliver a sufficient amount of ferrous source to tumor tissues. In addition, uncontrolled release of hydrogen peroxide and iron sources in the blood circulation and normal tissues also results in toxic side effects on normal tissues. Therefore, developing a delivery vehicle that responds to drug release in tumor tissue and that can stably deliver sufficient ferrous and hydrogen peroxide sources is one of the technical challenges faced by current CDT therapies.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a polymer prodrug modified coordination nano chemical power carrier, which is characterized in that a coordination nano carrier core is formed by using a heme (ferrous source) and zinc ions, and meanwhile, bortezomib (hydrogen peroxide source) is covalently modified on a hyaluronic acid long chain through a pH sensitive borate bond, and finally, the two are assembled together, so that the heme coordination nano carrier modified by the pH responsive bortezomib hyaluronic acid prodrug is constructed, and the efficient co-delivery of the hydrogen peroxide source and the iron source at a tumor part is realized, and the synergy of efficient chemotherapy-chemical kinetic treatment is realized. The coordination carrier is gathered at a tumor part through the active targeting effect mediated by hyaluronic acid, the meta-acidic environment of the tumor part triggers the release of bortezomib original drug, a large amount of hydrogen peroxide at the tumor part is accumulated, and meanwhile, the chlorhexidine coordination core converts the hydrogen peroxide into hydroxyl free radicals with strong oxidative activity through the superior peroxidase activity, so that the efficient tumor killing effect is realized.
The invention aims to overcome two difficulties in the prior art, namely, the stable co-delivery of a hydrogen peroxide source and a ferrous source in space-time in CDT therapy is realized, a treatment strategy for efficiently treating solid tumors such as triple negative breast cancer is provided, and the accumulation of drugs at tumor positions is improved by a high polymer targeting and sensitive drug release stimulation means, so that the toxic and side effects on normal tissues are reduced.
The aim of the invention can be achieved by the following technical scheme:
a polymer prodrug-modified coordination nano-chemical power carrier, which is characterized by comprising a polymer prodrug and a coordination nano-carrier; the coordination nano-carrier comprises metal ions and organic drug ligands; the polymer prodrug is a covalent drug conjugate, and the coupling mode is 'small molecular drug-stimulus response sensitive bond-high molecular polymer'; the construction mode of the coordination chemical power carrier modified by the polymer prodrug is that the polymer prodrug is modified on the nano coordination carrier by physical or coordination action.
In some of these embodiments, the metal ions include, but are not limited to, one or more of the following: calcium ion, copper ion, zinc ion, manganese ion, cobalt ion or iron ion; the organic drug ligand comprises, but is not limited to, organic molecules containing carboxyl, amino and other coordinatable structures such as heme, ferrocene and the like; the nano coordination carrier is prepared by coordination of metal ions and organic drug ligands.
In some of these embodiments, the nano-coordinating carriers are prepared by solvothermal methods and high pressure homogenization; solvents for the solvothermal process include, but are not limited to, deionized water, absolute ethanol, and the like; the reaction temperature of the solvothermal method can be 60-100 ℃ and the reaction time can be 4-48 h; the particle size of the nano coordination carrier obtained after high-pressure homogenization is 20-500 nm.
In some of these embodiments, the small molecule drug in the polymeric prodrug includes, but is not limited to, bortezomib, ifenesin Sha Zuomi, toyocamycin, dihydroartemisinin, camptothecins, cinnamaldehyde, or cisplatin, among others, which are small molecules capable of producing hydrogen peroxide in cells.
In some of these embodiments, the stimulus-responsive sensitive bond in the polymeric prodrug is responsive to pH, glutathione, reactive oxygen species, or highly expressed enzymes in the tumor microenvironment or tumor cells; the enzymes highly expressed by the tumor tissue include, but are not limited to, matrix metalloproteinase, furin, legumain, FAP-alpha, or cathepsin, etc.
In some of these embodiments, the high molecular polymer includes, but is not limited to, hyaluronic acid, fucan, polyethylene glycol, sodium alginate, chitosan, chondroitin sulfate, polyvinyl alcohol, polylactic acid, dextran, polyvinylpyrrolidone, dextran, or the like; the molecular weight of the high molecular polymer is 2 k-50 w.
Another object of the present invention is to provide an application of the polymer prodrug modified coordination nano-chemical power carrier in preparing a medicine for treating solid tumor.
In some embodiments, the polymer prodrug modified coordination nano-chemical power carrier can synchronously increase the hydrogen peroxide source and the iron source in tumor tissues, and can generate high-activity active oxygen through Fenton reaction to realize the synergy of chemotherapy-chemical kinetics treatment.
Compared with the prior art, the invention has the following beneficial effects:
the polymer prodrug modified coordination nano chemical power carrier designed and synthesized by the invention can accumulate at a tumor part through the active targeting effect of hyaluronic acid, stimulate response and break bonds at the tumor part, release bortezomib original-shaped drugs, further generate a large amount of hydrogen peroxide, and simultaneously convert the hydrogen peroxide into hydroxyl free radicals with higher toxicity by using a hemin-zinc coordination carrier, thereby realizing the cascade amplification effect of oxidative stress. The invention realizes the problem of synchronous targeted delivery of the hydrogen peroxide source and the iron source to the tumor part and realizes a high-efficiency and low-toxicity treatment strategy for solid tumors such as triple negative breast cancer.
Drawings
The drawings in the present invention are described in detail below:
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a bortezomib hyaluronic acid prodrug in example 1.
FIG. 2 is a graph of dynamic light scattering particle size and Zeta potential for the chlorhexidine-zinc coordination carrier and the bortezomib hyaluronic acid prodrug chlorhexidine-zinc coordination carrier of examples 2 or 3;
wherein FIG. 2A is a graph showing the dynamic light scattering particle size distribution before and after loading of the chlorhexidine-zinc coordination carrier, and FIG. 2B is a graph showing the Zeta potential change before and after loading of the chlorhexidine-zinc coordination carrier. After drug loading, the particle size of the coordination carrier of the hemin-zinc is slightly increased, and the negative potential is increased.
FIG. 3 is a graph showing the cytotoxicity of the coordination carrier of the bortezomib hyaluronic acid prodrug, hemin-zinc, on MDA-MB-231 tumor in example 4.
FIG. 4 is a graph showing the results of intracellular ROS production by a coordination carrier carrying the bortezomib hyaluronic acid prodrug hemin-zinc in example 5.
FIG. 5 is a graph showing the tumor suppression effect of example 6 on the co-ordinated delivery system of the bortezomib hyaluronic acid prodrug, hemin-zinc;
the drug delivery system has obvious tumor treatment effect on triple negative breast cancer.
Detailed Description
The following description of preferred embodiments of the present invention is provided only for the purpose of explaining the present invention, and the present invention is not limited thereto, and the concentration, volume, reaction time, etc. of the reagents used may be adjusted according to the specific circumstances.
Example 1: preparation of bortezomib hyaluronic acid prodrug (HA-DA-BTZ)
2.00g of sodium hyaluronate (1-10W) was weighed, added to 80ml of absolute ethanol, 8ml of concentrated hydrochloric acid was added under stirring, and stirred at room temperature for 1 hour. Standing for 1 hr, and removing supernatant. Then, 80ml of absolute ethanol was added thereto, 8ml of concentrated hydrochloric acid was added thereto with stirring, stirring was performed at room temperature for 1 hour, and the supernatant was removed after standing, and the above procedure was repeated three times. After removing the supernatant for the third time, the mixture was centrifuged at 4000rpm for 7 minutes, the supernatant was removed, and the centrifugation was repeated 3 times. The obtained solid is dissolved in 100mL of ultrapure water, tetrabutylammonium hydroxide is added dropwise into the solution to adjust the pH to be neutral, and the product HA-TBA is obtained after freeze drying.
1.00g of HA-TBA was dissolved in 50mL of DMF, 0.48g of HDBT and 0.32g of DIC were added thereto, and the mixture was stirred well under nitrogen atmosphere at room temperature for 1 hour. After the reaction was completed, 0.48g of Dopamine (DA), 0.31g of DMAP and 1.62g of DIPEA were added in this order, and stirred at room temperature for 4 hours. After the reaction, the solution was dialyzed in sodium chloride solution having a pH of 4 to 5 for 36 hours, and then dialyzed in pure water for 36 hours. And after the dialysis is finished, freeze-drying to obtain the product HA-DA.
0.20g of HA-DA is weighed and dissolved in a proper amount of formamide, then 0.29g of Bortezomib (BTZ) is weighed and dissolved in a proper amount of DMSO, and the BTZ solution is slowly dripped into the HA-DA solution and stirred for 24 hours at room temperature. After the complete reaction, the mixture was dialyzed in pure water for 24 hours, and the final product HA-DA-BTZ was obtained by freeze-drying.
According to the nuclear magnetic resonance results (figure 1), the synthesized product has characteristic peaks on methyl on a hyaluronic acid chain between 1.0 and 2.0ppm, characteristic peaks on benzene ring of phenylboronic acid between 6.55 and 6.98ppm, characteristic peaks on benzene ring of bortezomib between 7.00 and 7.50ppm, and characteristic peaks on bortezomib pyrazine cyclic group between 8.65 and 9.20ppm, which indicates that the bortezomib hyaluronic acid prodrug has been successfully synthesized.
Example 2: preparation of Hemin-Zinc ligand (Hemin-MOF)
Weighing appropriate amount of Hemin (Hemin) and dissolving in DMSO to prepare 0.5mM concentration of Hemin PBS solution, and weighing appropriate amount of Zn (NO) 3 ) 2 6H2O was dissolved in ultrapure water to prepare a zinc ion aqueous solution having a concentration of 27 mM. Firstly, a proper amount of zinc ion aqueous solution is added into a round-bottom flask, half volume of chlorhexidine PBS solution is slowly dripped into the round-bottom flask during stirring, stirring is continued for 15 minutes until the mixture is fully mixed after the dripping is finished, and the mixture is transferred into a polyvinyl fluoride high-pressure reaction kettle and then is put into an oven at 80 ℃ for reaction overnight. And (3) after the reaction kettle is cooled to room temperature, centrifuging the mixed solution for 15 minutes at 13000rpm, collecting to obtain a blackish brown solid, washing 3-5 times by using ultrapure water, and drying in a 50 ℃ oven to obtain the micron-sized Hemin-MOF. Nanoscale Hemin-MOFs were prepared by repeated high pressure homogenization and extensive sonication.
According to the dynamic light scattering particle size results (FIG. 2A), the particle size of the Hemin-MOF obtained after high-voltage mean is about 150-180nm, the particle size is uniform, and the Zeta potential measurement results show that the Hemin-MOF is negative in Zeta potential (FIG. 2B).
Example 3: coordination of hemin-zinc of bortezomib hyaluronic acid prodrugsConstruction of drug delivery System
(Hemin@HA-BTZ)
The powder of Hemin-MOF prepared in example 2 was ultrasonically dispersed in ultrapure water to prepare a 1mg/mL solution of Hemin-MOF, and the HA-DA-BTZ material prepared in example 1 was ultrasonically dispersed in ultrapure water to prepare a 2mg/mL solution of HA-DA-BTZ. 1mL of the prepared Hemin-MOF solution was added to 4mL of the HA-DA-BTZ solution, and the mixture was stirred at a low speed at room temperature for 4 hours. After the full reaction, centrifuging for 15 minutes at 13000rpm, collecting the precipitate, washing 3-5 times by ultrapure water, and drying in a 50 ℃ oven to obtain the drug-loaded nanoparticle Hemin@HA-BTZ.
According to the dynamic light scattering particle size results (FIG. 2A), the particle size of the obtained drug-loaded nanoparticle Hemin@HA-BTZ is slightly larger than that of the drug-unloaded Hemin-MOF, and is about 150-200nm. Zeta potential measurement results show (figure 2B) that negative potential becomes strong after the Hemin-MOF is coated with the bortezomib prodrug, indicating that the negatively charged HA-DA-BTZ is successfully coated on the surface of the Hemin-MOF.
Example 4: hemin@HA-BTZ in vitro cytotoxicity experiment
Will be 5X 10 4 MDA-MB-231 cells at individual/well density were seeded in 96-well plates at 5% CO 2 The cells were cultured in a cell incubator for 24 hours, and after adding culture medium (89% DMEM medium+10% fetal bovine serum+1% diab) containing 0, 0.78, 1.56, 3.13, 6.25, 12.5, 25. Mu.M Hemin (0, 0.078, 0.156, 0.313, 0.625, 1.25, 2.5. Mu.M BTZ) hemin@HA-BTZ to the cells for 48 hours, 20. Mu.L MTT (5 mg/mL, PBS solution) was added to each well, and incubated for 4 hours under dark conditions. After the culture broth was aspirated, 100. Mu.L of DMSO was added to each well, and immediately after shaking for 15min, the absorbance at 490nm was measured with an ELISA reader. The survival rate of cells was calculated using the drug-free group as a control group and the cell-free hole as a blank group according to the following formula: cell viability (%) = (OD sample-OD blank)/(OD control-OD blank) ×100%.
As shown in FIG. 3, in MDA-MB-231 tumor cells, hemin@HA-BTZ HAs obvious cytotoxicity, and the action mechanism of the Hemin@HA-BTZ is probably that the bortezomib prodrug HA-DA-BTZ can cause accumulation of hydrogen peroxide in the cells, and Hemin-MOF HAs the action of peroxidase and can convert the hydrogen peroxide in the cells into hydroxyl free radicals with stronger killing effect, so that the effect of killing the tumor cells to chemical kinetics is achieved.
Example 5: hemin@HA-BTZ intracellular ROS investigation experiment
MDA-MB-231 cells at a density of 1X 105 cells/well were seeded in 6-well plates at 5% CO 2 After incubation in a cell incubator for 24h, the cells were incubated with a culture medium (89% DMEM medium+10% fetal bovine serum+1% diab) containing 0, 50. Mu.g/mL of Hemin@HA-BTZ for 12h, the culture medium was aspirated, and 1mL of DCFH-DA (10. Mu.M in DMEM) was added to each well and incubated in the incubator at 37℃for 20 min. The probe was aspirated, washed 3 times with 1ml pbs per well, and the cells were collected by digestion and examined for intracellular ROS production using a flow cytometer.
As shown in fig. 4, after MDA-MB-231 cells were incubated with hemin@ha-BTZ, fluorescence of the obvious DCFH-DA probe could be detected in the cells, indicating that intracellular ROS were significantly increased after administration, demonstrating that hemin@ha-BTZ may cause mitochondrial damage by increasing intracellular ROS content, thereby causing killing of tumor cells.
Example 6: hemin-MOF@HA-BTZ in vivo pharmacodynamics evaluation
Preparation of 2X 10 by digesting and collecting MDA-MB-231 cells 7 The PBS cell suspension of each mL is subcutaneously injected into the armpit of a nude mouse with 100 mu L of the cell suspension to construct a model of MDA-MB-231 nude mouse subcutaneous breast cancer. Observing the tumor state of the nude mice when the subcutaneous tumor volume of the nude mice reaches 100mm 3 At this time, mice were randomly divided into 2 groups (n=5), PBS group and hemin@ha-BTZ group. The nude mice were injected with different drugs according to the group, and were dosed on days 1, 3, 5, 7, 9, the tumor volume and body weight of the mice were recorded and calculated after the first day of dosing, every two days, and the nude mice were sacrificed after 17 days.
As shown in FIG. 5, the PBS group nude mice tumor grows rapidly, and the Hemin@HA-BTZ group nude mice tumor has obvious growth inhibition effect. It is shown that the Hemin@HA-BTZ can generate a large amount of ROS to obviously inhibit tumors by simultaneously increasing the hydrogen peroxide concentration and the ferrous iron concentration in tumors of nude mice.
Claims (2)
1. A polymer prodrug modified coordination nano-chemical power carrier, which is characterized by being prepared from a coordination nano-carrier and a polymer prodrug; the preparation process of the polymer prodrug modified coordination nano-chemical power carrier comprises the following 3 steps:
a. synthesizing a bortezomib hyaluronic acid polymer prodrug, wherein the coupling mode of the polymer and the prodrug is a small molecular drug-a borate bond-a hyaluronic acid dopamine derivative; the specific synthesis process comprises the steps of weighing 2.00g of sodium hyaluronate (1-10W), adding into 80mL of absolute ethyl alcohol, adding 8mL of concentrated hydrochloric acid under stirring, stirring for 1 hour at room temperature, standing for 1 hour, removing supernatant, adding into 80mL of absolute ethyl alcohol under stirring, adding 8mL of concentrated hydrochloric acid under stirring for 1 hour at room temperature, standing, removing supernatant, repeating the above steps for three times, centrifuging at 4000rpm for 7 minutes after removing supernatant for the third time, pouring out supernatant, repeating centrifuging for 3 times, dissolving the obtained solid into 100mL of ultrapure water, dropwise adding tetrabutylammonium hydroxide into the solution to adjust pH to be neutral, and freeze-drying to obtain the hyaluronic acid-tetrabutylammonium hydroxide product; then, 1.00g of hyaluronic acid-tetrabutylammonium hydroxide is weighed and dissolved in 50mL of N, N-dimethylformamide, 0.48g of N, N-diisopropylcarbodiimide and 0.32g of 1-hydroxybenzotriazole are added, and then the mixture is fully stirred for 1 hour at room temperature under the protection of nitrogen, after fully reacting, 0.48g of dopamine, 0.31g of 4-dimethylaminopyridine and 1.62g of N, N-diisopropylethylamine are sequentially added, and stirred for 4 hours at room temperature, after fully reacting, the mixture is dialyzed for 36 hours in sodium chloride solution with pH of 4-5, and then dialyzed for 36 hours in pure water, and after dialysis is finished, the product hyaluronic acid-dopamine is obtained through freeze drying; finally, weighing 0.20g of hyaluronic acid-dopamine, dissolving in a proper amount of formamide, weighing 0.29g of bortezomib, dissolving in a proper amount of dimethyl sulfoxide, slowly dripping the bortezomib solution into the hyaluronic acid-dopamine solution, stirring for 24 hours at room temperature, fully reacting, dialyzing in pure water for 24 hours, and freeze-drying to obtain a final product of bortezomib hyaluronic acid polymer prodrug;
b. preparation of nano-complex of zinc ion and hemin coordination by solvothermal method and high-pressure homogenizationThe preparation method of the carrier comprises weighing appropriate amount of chlorhexidine, dissolving in dimethyl sulfoxide, preparing 0.5mM chlorhexidine PBS solution, and weighing appropriate amount of Zn (NO 3 ) 2 ·6H 2 O is dissolved in ultrapure water to prepare a zinc ion aqueous solution with the concentration of 27mM, a proper amount of zinc ion aqueous solution is firstly taken and added into a round bottom flask, half volume of chlorhexidine PBS solution is slowly dripped into the round bottom flask during stirring, stirring is continued for 15 minutes until the solution is fully mixed after the dripping is finished, the solution is transferred into a polyvinyl fluoride high-pressure reaction kettle and then is put into an 80 ℃ oven for reaction overnight, the reaction kettle is cooled to room temperature, the mixed solution is centrifuged for 15 minutes under the condition of 13000rpm, black brown solid is obtained after collection, the solid is washed for 3 to 5 times by ultrapure water, the micron-sized carrier is obtained after drying in the oven at 50 ℃, and the nanometer-sized carrier is prepared by repeated high-pressure homogenization and full ultrasonic;
c. and b, ultrasonically dispersing the nano-scale ligand carrier powder prepared in the step b in ultrapure water to prepare a 1mg/mL solution, ultrasonically dispersing the bortezomib hyaluronic acid polymer prodrug material prepared in the step a in ultrapure water to prepare a 2mg/mL bortezomib hyaluronic acid polymer prodrug solution, adding 1mL of the prepared nano-scale ligand carrier solution into 4mL of bortezomib hyaluronic acid polymer prodrug solution, stirring for 4 hours at a low speed under the condition of room temperature, centrifuging for 15 minutes under the condition of 13000rpm after full reaction to collect precipitate, washing 3-5 times with ultrapure water, and drying in a 50 ℃ oven to obtain the coordination nano-chemical power carrier modified by the polymer prodrug.
2. Use of a polymer prodrug modified coordination nano-chemical power carrier according to claim 1 in the preparation of a medicament for treating solid tumors.
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