CN114515272A - Near-infrared response gemcitabine prodrug nano polymer medicine and preparation method thereof - Google Patents

Abstract

The invention relates to a near-infrared response gemcitabine prodrug nano polymer drug and a preparation method thereof. A method for preparing a near-infrared-responsive gemcitabine prodrug nano-polymer drug, comprising: (1) carrying out free radical polymerization reaction on a thioketal monomer containing active oxygen response, a coumarin monomer and a methyl polyethylene glycol monomer to obtain an amphiphilic polymer; (2) coupling the amphiphilic polymer and gemcitabine to obtain a prodrug polymer; (3) the prodrug polymer is wrapped with photosensitizer to obtain the near infrared response gemcitabine prodrug nano polymer drug. The invention utilizes polymerizable functional monomers to realize one-step preparation of multifunctional polymer prodrug molecules, improves the synthesis efficiency, overcomes the defects of low utilization rate and strong toxic and side effects of the traditional GEM due to easy decomposition by cytidine deaminase in blood circulation, solves the problem of site-specific drug release by utilizing photosensitizer, realizes the stability of a nano carrier by PEG and achieves the aim of biological safety.

Description

A near-infrared responsive gemcitabine prodrug nanopolymer drug and preparation method thereof

technical field

The invention belongs to the field of nano-drug carrier materials, in particular to a near-infrared response gemcitabine prodrug nano-polymer drug and a preparation method thereof.

Background technique

In recent years, with the development of molecular biology and pharmacy, people have a deeper understanding of the metabolic dynamics of drug molecules, and also have a more in-depth exploration of their physical and chemical properties. A prodrug is a derivative of a drug molecule, which is obtained by chemically modifying the original drug. As a drug precursor, this molecule needs to be transformed in vivo to exert drug activity. The research on nano-drug carriers is expected to solve the problems of low efficiency and systemic toxicity. It has designable physical, chemical and biological properties, which can improve the distribution of drugs in tissues and organs in the body to a certain extent, and effectively improve drug availability. Thereby improving the biological safety of chemotherapeutic drugs.

The birth of prodrugs greatly exploits the potential of existing drug molecules, and provides new ideas for improving the physicochemical properties and therapeutic effects of drugs. It effectively helps the original drug to overcome a series of physiological defects, such as solubility, chemical stability, body absorption barriers and penetration, local irritation and biological selectivity and so on. Especially for hydrophilic drugs that are not easy to be physically embedded, chemical bonding provides the possibility for their loading. And through molecular design, the prodrug can also be endowed with stimuli responsiveness, which not only avoids the leakage problem of physically embedded drugs, but also realizes the controllable release of drugs, which is the best of both worlds. In addition to linking a single drug, multiple drug molecules can also be co-loaded to achieve synergistic therapy.

Gemcitabine (GEM) is currently a widely used chemotherapy drug, especially the first-line drug for pancreatic cancer. However, its metabolism in the body is not ideal, and it is easily degraded by deaminase resulting in inactivation, so its bioavailability is very low. In order to improve the stability of GEM, prolong the circulation time in vivo, and optimize biodistribution, the present invention proposes a new gemcitabine prodrug nano-polymer drug and a preparation method thereof. The drug delivery system (DDS) technology is used to realize the efficient delivery of GEM.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a preparation method of a near-infrared response gemcitabine prodrug nanopolymer drug, which utilizes a polymerizable functional monomer to realize the one-step preparation of a multifunctional prodrug polymer molecule, which greatly improves the synthesis efficiency and makes up for the The traditional GEM is easy to be decomposed by cytidine deaminase in the blood circulation, the utilization rate is low, and the toxic and side effects are strong. The photosensitizer is used to solve the problem of fixed-point drug release, and the stability of the nanocarrier is realized by PEG, and the biosafety is achieved. Purpose.

In order to achieve the above purpose, the adopted technical scheme is:

A preparation method of a near-infrared responsive gemcitabine prodrug nano-polymer drug, comprising the following steps:

(1) carrying out radical polymerization reaction of thioketal monomer containing active oxygen response, coumarin monomer and methyl polyethylene glycol monomer to obtain amphiphilic polymer;

(2) coupling the amphiphilic polymer and gemcitabine to obtain a prodrug polymer;

(3) The prodrug polymer is coated with a photosensitizer to obtain the near-infrared response gemcitabine prodrug nanopolymer drug.

Further, in the step (1), after the reactive oxygen species-responsive thioketal monomer is coupled to p-nitrophenyl chloroformate, radical polymerization is performed.

Still further, the operation of the thioketal monomer coupling intermediate containing active oxygen response is as follows: after the thioketal monomer and triethylamine are dissolved in dichloromethane, the reaction solution is added dropwise, and the reaction is completed. After quenching reaction with saturated ammonium chloride, washing with brine, reverse extraction with water, collecting the organic phase and spin-drying, chromatographic separation;

The reaction solution is a dichloromethane solution containing p-nitrophenyl chloroformate.

Further, in the step (1), AIBN is used to initiate radical polymerization.

Further, in the step (1), the step of free radical polymerization is as follows: mixing according to the mass ratio of hydrophilic and hydrophobic segments of 2:1, adding AIBN, initiating monomer polymerization, and reacting under argon at 70°C for 24 hours, Dialysis was performed at 40° C. for 2 days, then at room temperature for 3 days, and then dried to obtain an amphiphilic polymer.

Further, in the step (2), the amphiphilic polymer and gemcitabine are coupled by triethylamine;

In the step (3), the photosensitizer is ZnPc.

Still further, the coupling step is as follows: dissolving the amphiphilic polymer and excess gemcitabine in DMSO, adding excess triethylamine, stirring for 24 hours, dialysis with hot water for 3 days, and freeze-drying, Prodrug polymers are obtained.

Further, the operation of the step (3) is: dissolving the prodrug polymer and the photosensitizer in DMSO, dropwise adding PBS, stirring for 4h, dialyzing for 3 days, and freeze-drying.

Still further, the mass ratio of the prodrug polymer and the photosensitizer is 10:0.4;

The stirring speed should be 1500rpm.

Another object of the present invention is to provide a near-infrared responsive gemcitabine prodrug nano-polymer drug, prepared by the above-mentioned preparation method, which has better biocompatibility of the drug carrier, and is stable and reliable in the human body. controllable and can be used for drug delivery in cancer cells.

Compared with the prior art, the beneficial effects of the present invention are:

The technical scheme of the present invention prepares a near-infrared response prodrug nano-polymer drug, which has the following advantages:

(1) The use of reactive oxygen species to obtain thioketal to connect the drug makes the drug less susceptible to being disturbed by acid and alkali in the body and falls off, so as to achieve the purpose of safely delivering the drug.

(2) The addition of the photosensitizer ZnPc enables the prodrug polymer to obtain a spatial drug release pathway, that is, light generates reactive oxygen species to cleave the thioketal for local drug release chemotherapy, and the excess reactive oxygen species continue to destroy cancer cells and cause their apoptosis, which makes Cancer treatment achieves better safe therapeutic effects in space and time.

(3) The outer layer modification of PEG enables the carrier to ensure the stability of effective circulation in vivo.

(4) The design of the prodrug polymer provides a good loading effect for the loading of gemcitabine, a hydrophilic drug that is easily degraded in vivo. The drug of the present invention exhibits the characteristics of improving the biocompatibility and safety of the carrier and the controlled drug release at the tumor site at a fixed point in time and space, and can be used for drug delivery at the tumor site.

Description of drawings

Fig. 1 is the 1H NMR spectrum of the prodrug polymer in Example 1; wherein, Fig. 1a is the 1H NMR spectrum when the drug is not conjugated; Fig. 1b is the 1H NMR spectrum after the drug is conjugated;

Fig. 2 is the TEM image of the prodrug polymer micelle before and after reactive oxygen response in Example 2; wherein, Fig. 2a is the TEM image of the prodrug polymer micelle under no illumination condition, and Fig. 2b is the near-infrared illumination condition TEM image of the lower prodrug polymer micelles;

Fig. 3 is the infrared spectrogram of polymer in embodiment 3;

Fig. 4 is a graph of simulated drug release in vitro in Example 4;

Fig. 5 is a graph of the cytotoxicity experiment in Example 5; wherein, Fig. 5a is a graph of the cytotoxicity experiment under no illumination condition, and Fig. 5b is a graph of the cytotoxicity experiment under an illumination condition.

Detailed ways

In order to further describe a near-infrared responsive gemcitabine prodrug nanopolymer drug of the present invention and a preparation method thereof, and achieve the intended purpose of the invention, the following describes a near-infrared responsive gemcitabine prodrug nanopolymer proposed according to the present invention with reference to the preferred embodiments. Drugs and their preparation methods, their specific embodiments, structures, characteristics and their efficacy, are described in detail as follows. In the following description, different "an embodiment" or "embodiments" do not necessarily refer to the same embodiment. Furthermore, the particular features, structures or characteristics in one or more embodiments may be combined in any suitable form.

Below in conjunction with specific embodiment, a kind of near-infrared response gemcitabine prodrug nano-polymer medicine of the present invention and its preparation method will be further introduced in detail:

The object of the present invention is to achieve efficient delivery of GEMs through drug delivery system (DDS) technology. Stimuli-responsive DDS has ideal drug-controlled release properties. It can maintain good stability during circulation, prevent drug leakage, and achieve stimuli-responsive drug release in the special microenvironment of the tumor site. According to different drug properties, choosing appropriate DDS can effectively solve the defects of the drug itself. Based on this, the present invention designs a reactive oxygen species-responsive polymer prodrug micelle carrier for water-soluble GEM, and grafts drug molecules through a post-modification method. The system has good biocompatibility, and can release drugs under the action of ROS generated by exposure to light in the tumor site to synergize with chemotherapy and photodynamic therapy. In order to simplify the preparation process and avoid the tedious post-modification process, the present invention proposes the concept of modular polymerization, and utilizes polymerizable functional monomers to realize one-step preparation of multifunctional prodrug polymer molecules, which greatly improves the synthesis efficiency. Efficiently kill tumor cells, improve efficiency, and reduce biological toxicity. The preparation process of the present invention is simple, the material preparation is safe and effective, and has the characteristics of personalized nano-carriers, which will provide research ideas and basis for designing nano-drug carriers with practical application value. for nanomedicine.

The technical scheme of the present invention is:

A preparation method of a near-infrared responsive gemcitabine prodrug nano-polymer drug, comprising the following steps:

(1) carrying out radical polymerization reaction of thioketal monomer containing active oxygen response, coumarin monomer and methyl polyethylene glycol monomer to obtain amphiphilic polymer;

(2) coupling the amphiphilic polymer and gemcitabine to obtain a prodrug polymer;

(3) The prodrug polymer is coated with a photosensitizer to obtain the near-infrared response gemcitabine prodrug nanopolymer drug.

Preferably, in the step (1), after the reactive oxygen species-responsive thioketal monomer is coupled to p-nitrophenyl chloroformate, free radical polymerization is performed.

Further preferably, the operation of the thioketal monomer coupling intermediate containing active oxygen response is as follows: after the thioketal monomer and triethylamine are dissolved in dichloromethane, the reaction solution is added dropwise, and the reaction is completed. After quenching reaction with saturated ammonium chloride, washing with brine, reverse extraction with water, collecting the organic phase and spin-drying, chromatographic separation;

The reaction solution is a dichloromethane solution containing p-nitrophenyl chloroformate.

Preferably, in the step (1), AIBN is used to initiate radical polymerization.

Preferably, in the step (1), the step of free radical polymerization is: according to the mass ratio of hydrophilic segment and hydrophobic segment of 2:1, mixing in DMSO, adding AIBN, initiating monomer polymerization, argon After reacting at 70°C for 24 hours, the amphiphilic polymer was obtained by dialysis at 40°C for 2 days and then at room temperature for 3 days.

Preferably, in the step (2), the amphiphilic polymer and gemcitabine are coupled by triethylamine;

In the step (3), the photosensitizer is ZnPc.

Further preferably, the coupling step is: dissolving the amphiphilic polymer and excess gemcitabine in DMSO, adding excess triethylamine, stirring for 24 hours, dialysis with hot water for 3 days, and freeze-drying, Prodrug polymers are obtained.

Preferably, the operation of the step (3) is as follows: dissolving the prodrug polymer and the photosensitizer in DMSO, adding PBS dropwise, stirring for 4 hours, dialyzing for 3 days, and freeze-drying.

Further preferably, the mass ratio of the prodrug polymer and the photosensitizer is 10:0.4;

The stirring speed should be 1500rpm.

In the present invention, by synthesizing active oxygen-responsive small molecular monomers and hydrophilic and hydrophobic monomers and combining them to form nano-polymer prodrugs, small molecular drugs and polymers can be formed into polymer prodrugs, and the nano-drugs are rich in photosensitizers and can be used in Under the irradiation of near-infrared light, the photosensitizer generates reactive oxygen species, so that the reactive oxygen species-responsive drug monomers are broken to release drug molecules, which is conducive to the effective release of drugs in the current environment with insufficient oxidative stress inside the tumor. The strong permeability can effectively penetrate the skin tissue to reach the vicinity of the tumor, and reduce the non-specific leakage of the drug-loaded carrier in the body environment. Gemcitabine is currently the first-line drug for the clinical treatment of pancreatic cancer. However, due to its poor stability in the circulation in vivo, it is easily degraded and inactivated by deaminase, so it has to be taken in high doses clinically to make up for its low bioavailability, resulting in unavoidable side effects. The emergence of nano-drug carriers provides the possibility for the efficient delivery of GEMs. The invention can effectively improve the utilization rate of GEM in the body and maintain circulation inertness. By irradiating the tumor site with near-infrared light, the photosensitizer generates a sufficient amount of reactive oxygen species to break the thioketal and release the drug. At the same time, the excess reactive oxygen species can damage the cell membrane or organelle membrane. Thereby, the effect of targeted tumor killing is achieved; the present invention is based on biological safety, which greatly improves the efficiency of targeted drug release and reduces the problem of non-specific drug release in the blood environment and GEM degradation. The nanoparticles are assembled into micelles after coupling with covalent bonds, so that the drug is protected in the inner core of the micelle and should not leak. Through near-infrared light irradiation, it reaches the photosensitizer ZnPc in the polymer micelles near the tumor, making the tumor environment The active oxygen is greatly improved, which is conducive to the targeted release of drugs, and the increased active oxygen causes the cells to be destroyed and die.

Example 1.

The specific operation steps are as follows: (the amount "parts" taken is parts by weight)

(1) Synthesis of active oxygen-responsive monomer molecule thioketal monomer, and coupling of its coupling intermediate. The operation steps are as follows:

After mixing 6 g of trimercaptopropionic acid and 6.5 g of acetone, it was placed in a cold trap, and 4 mL of concentrated hydrochloric acid was slowly added dropwise. (In this step: the excess of acetone is enough, the dropwise addition of concentrated hydrochloric acid should be slow, the stirring speed should be about 300rpm, the temperature of the cold trap should be about -5°C during the dropwise addition, and the reaction temperature should be at 0°C to prevent the volatilization of acetone caused by exothermic heat, reaction is difficult)

Then take 1g of double-terminated carboxyl thioketal and dissolve it in dewatered tetrahydrofuran, add 1.6g lithium aluminum tetrahydrogen to it slowly and in batches, after refluxing for 1h, slowly add 1.6g H ₂ O, 4.8g 10% NaOH aqueous solution, 4.8g gH ₂ O was used to quench the reaction. After cooling for a period of time, the tetrahydrofuran solution was slowly added until no bubbles were formed in the reaction vessel, suction filtration, and the supernatant liquid was removed by rotary evaporation, and vacuum-dried to obtain a double-ended hydroxythioketal. (In this step: the reflux temperature must be 60°C, and the vacuum drying temperature must not be higher than 40°C)

Finally, take 2.69g of double-ended hydroxythioketal and 1.012g of TEA (that is, triethylamine), dissolve them in 50mL of dichloromethane, slowly add 1.045g of methacryloyl chloride dissolved in 20mL of dichloromethane, and react at room temperature for 24h. , and purified by chromatography to obtain a thioketal monomer with one double bond and one hydroxyl group. (in this step: all solvents need to be refluxed to remove water. During chromatographic purification, the ratio of ethyl acetate: sherwood oil is 4: 1)

In order to further enable the monomer to efficiently couple gemcitabine drug molecules, 400 mg of thioketal monomer and 0.202 g of TEA were dissolved in 5 mL of dichloromethane, and 5 mL of 398 mg of p-nitrophenyl chloroformate was added dropwise to the mixture. Dichloromethane. After the reaction was completed, the reaction was quenched with 30 mL of saturated ammonium chloride, washed with brine, and extracted in reverse with water. The organic phase was collected, spin-dried, and separated by chromatography. In this step: the ratio of n-hexane: dichloride is 3:7 to 0:1 during chromatographic purification)

(2) Synthesis of hydrophobic coumarin monomer:

Mix 3 g of 7-hydroxy-4-methylcoumarin, 4.71 g of potassium carbonate and 30 mL of DMF, stir vigorously for 30 min, add 0.142 g of potassium iodide and 2.76 g of 2-bromoethanol, heat to 110 °C for reaction for 5 h, cool and add 800 mL of ice water was placed at 4°C for 12 h, and the solid was separated and washed with water to obtain the crude product.

The crude product was recrystallized once from aqueous ethanol to obtain AMC, a relatively pure pale pink substance. Under the protection of argon, 2.7g AMC and 3.3g TEA were suspended in 40mL THF and stirred for 1h, and then 10mL THF containing 3.5g methacryloyl chloride was slowly added dropwise, and after 48h reaction at room temperature, suction filtration, rotary evaporation, The ice-water precipitation was filtered, and the filter cake was washed three times with ice-water and recrystallized twice in ethanol to obtain pure coumarin monomer CMA.

(3) Synthesis of hydrophilic methyl polyethylene glycol monomer:

10 g of mPEG2000 and 1.5 g of TEA were dissolved in 40 mL of dichloromethane, and then a solution of 10 mL of dichloromethane containing 1.6 g of methacryloyl chloride was slowly added dropwise at 0 °C under the protection of N ₂ . Then, after reacting at room temperature for 24 hours, the ammonium salt was removed by suction filtration, and the unreacted ether was removed by extraction with saturated sodium chloride three times.

(4) According to hydrophilic segment (hydrophilic methyl polyethylene glycol monomer 0.8g), hydrophobic segment (coupled thioketal monomer 0.25g, coumarin monomer 0.15g), namely According to the mass ratio of hydrophilic and hydrophobic segments of 2: 1, the polymerization reaction was charged, and AIBN was added as an initiator to initiate the polymerization of the monomers. The amphiphilic polymer was prepared by freeze-drying after dialysis at room temperature for 3 days.

(5) 200 mg of amphiphilic polymer and excess 50 mg of gemcitabine were co-dissolved in 20 mL of DMSO, added with excess TEA, stirred for 24 h, lyophilized with hot water for 3 days, and lyophilized to obtain a long chain of the prodrug polymer.

Prodrug polymer hydrogen spectrum detection was performed on the prodrug polymer. The results are shown in Figure 1. The 1H NMR spectrum of the polymer without drug conjugate (Figure 1a) and the 1H NMR spectrum after drug conjugate (Figure 1b), the aromatic region (8.3ppm and 7.4ppm) of unconjugated drug ) on the benzene ring, after coupling with the drug, after the p-nitrobenzene protecting group is removed, the peak of hydrogen here disappears; a new peak s appears at 5.3ppm, s is the characteristic of hydrogen on GEM peak. This indicates that the drug was successfully conjugated.

Example 2.

Dissolve 10 mg of the prodrug polymer and 0.4 mg of ZnPc photosensitizer in 2 mL of DMSO, and slowly add 2 mL of PBS dropwise at a rate of 10 μL/min with a syringe pump. Day, freeze-dried micelles.

The successful preparation of nanoparticles was further demonstrated by transmission electron microscopy.

The results are shown in Fig. 2, Fig. 2a is under no illumination condition, and Fig. 2b is under near-infrared illumination condition. After near-infrared irradiation, the micelles are unstable due to the cleavage of hydrophilic drugs, but they tend to exist stably in solution and reconstitute larger micelles.

In various prodrug structures, polymers have strong design properties, and multifunctionalization can be achieved through molecular design. The preparation of amphiphilic prodrug polymer molecules can self-assemble to form nanoscale micelles. Such prodrug polymer micelles have great advantages. First, the nano-scale gelatin has EPR effect; secondly, the choice of degradable polymer backbone can reflect good biocompatibility; thirdly, the design of special linkages can achieve stimuli-responsive drug release behavior; Finally, such polymeric micelles have strong modifiability properties. The selective enrichment of micelles can be enhanced by modification of targeted molecules. The introduction of PEG stealth molecules can achieve long-term circulation. Combined with fluorescent molecules, cell imaging functions can be achieved.

Example 3.

The comparative samples before and after drug application prepared in Example 1 (ie, the amphiphilic polymer prepared in step (4) of Example 1 and the prodrug polymer prepared in step (5)) were compared with PEG monomers for infrared spectrum analysis.

The results are shown in Fig. 3, the peaks of NH and CN appearing at 1530 cm ^-1 and 1220 cm ^-1 demonstrate the successful coupling of GEM.

Example 4: Simulation of drug release behavior in vitro.

The drug release behavior of the prodrug polymer nanoparticles prepared in Example 2 was investigated within 48 hours.

The results are shown in Figure 4. Through the detection of UV light at the absorbance of 268 nm, when light is applied before the drug release experiment, the drug release will increase with the light. In the group without light, the release curve quickly leveled off.

Example 5: Determination of cytotoxicity of prodrug polymer nanomicelles.

The comparison of the cytotoxicity of the drug-loaded micelles prepared in Example 1 and the non-drug-loaded micelles with different concentrations under the conditions of illumination and non-illumination, respectively, when co-incubating with HeLa cells, the cytotoxicity was detected. 5000 cells per well of a 96-well plate, near-infrared illumination for 30 min at 24 h after drug application, and continued culture for 48 h to conduct MTT test on the cells.

The results are shown in Fig. 5. It can be seen from Fig. 5a that the number of cells does not decrease when different concentrations of nanoparticles are used for Hela cells when no light is applied. It can be seen from Figure 5b that both drug-loaded nanoparticles and non-drug-loaded nanoparticles can kill cells after applying light. The reason for this result is that when the polymer is exposed to light, reactive oxygen species are generated to break the thioketal and release the toxic p-nitrophenol to kill the cells rapidly. For the drug-loaded group, the application of gemcitabine makes the Apoptosis of cancer cells.

It can be seen from the examples of the present invention that the present invention utilizes the active oxygen-responsive thioketal combined with near-infrared light to generate active oxygen-producing ZnPc to perform the function of fixed-point controllable drug release. The drug-loading stability of nanoparticles is achieved by coupling the drug to the polymer. The invention utilizes the linkage action of near-infrared light, photosensitizer and ROS-responsive thioketal bond to form a near-infrared light-responsive nano-prodrug polymer. After the nanoparticles are formed, the drug-loaded nano-carriers are biosafe to prevent non-specific drug leakage, and at the same time, the modular design of the drug carriers can be realized, and the non-specific toxicity of the patients to the nano-drug carriers can be reduced.

The above descriptions are only preferred embodiments of the embodiments of the present invention, and are not intended to limit the embodiments of the present invention in any form. Any simple modifications, equivalent changes, and Modifications still fall within the scope of the technical solutions of the embodiments of the present invention.

Claims (10)

1. a preparation method of near-infrared response gemcitabine prodrug nano-polymer medicine, is characterized in that, comprises the following steps: (1) carrying out radical polymerization reaction of thioketal monomer containing active oxygen response, coumarin monomer and methyl polyethylene glycol monomer to obtain amphiphilic polymer; (2) coupling the amphiphilic polymer and gemcitabine to obtain a prodrug polymer; (3) The prodrug polymer is coated with a photosensitizer to obtain the near-infrared response gemcitabine prodrug nanopolymer drug. 2. preparation method according to claim 1, is characterized in that, In the step (1), after the reactive oxygen species-responsive thioketal monomer is coupled to p-nitrophenyl chloroformate, radical polymerization is performed. 3. preparation method according to claim 2, is characterized in that, The operation of the thioketal monomer coupling intermediate containing active oxygen response is as follows: after dissolving the thioketal monomer and triethylamine in dichloromethane, the reaction solution is added dropwise, and saturated chlorine is used after the reaction is completed. Quenching reaction with ammonium chloride, washing with brine, reverse extraction with water, collecting the organic phase and spin-drying, chromatographic separation; The reaction solution is a dichloromethane solution containing p-nitrophenyl chloroformate. 4. preparation method according to claim 1, is characterized in that, In the step (1), AIBN is used to initiate free radical polymerization. 5. preparation method according to claim 1, is characterized in that, In the step (1), the free radical polymerization step is as follows: mixing the hydrophilic segment and the hydrophobic segment according to a mass ratio of 2:1, adding AIBN to initiate monomer polymerization, and reacting under argon at 70° C. for 24 hours Then, dialysis was performed at 40° C. for 2 days, then at room temperature for 3 days, and then dried to obtain an amphiphilic polymer. 6. preparation method according to claim 1, is characterized in that, In the described step (2), the coupling of the amphiphilic polymer and gemcitabine is catalyzed by providing basic conditions with triethylamine; In the step (3), the photosensitizer is ZnPc. 7. preparation method according to claim 6, is characterized in that, The coupling step is as follows: dissolving the amphiphilic polymer and excess gemcitabine in DMSO, adding excess triethylamine, stirring for 24 hours, dialysis with hot water for 3 days, and freeze-drying to obtain a prodrug polymerization. thing. 8. preparation method according to claim 1, is characterized in that, The operation of the step (3) is as follows: dissolving the prodrug polymer and the photosensitizer in DMSO, dropwise adding PBS, stirring for 4 hours, dialyzing for 3 days, and freeze-drying. 9. preparation method according to claim 8, is characterized in that, The mass ratio of the prodrug polymer and the photosensitizer is 10:0.4; The stirring speed should be 1500rpm. 10. A near-infrared responsive gemcitabine prodrug nanopolymer drug, characterized in that it is prepared by the preparation method of any one of claims 1-9.

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