PH / hypoxia dual-response polymer, nano-micelle, and preparation method and application of pH / hypoxia dual-response polymer and nano-micelle

Abstract

The invention belongs to the technical field of nano-agents, and particularly relates to a pH / hypoxia dual-response polymer, a nano-micelle, a preparation method and application of the pH / hypoxia dual-response polymer and the nano-micelle. The pH / hypoxia dual-response polymer is hydroxyethyl chitosan modified by p-nitrobenzyl chloroformate and cinnamyl aldehyde. The ropivacaine-loaded nano-micelle is used as a drug delivery system after a tumor operation, and due to the acid sensitivity and the hypoxia response performance of the ropivacaine-loaded nano-micelle, the tumor microenvironment can be intelligently recognized, and accurate delivery of drugs is achieved.

Description

Technical Field

[0001] The present invention belongs to the technical field of nano pharmaceuticals, and particularly relates to a pH / hypoxia dual-responsive polymer, nano micelles, a preparation method thereof, and an application thereof. Background Art

[0002] Cancer pain refers to the pain directly caused by cancer or cancer-related lesions and anti-cancer treatments. It is often chronic pain and is a common symptom in cancer patients. In clinical practice, the pain after tumor resection cannot be completely controlled by analgesics, and long-term use of large doses is prone to side effects such as drug tolerance, addiction, and neurological dysfunction. Based on this, some studies have proposed encapsulating analgesics into nano carriers. Nano carriers are a nano-level delivery system, and their applications are extremely extensive, playing a key role in nano medicine fields such as multimodal imaging, drug delivery, and targeted therapy of human diseases. However, the limitations of traditional nano carriers include drug leakage and stability problems. To overcome these problems, methods such as coating NPs and using stimulus-responsive nano carriers have been considered. A stimulus-responsive drug delivery system is a system in which drugs are released or delivered through stimuli. In recent years, great progress has been made in the research of stimulus-responsive nano carriers, and many nano carriers have been designed to be able to respond to physical and chemical changes of external stimuli (such as ultrasound, heat, light, and magnetic fields) as well as internal stimuli (including pH, redox potential, hypoxia, and enzymes). Stimulus-responsive nano carriers can respond to the physical and chemical and pathological factors inherent in the disease area, thereby improving the specificity of drug delivery, overcoming multidrug resistance, and achieving accurate diagnosis and precise treatment.

[0003] Polymer micelles have good self-assembly ability, can increase drug solubility, have strong drug-loading capacity, few adverse reactions, and can improve the bioavailability of drugs; their unique shell-core structure allows for the free selection of suitable micelle carriers according to the properties of drugs; by connecting specific antibodies, ligands, or certain stimulus-sensitive systems to the hydrophilic segments of micelles, drug targeted delivery can be achieved. Currently, most anti-cancer drugs or analgesics, after being injected into the body, have the problem of short half-life and cannot achieve long-circulation in the body, and the drug delivery is not targeted. Therefore, it is necessary to develop a polymer micelle that can intelligently respond to the unique microenvironment of diseased tissues (such as tumors) and achieve precise drug release. Summary of the Invention

[0004] The object of the present invention is to provide a pH / hypoxia dual-responsive polymer, nano micelles, a preparation method thereof, and an application thereof. The polymer nano micelles have hypoxia-responsive and acid-responsive characteristics, and have good specificity in drug delivery.

[0005] To solve the above problems, the technical solutions provided by the present invention are as follows:

[0006] In the first aspect of the present invention, a pH / hypoxia dual-responsive polymer is provided, and the pH / hypoxia dual-responsive polymer is hydroxyethyl chitosan modified with p-nitrobenzyl chloroformate and cinnamaldehyde.

[0007] In the second aspect of the present invention, a preparation method of the above-mentioned pH / hypoxia dual-responsive polymer is provided, and the preparation method is as follows: adding p-nitrobenzyl chloroformate and cinnamaldehyde to a dimethyl sulfoxide solution of hydroxyethyl chitosan, and continuing to stir at room temperature until the reaction is complete, followed by dialysis with pure water and freeze-drying to obtain the pH / hypoxia dual-responsive polymer.

[0008] Furthermore, the synthesis route of the preparation method of the above-mentioned pH / hypoxia dual-responsive polymer is as follows:

[0009]

[0010] Furthermore, in the preparation method of the above-mentioned pH / hypoxia dual-responsive polymer, the molar ratio of hydroxyethyl chitosan, p-nitrobenzyl chloroformate and cinnamaldehyde is 1:(0.5-3):(0.6-5).

[0011] Furthermore, in the preparation method of the above-mentioned pH / hypoxia dual-responsive polymer, the dimethyl sulfoxide solution of hydroxyethyl chitosan further contains a catalyst.

[0012] Furthermore, in the preparation method of the above-mentioned pH / hypoxia dual-responsive polymer, the catalyst is N,N-diisopropylethylamine.

[0013] Furthermore, in the preparation method of the above-mentioned pH / hypoxia dual-responsive polymer, the reaction time is 12-24 h.

[0014] In the third aspect of the present invention, a pH / hypoxia dual-responsive polymer nanomicelle is provided, and the pH / hypoxia dual-responsive polymer nanomicelle is prepared from the above-mentioned pH / hypoxia dual-responsive polymer.

[0015] In the fourth aspect of the present invention, a preparation method of the above-mentioned pH / hypoxia dual-responsive polymer nanomicelle is provided, and the preparation method is as follows: dissolving the above-mentioned pH / hypoxia dual-responsive polymer in a solvent, and dialyzing to obtain the pH / hypoxia dual-responsive polymer nanomicelle; the mass / volume ratio of the pH / hypoxia dual-responsive polymer to the solvent is (5-10):1.

[0016] In the fifth aspect of the present invention, an application of the above-mentioned pH / hypoxia dual-responsive polymer or the pH / hypoxia dual-responsive polymer nanomicelle as above in preparing a drug as a drug carrier is provided.

[0017] In a sixth aspect of the present invention, there is provided an antitumor drug, which is obtained by loading ropivacaine on the above-mentioned pH / hypoxia dual-responsive polymer.

[0018] Further, the antitumor drug is a drug for postoperative analgesia and treatment of tumors.

[0019] Further, the antitumor drug is used for targeted delivery of analgesic drugs in vivo to inhibit pain after tumor resection, especially postoperative cancer-related neuropathic pain.

[0020] Further, the pain corresponding to the analgesia is pain directly or indirectly caused by tumor resection, including pain caused by direct damage to the nervous system by tumor recurrence or metastatic tumors, or pain caused by postoperative treatment.

[0021] Further, the antitumor drug further comprises a pharmaceutically acceptable excipient.

[0022] The pH / hypoxia dual-responsive polymer, nano-micelles, their preparation methods and applications according to the embodiments of the present invention have at least one of the following advantages:

[0023] (1) In the present invention, p-nitrobenzyl chloroformate and cinnamaldehyde are used to modify hydroxyethyl chitosan deacetate, and the hypoxia-responsive group is connected to the chitosan amino group. The imine bond formed by cinnamaldehyde and the chitosan amino group has strong acid sensitivity. Subsequently, the drug is encapsulated in the polymer nano-micelle carrier, and the prepared polymer nano-micelles have hypoxia responsiveness and acid sensitivity. The design of hypoxia response and acid sensitivity enables the micelles to intelligently respond to the unique microenvironment of diseased tissues (such as tumors), realizing the precise release of drugs, thereby significantly improving the curative effect and reducing side effects.

[0024] (2) It can achieve targeted delivery of analgesic drugs in vivo to inhibit pain after tumor resection, especially postoperative cancer-related neuropathic pain. At the same time, it prolongs the blood circulation time of the drug in vivo, improves the specificity of drug delivery, enhances the bioavailability of the drug, overcomes multidrug resistance, reduces drug adverse reactions and side effects, and realizes accurate diagnosis and precise treatment.

[0025] (3) The preparation obtained in the present invention can prevent aggregation between particles, reduce the binding of particles to plasma proteins in vivo, prolong the blood circulation time of the drug, and improve the bioavailability of the drug in the nano-carrier.

[0026] (4) The polymer nanomicelles prepared by the present invention have good self-assembly ability, can increase drug solubility, have strong drug-loading capacity, few adverse reactions, and can improve drug bioavailability; due to their unique core-shell structure, suitable micelle carriers can be freely selected according to the properties of the drug; by connecting specific antibodies, ligands or some stimulus-sensitive systems, etc. to the hydrophilic segments of the micelles, targeted drug delivery can be achieved. In addition, its preparation is simple and convenient, the surface is easy to modify, and it can be produced rapidly on a large scale. Description of the Drawings

[0027] The technical solutions of the present invention will be further specifically described below through examples in combination with the drawings. The description of the embodiments of the present invention with reference to the drawings is intended to explain the overall inventive concept of the present invention, and should not be construed as a limitation of the present invention. In the drawings:

[0028] Figure 1 It is the hydrated particle size diagram of the polymer nanomicelles loaded with ropivacaine obtained in Example 2;

[0029] Figure 2 It is the potential diagram of the polymer nanomicelles loaded with ropivacaine obtained in Example 2;

[0030] Figure 3 It is the transmission electron microscope diagram of the polymer nanomicelles loaded with ropivacaine obtained in Example 2;

[0031] Figure 4 It is the in vitro drug release curve diagram obtained in Experimental Example 1;

[0032] Figure 5 It is the cell fluorescence picture taken by a laser confocal microscope and the statistical result diagram of fluorescence intensity in Experimental Example 2;

[0033] Figure 6 It is the fluorescence intensity change diagram of bilateral dorsal root ganglia taken by a laser confocal microscope in Experimental Example 3;

[0034] Figure 7 It is the weight change and tumor volume growth curve diagram of female BALB / c mice within 15 days after melanoma resection in different treatment groups in Experimental Example 4;

[0035] Figure 8 It is the statistical diagram of the changes in mechanical pain threshold of mice at 2 hours, 6 hours, 12 hours, and 24 hours after drug administration in Experimental Example 5;

[0036] Figure 9 It is the statistical diagram of the changes in thermal pain threshold of mice at 2 hours, 6 hours, 12 hours, and 24 hours after drug administration in Experimental Example 5. Detailed Embodiments

[0037] To further understand the present invention, the preferred embodiments of the present invention will be specifically described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the present invention.

[0038] There are no particular restrictions on the sources of all raw materials of the present invention, and they can be purchased on the market or prepared according to conventional methods well-known to those skilled in the art.

[0039] In a typical embodiment of the present application, a pH / low-oxygen dual-responsive polymer is provided, and the pH / low-oxygen dual-responsive polymer is hydroxyethyl chitosan modified with p-nitrobenzyl chloroformate and cinnamaldehyde.

[0040] In a second typical embodiment of the present application, a method for preparing a pH / low-oxygen dual-responsive polymer is provided, specifically: adding p-nitrobenzyl chloroformate and cinnamaldehyde to a dimethyl sulfoxide solution of hydroxyethyl chitosan, and continuing to stir at room temperature until the reaction is complete, followed by dialysis with pure water and freeze-drying to obtain the pH / low-oxygen dual-responsive polymer.

[0041] In the above method for preparing a pH / low-oxygen dual-responsive polymer, hydroxyethyl chitosan is modified with p-nitrobenzyl chloroformate and cinnamaldehyde, and the low-oxygen responsive group is connected to the amino group of chitosan. The imine bond formed by cinnamaldehyde and the amino group of chitosan has strong acid sensitivity, so that the obtained pH / low-oxygen dual-responsive polymer has strong low-oxygen responsiveness and acid sensitivity, and is specific for low-oxygen and acidic microenvironments. The dual targeting of low-oxygen response and acid sensitivity has certain synergistic advantages. The micelles first initially release drugs in the tumor microenvironment (with a lower pH) through the acid-sensitive property, and when further penetrating into the low-oxygen core region, the low-oxygen response mechanism triggers secondary release. Precise delivery can reduce the waste of drugs at non-target sites and avoid the generation of drug resistance in tumor cells due to insufficient drug concentration.

[0042] In some preferred embodiments of the present invention, in order to have sufficient low-oxygen responsive groups, the molar ratio of hydroxyethyl chitosan, p-nitrobenzyl chloroformate and cinnamaldehyde is 1:(0.5 - 3):(0.6 - 5).

[0043] In some preferred embodiments of the present invention, the dimethyl sulfoxide solution of hydroxyethyl chitosan further contains a catalyst, such as N,N-diisopropylethylamine.

[0044] In some preferred embodiments of the present invention, the preparation method of the pH / hypoxia dual-responsive polymer is specifically as follows: Dissolve hydroxyethyl chitosan and N,N-diisopropylethylamine in dimethyl sulfoxide, magnetically stir at 0°C - 4°C until evenly mixed, then add p-nitrobenzyl chloroformate and cinnamaldehyde, and then transfer to room temperature and continue stirring until the reaction is complete. After dialysis with pure water and freeze-drying, the pH / hypoxia dual-responsive polymer is obtained. Preferably, the time of magnetic stirring is 0.5 - 1 h; the reaction time is 12 - 24 h. Preferably, dialysis is carried out with pure water, the dialysis bag used has a molecular weight cut-off of 3500 - 14000, and the dialysis time is 2 - 3 days. The research of our research group found that compared with other organic solvents, dimethyl sulfoxide (DMSO) can dissolve hydroxyethyl chitosan well. Therefore, when preparing the pH / hypoxia dual-responsive polymer, dimethyl sulfoxide (DMSO) is used as the solvent.

[0045] In the third typical embodiment of the present invention, a pH / hypoxia dual-responsive polymer nanomicelle is provided, which is prepared from the above-mentioned pH / hypoxia dual-responsive polymer.

[0046] In the fourth typical embodiment of the present invention, a preparation method of a pH / hypoxia dual-responsive polymer nanomicelle is provided. The preparation method is: Dissolve the pH / hypoxia dual-responsive polymer described in claim 1 in a solvent, and after dialysis, the pH / hypoxia dual-responsive polymer nanomicelle is obtained; the mass / volume ratio of the pH / hypoxia dual-responsive polymer to the solvent is (5 - 10):1. Preferably, the molecular weight cut-off of the dialysis bag used for dialysis can be 3500 - 14000. Specifically, it can be dialyzed with pure water under magnetic stirring for 6 - 8 hours.

[0047] In the fourth typical embodiment of the present invention, the above-mentioned pH / hypoxia dual-responsive polymer or the pH / hypoxia dual-responsive polymer nanomicelle as described above is provided for use in preparing a drug as a drug carrier.

[0048] In the fifth typical embodiment of the present invention, an antitumor drug is provided. The antitumor drug is obtained by loading ropivacaine on the above-mentioned pH / hypoxia dual-responsive polymer. Compared with opioid or other analgesic drugs, ropivacaine has lower toxicity and fewer side effects. The antitumor drug is a drug delivery system loaded with ropivacaine. Since the pH / hypoxia dual-responsive polymer therein has hypoxia response and acid sensitivity, it can specifically select the tumor microenvironment for postoperative tumors, achieve precise drug use, and solve the problems of drug leakage and stability.

[0049] In some preferred embodiments of the present invention, the method for preparing the tumor drug is as follows: slowly add water dropwise to an organic mixed solution containing a pH / hypoxia dual-responsive polymer and ropivacaine, and after the addition is completed, stir at room temperature for 3-6 h. Transfer the obtained solution to a dialysis bag and dialyze with pure water under magnetic stirring for 6-8 hours to remove free drug, thereby obtaining the tumor drug.

[0050] In a preferred embodiment of the present invention, in the organic mixed solution of the pH / hypoxia dual-responsive polymer and ropivacaine, the mass ratio of the pH / hypoxia dual-responsive polymer to ropivacaine is (3-5):1.

[0051] In some preferred embodiments of the present invention, the hydrodynamic diameter of the above-mentioned tumor drug is 200-300 nm.

[0052] The present invention will be described in detail below through examples. In the following examples, unless otherwise specified, various raw materials used are commercially available products.

[0053] Example 1: Preparation of pH / hypoxia dual-responsive polymer

[0054] Dissolve hydroxyethyl chitosan (GC) and N,N-diisopropylethylamine (DIPEA) (GC / DIPEA: 1 / 1.5, mol / mol) separately in 2 mL of dimethyl sulfoxide (DMSO), mix them evenly and place them in a 50 mL round-bottom flask. Stir magnetically at 0 °C for 0.5-1 hour, then add p-nitrobenzyl chloroformate (NBCF) and cinnamaldehyde (CA) (GC / NBCF / CA: 1 / 1.5 / 2, mol / mol / mol) dissolved in 1 mL of dimethyl sulfoxide. Subsequently, transfer to room temperature and continue stirring for 12-24 hours until the reaction is complete. Use a dialysis bag with a molecular weight cut-off of MW = 3500 and dialyze with pure water for 48 hours. Then, freeze-dry the dialyzed product GC-NBCF-CA to prepare a powder.

[0055] Example 2: Preparation of polymer nanomicelles loaded with ropivacaine (PMs / Rop)

[0056] During the preparation process, control the mass ratio of the pH / hypoxia dual-responsive polymer (GC-NBCF-CA) to ropivacaine to be 4:1. Dissolve the pH / hypoxia dual-responsive polymer and the drug in dimethyl sulfoxide. Subsequently, slowly dropwise mix the organic solution and pure water at a volume ratio of 1:4, and stir magnetically at room temperature for 3-4 hours. Transfer the obtained solution to a dialysis bag (MW = 3500) and dialyze with pure water under magnetic stirring for 6 hours to remove free ropivacaine. Finally, obtain polymer nanomicelles loaded with ropivacaine (PMs / Rop).

[0057] Example 3: Preparation of Polymer Nanomicelles Loaded with Rhodamine B

[0058] Replace ropivacaine in Example 2 with rhodamine B, and keep the other process parameters the same.

[0059] Test Example 1

[0060] Using a Malvern particle size analyzer, the particle size and zeta potential value of the polymer nanomicelles loaded with ropivacaine (PMs / Rop) obtained in Example 2 were measured. The results are as Figure 1 、 Figure 2 shown. According to Figure 1 it can be seen that the particle size of PMs / Rop is between 200 - 300 nm. According to Figure 2 it can be seen that the zeta potential of PMs / Rop is positive.

[0061] Using a transmission electron microscope, the polymer nanomicelles loaded with ropivacaine (PMs / Rop) obtained in Example 2 were photographed. The results are as Figure 3 it can be seen that the prepared polymer nanomicelles are uniformly spherical.

[0062] Experimental Example 1: Polymer nanomicelles loaded with ropivacaine (i.e., GC - BCF - PMs / Rop, GC - NBCF - PMs / Rop, GC - NBCF - CA - PMs / Rop) were prepared using chitosan derivatives modified with benzyl chloroformate (BCF), p - nitrobenzyl chloroformate (NBCF), p - nitrobenzyl chloroformate (NBCF) and cinnamaldehyde (CA), respectively. 1 mL of the polymer micelle solution was taken and placed in a dialysis bag, and then placed in 20 mL of phosphate buffer solution (PBS) with different environments (i.e., weakly alkaline pH = 7.4, normoxia; weakly acidic pH = 6.0, normoxia; weakly acidic, hypoxia). Samples were taken at different time intervals, and the content of ropivacaine in the dialysis external fluid was detected by high - performance liquid chromatography, and the in vitro drug release curve was plotted.

[0063] The in vitro drug release results are as Figure 4As shown. According to Figure A, there is no difference in the drug release curves of GC-BCF-PMs / Rop under weakly alkaline pH = 7.4, normoxia; weakly acidic pH = 6.0, normoxia; and hypoxia conditions, and the cumulative drug release rate is relatively low, indicating that GC-BCF does not have hypoxia responsiveness and pH responsiveness. From Figure B, it can be seen that GC-NBCF-PMs / Rop releases faster and has the highest cumulative drug release amount under hypoxia conditions, while there is no difference in release and the cumulative drug release rate is relatively low under weakly alkaline pH = 7.4, normoxia; and weakly acidic pH = 6.0, normoxia conditions, indicating that GC-NBCF has hypoxia responsiveness. Under hypoxia conditions, the hydrophobic nitro group is transformed into a hydrophilic amino group, promoting rapid drug release. From Figure C, it can be seen that the drug release rate and cumulative release rate of GC-NBCF-CA-PMs / Rop under weakly acidic pH = 6.0, normoxia and hypoxia conditions are higher than those under weakly alkaline pH = 7.4, normoxia conditions. Thus, it shows that GC-NBCF-CA has pH / hypoxia dual responsiveness. Under weakly acidic conditions, the acid-sensitive imine bond breaks, and the polymeric micelles decompose, promoting rapid drug release.

[0064] Experimental Example 2: B16 cells were seeded in a 24-well plate. When the cell density reached 60%, polymeric nanomicelles loaded with rhodamine B and modified with BCF, NBCF, NBCF, and CA at a drug concentration of 5 μg / mL were added to the B16 cells. After culturing in normoxia for 1 hour, they were placed in normoxia (21% O 2 ) and hypoxia (1% O 2 ) conditions for 4 hours. The cells were fixed with 4% paraformaldehyde, and the cell nuclei were stained with DAPI for 10 minutes. Images were taken using a laser confocal microscope. As Figure 5 shown, the left figure is the fluorescence intensity of rhodamine B in the cells observed by CLSM (from top to bottom in the left figure are GC-BCF-PMs / RhB, GC-NBCF-PMs / RhB, GC-NBCF-CA-PMs / RhB), and the right figure is the statistical chart of the fluorescence intensity of rhodamine B in the cells (n = 5, ***P < 0.001, mean ± SD).

[0065] According to Figure 5 it can be known that the fluorescence intensity of the polymeric nanomicelles modified with NBCF and loaded with the fluorescent dye rhodamine B increases significantly under hypoxia conditions, and it has statistical significance.

[0066] Experimental Example 3: The polymer nanomicelles modified with BCF, NBCF, NBCF and CA and loaded with rhodamine B were intrathecally injected into the model mice after melanoma resection. Six hours later, bilateral dorsal root ganglia were taken, and after fluorescence staining, they were photographed by a laser confocal microscope. The results are as Figure 6 shown. The upper figure shows the rhodamine B fluorescence intensity of bilateral DRGs in the model mice after tumor resection detected by CLSM (from left to right in the upper figure are GC-BCF-PMs / RhB, GC-NBCF-PMs / RhB, GC-NBCF-CA-PMs / RhB). The lower figure is the statistical chart of the rhodamine B fluorescence intensity in bilateral DRGs of the model mice after melanoma resection (n = 3, **P < 0.01, mean ± SD). The fluorescence intensity of the dorsal root ganglia on the modeled side was significantly increased, and the results were statistically significant.

[0067] Experimental Example 4: Mouse melanoma (B16) cells were selected, and 100 μL of cell suspension was intramuscularly injected near the sciatic nerve in the left hind limb thigh using a syringe to establish a melanoma model. When the tumor volume reached 100 mm 3 , surgical resection was performed. Starting from the 3rd day after surgery, PBS, GC-PMs / Rop, GC-NBCF-PMs / Rop, and GC-NBCF-CA-PMs / Rop were injected at a drug dose of 5 mg / kg. The drug was administered once every other day, and the changes in mouse body weight and the growth of tumor volume were recorded. The results are as Figure 7 shown. There was no significant difference in body weight among the groups of mice. The PBS group showed the earliest recurrence after tumor resection and had the highest recurrence rate. From the volume of the recurrent tumors, it can be seen that compared with the other treatment groups, the volume and weight of the recurrent tumors were smaller after treatment with GC-NBCF-CA-PMs / Rop.

[0068] Experimental Example 5: The polymer nanomicelles modified with NBCF and CA and loaded with ropivacaine were intrathecally injected into the model mice after melanoma resection, and their analgesic effects were detected by pain hypersensitivity behavioral experiments such as mechanical pain and thermal pain.

[0069] Three days after melanoma resection in mice, their mechanical pain and thermal pain thresholds were detected. The polymer nanomicelles modified with NBCF and CA and loaded with ropivacaine were intrathecally injected into the model mice after melanoma resection. Subsequently, the mechanical pain and thermal pain thresholds of the mice were detected 2 hours, 6 hours, 12 hours, and 24 hours after drug administration. As Figure 8 、 9, The results showed that the pain threshold of the model mice after melanoma resection was significantly increased at 2 hours, 6 hours, 12 hours, and 24 hours after administration of the polymer nanomicelles loaded with ropivacaine and modified with NBCF and CA by intrathecal injection, and the results were statistically significant, indicating that the polymer nanomicelles loaded with ropivacaine and modified with NBCF and CA had good analgesic effects.

[0070] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. For those skilled in the art, it is obvious that the present invention is not limited to the details of the above-described exemplary embodiments, and can be implemented in other specific forms without departing from the spirit or basic characteristics of the present invention. Therefore, in any aspect, the embodiments should be regarded as exemplary and non-limiting. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, it is intended to embrace all changes within the meaning and scope of the equivalent elements of the claims in the present invention. Although the embodiments of the present invention have been shown and described, for those of ordinary skill in the art, it can be understood that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A pH / hypoxia dual-responsive polymer, characterized in that: The pH / hypoxia dual-responsive polymer is hydroxyethyl deacetylated chitosan modified by p-nitrobenzyl chloroformate and cinnamaldehyde.

2. A method for preparing a pH / hypoxia dual-responsive polymer as claimed in claim 1, characterized in that: The preparation method comprises the following steps: adding p-nitrobenzyl chloroformate and cinnamaldehyde to a dimethyl sulfoxide solution of hydroxyethyl chitosan, stirring continuously until the reaction is complete under room temperature, dialyzing with pure water and then freeze-drying to obtain the pH / hypoxia dual-responsive polymer.

3. The preparation method according to claim 2, characterized in that: The molar ratio of hydroxyethyl deacetylated chitosan, p-nitrobenzyl chloroformate and cinnamaldehyde is 1:(0.5-3):(0.6-5).

4. The preparation method according to claim 2, characterized in that: The dimethyl sulfoxide solution of hydroxyethyl chitosan further comprises a catalyst.

5. The preparation method according to claim 4, characterized in that: The catalyst is N,N-diisopropylethylamine.

6. The preparation method according to claim 5, characterized in that: The reaction time is 12-24h.

7. A pH / hypoxia dual-responsive polymer nanomicelle, characterized in that: The pH / hypoxia dual-responsive polymer nanomicelles are prepared from the pH / hypoxia dual-responsive polymer according to claim 1.

8. A method for preparing pH / hypoxia dual-responsive polymer nanomicelles as claimed in claim 7, characterized in that: The preparation method is: Dissolving the pH / hypoxia dual-responsive polymer according to claim 1 in a solvent, and dialyzing to obtain the pH / hypoxia dual-responsive polymer nano-micelles; The mass / volume ratio of the pH / hypoxia dual-responsive polymer to the solvent is (5-10):

1.

9. Use of the pH / hypoxia dual-responsive polymer according to claim 1 or the pH / hypoxia dual-responsive polymer nano-micelle according to claim 7 as a drug carrier in the preparation of drugs.

10. A tumor drug, characterized in that: The tumor drug is obtained by loading ropivacaine on the pH / hypoxia dual-responsive polymer according to claim 1.

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