pH-sensitive membrane-breaking polyester and its application

Abstract

The present invention provides a membrane-breaking polyester having a structure shown in formula (I) and its application. The membrane-breaking polyester has a low protonation degree at normal physiological pH, weak cell membrane damage, and low cytotoxicity, and has a high protonation degree under slightly acidic pH conditions, thereby having strong membrane-breaking activity, and can kill tumor cells efficiently and selectively. In addition, the membrane-breaking polyester does not cause long-term toxicity due to its degradable main chain structure.

Description

Technical Field

[0001] The invention relates to the technical field of polymer polyester materials and medicines, and in particular to a pH-sensitive film-breaking polyester and application thereof. Background Art

[0002] Chemotherapy is one of the most effective methods for treating cancer. However, cancer treatment is often difficult to succeed due to the risk of tumor metastasis or drug resistance. Recently, host defense peptides (HDPs) have shown cytotoxicity to cancer cells. These amphipathic cationic peptides exert their killing effects through rapid membrane damage and destruction involving various lipid interactions and embedding mechanisms. This damage interrupts the proton motive force and leaks important cellular components, leading to cell death. This mechanism of action gives it the advantages of broad-spectrum killing effects and low resistance, and has broad application prospects in the treatment of tumors and infectious diseases. However, due to their strong cytotoxicity to normal tissues, as well as their poor stability and low bioavailability, most drugs have stopped clinical research, and most of the drugs currently used in clinical practice are local injection treatments.

[0003] Over the past few decades, many researchers have studied the potential of synthetic amphiphilic cationic polymers as anticancer drugs, but their clinical application still requires the optimization of materials with high membrane-breaking activity and low toxicity to normal tissue cells. In addition, since most membrane-breaking polymers use non-degradable main chain skeletons, they may accumulate in the body and cause long-term toxicity. In order to further promote clinical applications, it is necessary to develop biodegradable membrane-breaking polymer materials with high membrane-breaking activity and low toxicity to normal tissue cells for tumors and infectious diseases. Summary of the invention

[0004] Based on this, the present invention provides a pH-sensitive membrane-breaking polyester polymer, which has a low degree of protonation at normal physiological pH, weak destructive effect on cell membranes, and low cytotoxicity. It has a high degree of protonation under slightly acidic pH conditions, thereby having strong membrane-breaking activity, and can kill tumor cells efficiently and selectively. In addition, the polymer will not cause long-term toxicity due to its degradable main chain structure.

[0005] The present invention includes the following technical solutions.

[0006] A film-breaking polyester having a structure shown in formula (I):

[0007]

[0008] in,

[0009] R1 is selected from the group consisting of: the residue of methoxypolyethylene glycol with the hydroxyl group removed;

[0010] R2 and R3 are independently selected from: H, aryl, alkyl, or R2, R3 and the carbon atom to which they are connected together form a cycloalkyl, cycloalkene, cycloalkynyl or aryl group;

[0011] Each R4 and R5 are independently selected from: alkyl, or R4, R5 and the nitrogen atom to which they are attached together form a heterocycloalkyl;

[0012] R6 is selected from: H, alkyl,

[0013] Each R is selected from: an alkylene group;

[0014] Both n and m are integers greater than 0.

[0015] On the other hand, the present invention also provides a membrane-breaking polyester nanoparticle, including the following technical solution.

[0016] The invention discloses a membrane-breaking polyester nanoparticle, which is formed by self-assembly of an organic solution of the membrane-breaking polyester in an aqueous medium.

[0017] On the other hand, the present invention also provides a method for preparing the above-mentioned film-breaking polyester nanoparticles, including the following technical solutions.

[0018] A method for preparing membrane-breaking polyester nanoparticles comprises the following steps: dissolving the membrane-breaking polyester in an organic solvent, then dropwise adding the obtained solution into water under stirring, continuing stirring, and removing the solvent by low-temperature dialysis to obtain the membrane-breaking polyester nanoparticles.

[0019] On the other hand, the present invention also provides the application of the above-mentioned film-breaking polyester or film-breaking polyester nanoparticles, including the following technical solutions.

[0020] The use of the above-mentioned membrane-breaking polyester in the preparation of drugs for preventing and / or treating tumors.

[0021] The use of the above-mentioned membrane-breaking polyester nanoparticles in the preparation of drugs for preventing and / or treating tumors.

[0022] The use of the above-mentioned membrane-perturbing polyester combined with an immune checkpoint inhibitor in the preparation of a drug for preventing and / or treating tumors.

[0023] Use of the above-mentioned membrane-breaking polyester nanoparticles combined with immune checkpoint inhibitors in the preparation of drugs for preventing and / or treating tumors.

[0024] On the other hand, the present invention also provides a drug for preventing and / or treating tumors, including the following technical solutions.

[0025] A drug for preventing and / or treating tumors is prepared from active ingredients and pharmaceutically acceptable excipients, wherein the active ingredients include the above-mentioned membrane-breaking polyester and / or membrane-breaking polyester nanoparticles.

[0026] On the other hand, the present invention also provides a combined drug for preventing and / or treating tumors, including the following technical solutions.

[0027] A combined drug for preventing and / or treating tumors, the active ingredients of which include:

[0028] Component 1: the membrane-breaking polyester and / or the membrane-breaking peptide nanoparticles; and

[0029] Component 2: anti-tumor drugs other than component 1;

[0030] The component 1 and the component 2 are respectively independent administration units, or the component 1 and the component 2 together form a combined administration unit.

[0031] Based on the above technical solution, the present invention has the following beneficial effects:

[0032] The present invention provides a pH-sensitive membrane-breaking polyester, which is composed of a hydrophilic polyethylene glycol, a polyester with a hydrophobic main chain and a tertiary amine with a hydrophilic and hydrophobic property convertible into a side group. Under normal physiological pH, the tertiary amine in the membrane-breaking polyester is hydrophobic and electrically neutral, and the polyester is in a hydrophobic conformation; and the membrane-breaking polyester can self-assemble to form nanoparticles with PEG as a shell layer, and the interaction with the cell membrane is weak, so that it has the advantage of low toxicity to normal tissues when circulating in the body, and the PEG shell can improve the biocompatibility of the polymer material and prolong its blood circulation time; under the slightly acidic pH condition of tumor tissue, the tertiary amine part of the membrane-breaking polyester will be protonated, so that the polyester fragment forms an amphiphilic structure composed of a hydrophobic domain and a cationic domain, so that it has a very strong interaction with the cell membrane and a strong membrane-breaking activity, so that it can kill tumor cells efficiently and selectively.

[0033] In addition, since the polymer material of the present invention is polyester, the ester bond of the main chain can be hydrolyzed or enzymatically hydrolyzed in vivo, thereby reducing the long-term toxicity of the material and making it more suitable for application in vivo. The membrane-breaking polyester of the present invention can be used to prepare anti-tumor drugs, and has the advantages of good anti-tumor effect, high selectivity and low toxicity. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is the NMR spectrum of aminothiol C6A hydrochloride.

[0035] Figure 2 This is the NMR spectrum of aminothiol C7A hydrochloride.

[0036] Figure 3 This is the NMR spectrum of aminothiol DPA hydrochloride.

[0037] Figure 4This is the NMR spectrum of the polymer material prepared in Example 1.

[0038] Figure 5 This is the NMR spectrum of the film-breaking polyester polymer material prepared in Example 1.

[0039] Figure 6 This is a graph showing the change in protonation rate of the film-breaking polyester polymer material prepared in Example 1 as a function of pH.

[0040] Figure 7 The cytotoxicity of the nanoparticles of the membrane-breaking polyester polymer material prepared in Example 1 under pH 7.4 and pH 6.8 conditions.

[0041] Figure 8 This is the NMR spectrum of the polymer material prepared in Example 2.

[0042] Fig. 9 This is the NMR spectrum of the film-breaking polyester polymer material prepared in Example 2.

[0043] Fig.10 This is a graph showing the change in protonation rate of the film-breaking polyester polymer material prepared in Example 2 as a function of pH.

[0044] Fig.11 The cytotoxicity of the nanoparticles of the membrane-breaking polyester polymer material prepared in Example 2 under pH 7.4 and pH 6.8 conditions.

[0045] Fig.12 This is the NMR spectrum of the polymer material prepared in Example 3.

[0046] Fig.13 This is the NMR spectrum of the partially broken film polyester polymer material prepared in Example 3.

[0047] Fig.14 This is the NMR spectrum of the partially broken film polyester polymer material prepared in Example 3.

[0048] Fig.15 This is a graph showing the change in protonation rate of the film-breaking polyester polymer material prepared in Example 3 as a function of pH.

[0049] Fig.16 The cytotoxicity of the nanoparticles of the membrane-breaking polyester polymer material prepared in Example 3 under pH 7.4 and pH 6.8 conditions.

[0050] Fig.17 This is the NMR spectrum of the double-bond polymer material prepared in Example 4.

[0051] Fig.18 This is the NMR spectrum of the partially broken film polyester polymer material prepared in Example 4.

[0052] Fig.19 This is the NMR spectrum of the partially broken film polyester polymer material prepared in Example 4.

[0053] Fig. 20 This is the NMR spectrum of the triple-bond polymer material prepared in Example 4.

[0054] Fig.21 This is the NMR spectrum of the partially broken film polyester polymer material prepared in Example 4.

[0055] Fig. 22 This is the NMR spectrum of the partially broken film polyester polymer material prepared in Example 4.

[0056] Fig.23 This is a graph showing the change in protonation rate of the film-breaking polyester polymer material prepared in Example 4 as a function of pH.

[0057] Fig.24 The cytotoxicity of the nanoparticles of the membrane-breaking polyester polymer material prepared in Example 4 under pH 7.4 and pH 6.8 conditions.

[0058] Fig.25 The cytotoxicity of the nanoparticles of the membrane-breaking polyester polymer material prepared in Example 4 under pH 7.4 and pH 6.8 conditions.

[0059] Fig.26 It is the maximum tolerated dose (MTD) of the film-breaking polyester polymer material nanoparticles prepared in Example 4.

[0060] Fig. 27 The particle size potential of the 5k-PA-C7 polymer material nanoparticles prepared in Example 4 at different pH values.

[0061] Fig.28 To investigate the effects of different temperatures, different endocytosis inhibitors, and different death inhibitors on the cytotoxicity of 5k-PA-C7 nanoparticles at different pH conditions, as well as the high-content images of 5k-PA-C7 nanoparticles at different pH values ​​and the quantification of their mCherry protein leakage rates.

[0062] Fig.29 This is the therapeutic effect of the 5k-PA-C7 nanoparticles prepared in Example 4 on the E0771 orthotopic tumor model.

[0063] Fig.30 The therapeutic effect of 5k-PA-C7 polymer material nanoparticles prepared in Example 4 combined with anti-PD1 on the MC38 subcutaneous tumor model.

[0064] Fig.31 This is the NMR spectrum of the film-breaking polyester polymer material prepared in Example 8.

[0065] Fig.32 This is the NMR spectrum of the film-breaking polyester polymer material prepared in Example 8.

[0066] Fig.33 The cytotoxicity of the membrane-breaking polyester polymer material nanoparticles prepared in Example 8 under pH 7.4 and pH 6.8 conditions. DETAILED DESCRIPTION

[0067] The experimental methods in the following examples of the present invention without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0068] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0069] The terms "including" and "having" and any variations thereof of the present invention are intended to cover non-exclusive inclusions. For example, a process, method, device, product or equipment comprising a series of steps is not limited to the listed steps or modules, but may optionally include steps not listed, or may optionally include other steps inherent to these processes, methods, products or equipment.

[0070] In the present invention, the term "multiple" refers to two or more than two. "And / or" describes the association relationship of associated objects, indicating that three relationships may exist. For example, A and / or B can represent the following three situations: A exists alone, A and B exist at the same time, and B exists alone. The character " / " generally indicates that the associated objects are in an "or" relationship.

[0071] In the compounds described herein, when any variable (e.g., R1, R2, etc.) occurs more than once in any component, its definition at each occurrence is independent of the definition at every other occurrence. Likewise, combinations of substituents and variables are permitted as long as such combinations render the compound stable. Lines drawn from substituents into the ring system indicate that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, it means that such bonds are attached only to any appropriate carbon atom of the adjacent ring. It is to be understood that one of ordinary skill in the art may select substituents and substitution patterns for the compounds of the invention to provide chemically stable compounds that can be readily synthesized from readily available raw materials by techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it is to be understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stable.

[0072] As used herein, the term "alkyl" is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. For example, the definition of "C1-C6" in "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched arrangement. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0073] The term "cycloalkene group" refers to an unsaturated monocyclic cyclic substituent containing a C=C double bond, wherein all the ring atoms are carbon, for example, cyclopentenyl, cyclohexenyl, and the like.

[0074] The term "cycloalkynyl" refers to an unsaturated monocyclic cyclic substituent containing a carbon-carbon triple bond, wherein all the ring atoms are carbon, for example, cyclopentynyl, cyclohexynyl, and the like.

[0075] The term "heterocycloalkyl" is a saturated monocyclic ring substituent, wherein one or more ring atoms are selected from N, O or S(O)m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon, for example: piperidinyl, pyrrolidinyl, etc.

[0076] In some embodiments of the present invention, a film-breaking polyester having a structure shown in formula (I) is provided:

[0077]

[0078] in,

[0079] R1 is selected from the group consisting of: the residue of methoxypolyethylene glycol with the hydroxyl group removed;

[0080] R2 and R3 are independently selected from: H, aryl, alkyl, or R2, R3 and the carbon atom to which they are connected together form a cycloalkyl, cycloalkene, cycloalkynyl or aryl group;

[0081] Each R4 and R5 are independently selected from: alkyl, or R4, R5 and the nitrogen atom to which they are attached together form a heterocycloalkyl;

[0082] R6 is selected from: H, alkyl,

[0083] Each R is selected from: an alkylene group;

[0084] Both n and m are integers greater than 0.

[0085] In some preferred embodiments, each R is independently selected from: C1-C6 alkylene.

[0086] In some preferred embodiments, each R is independently selected from: C1-C3 alkylene.

[0087] In some preferred embodiments, each R is independently selected from: methylene, ethylene, and propylene.

[0088] In some preferred embodiments, R1 is selected from: Where x is 1-200.

[0089] In some preferred embodiments, x is 40-120, for example, 40-48, or 108-116.

[0090] In some preferred embodiments, R1 is selected from:

[0091] In some preferred embodiments, R2 and R3 are independently selected from: H, C6-C 10 Aryl, C1-C 20 Alkyl, or R2, R3 and the carbon atom to which they are attached together form a C3-C8 cycloalkyl, C3-C8 cycloalkene, C3-C8 cycloalkyne or C6-C 10 Aryl.

[0092] In some preferred embodiments, R2 and R3 are independently selected from: H, phenyl, C4-C 12 Alkyl, or R2, R3 and the carbon atom to which they are attached together form a phenyl group.

[0093] In some preferred embodiments, R2 is selected from: H, phenyl, C6-C 10 Alkyl, R3 is H; or R2, R3 and the carbon atom to which they are attached together form a phenyl group.

[0094] In some preferred embodiments, R2 is selected from: H, phenyl, n-butyl, n-octyl, R3 is H; or R2, R3 and the carbon atom to which they are connected together form a phenyl group.

[0095] In some preferred embodiments, each R4 and R5 is independently selected from: C1-C6 alkyl, or R4, R5 and the nitrogen atom to which they are connected together form a 5-10 membered heterocycloalkyl.

[0096] In some preferred embodiments, each R4 and R5 is independently selected from: C1-C3 alkyl, or R4, R5 and the nitrogen atom to which they are connected together form a 5-8 membered heterocycloalkyl.

[0097] In some preferred embodiments, R4, R5 and the nitrogen atom to which they are connected together form the following group:

[0098]

[0099] In some preferred embodiments, R6 is selected from: H, C1-C 10 alkyl,

[0100] In some preferred embodiments, the film-breaking polyester has a structure shown in the following formula (II) or formula (III):

[0101]

[0102] In some preferred embodiments, the film-breaking polyester has a structure shown in the following formula (IV) or formula (V):

[0103]

[0104] Wherein, x is 40-48, and R2 is selected from: C8-C 10 Alkyl, R3 is H.

[0105] In some preferred embodiments, the film-breaking polyester has a structure shown in the following formula (IV) or formula (V):

[0106]

[0107] Wherein, x is 108-116, R2 is selected from: H, phenyl, C6-C 10 Alkyl, R3 is H; or R2, R3 and the carbon atom to which they are attached together form a phenyl group.

[0108] In some preferred embodiments, n and m are independently 1-200, preferably 20-180, for example, 25-35, 35-45, 45-55, 52-62, 60-70, 65-75, 75-85, 80-90, 95-105, or 165-180.

[0109] In another embodiment of the present invention, a membrane-breaking polyester nanoparticle is provided, which is formed by self-assembly of an organic solution of the membrane-breaking polyester in an aqueous medium.

[0110] In another embodiment of the present invention, a method for preparing the membrane-breaking polyester nanoparticles is also provided, comprising the following steps: dissolving the membrane-breaking polyester in an organic solvent, then adding the resulting solution dropwise into water under stirring, continuing stirring, and removing the solvent by low-temperature dialysis to obtain the membrane-breaking polyester nanoparticles.

[0111] In some preferred embodiments, the organic solvent is N,N-dimethylformamide.

[0112] In some preferred embodiments, the ratio of the film-breaking polyester, the organic solvent and the water is 45 mg-55 mg: 1-2 mL: 4-6 mL.

[0113] In some preferred embodiments, the preparation method of the membrane-breaking polyester nanoparticles comprises the following steps: dissolving the membrane-breaking polyester in N,N-dimethylformamide at a ratio of 45 mg to 55 mg: 1.5 mL, then adding the resulting solution dropwise into water under stirring at a speed of 400 to 800 rpm, continuing stirring at a speed of 200 to 600 rpm for 8 to 20 minutes, and dialyzing in water using a dialysis bag with a molecular weight cutoff of 3400-3600 to remove the solvent, thereby obtaining the membrane-breaking polyester nanoparticles.

[0114] In some preferred embodiments, the dialysis temperature is 0°C-5°C, the dialysis time is 24 hours, the water is changed every 0.8-1.2 hours in the first 6 hours, and the water is changed every 5-7 hours in the next 18 hours.

[0115] In another embodiment of the present invention, there is also provided the use of the membrane-breaking polyester in the preparation of a drug for preventing and / or treating tumors.

[0116] In another embodiment of the present invention, there is also provided the use of the membrane-broken polyester nanoparticles in the preparation of drugs for preventing and / or treating tumors.

[0117] In another embodiment of the present invention, there is also provided the use of the membrane-perturbing polyester combined with an immune checkpoint inhibitor in the preparation of a drug for preventing and / or treating tumors.

[0118] In another embodiment of the present invention, there is also provided the use of the membrane-breaking polyester nanoparticles combined with immune checkpoint inhibitors in the preparation of drugs for preventing and / or treating tumors.

[0119] The tumors include, but are not limited to, pancreatic cancer, melanoma, colorectal cancer, lung cancer, tongue squamous cell carcinoma, cervical cancer, ovarian cancer, osteosarcoma, liver cancer, breast cancer, bladder cancer, and ovarian epithelial cancer.

[0120] In some preferred embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor.

[0121] In another embodiment of the present invention, a drug for preventing and / or treating tumors is provided, which is prepared from active ingredients and pharmaceutically acceptable excipients, wherein the active ingredients include the membrane-breaking polyester and / or the membrane-breaking polyester nanoparticles.

[0122] In another embodiment of the present invention, a combined drug for preventing and / or treating tumors is provided, wherein the active ingredients include:

[0123] Component 1: the film-breaking polyester, and / or the film-breaking polyester nanoparticles; and

[0124] Component 2: anti-tumor drugs other than component 1;

[0125] The component 1 and the component 2 are respectively independent administration units, or the component 1 and the component 2 together form a combined administration unit.

[0126] In some preferred embodiments, component 2 is an immune checkpoint inhibitor.

[0127] In some preferred embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor.

[0128] The compounds of formula (I) to (V) (or their nanoparticles) of the present invention can be used in combination with other known anti-tumor drugs. When administered in combination, the compounds of formula (I) to (V) (or their nanoparticles) and the known drugs can be independent administration units, or together form a combined administration unit; the compounds of formula (I) to (V) (or their nanoparticles) can be administered simultaneously or separately with other known anti-tumor drugs. When the compounds of formula (I) to (V) (or their nanoparticles) are taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compounds of formula (I) to (V) (or their nanoparticles). The combination of drugs also includes taking the compounds of formula (I) to (V) (or their nanoparticles) and one or more other known drugs in overlapping time periods. When the compounds of formula (I) to (V) (or their nanoparticles) are used in combination with one or more other known drugs, the dosage of the compounds of formula (I) to (V) (or their nanoparticles) or the known drugs can be the same as the dosage of the single drug, or can be lower than the dosage when they are used alone.

[0129] Drugs or active ingredients that can be used in combination with the compounds of formula (I) to (V) (or their nanoparticles) include but are not limited to: immune checkpoint inhibitors, estrogen receptor modulators, androgen receptor modulators, retinal receptor modulators, cytotoxins / cytostatics, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, Serine / threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidine deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon-α, interleukin-12, COX-2 inhibitors, p53, p53 activators, VEGF antibodies, EGF antibodies, etc.

[0130] In some embodiments, the drugs or active ingredients that can be used in combination with the compounds of formula (I) to (V) (or their nanoparticles) include but are not limited to: aldesleukin, alendronic acid, interferon, atrenoin, allopurinol, allopurinol sodium, palonosetron hydrochloride, hexamethylmelamine, aminoglutethimide, amifostine, amrubicin, anacrine, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, arnosin, 5-azacytidine, azathioprine, bacillus Calmette-Guérin or ticé bacillus Calmette-Guérin, betadine, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromourea, bortezomib, busulfan, calcitonin, alezotocin injection, capecitabine , carboplatin, casodex, cefesone, cymoleukin, daunorubicin, chlorambucil, cisplatin, cladribine, cladribine, clodrophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin liposome, dexamethasone, dexamethasone phosphate, estradiol valerate, denileukin 2, depomet, deslorelin, delazosen, diethylstilbestrol, diflucan, docetaxel, doxorubicin, dronabinol, chin-166-chitosan complex, eligard, rasburicase, epirubicin hydrochloride, aprepitant, epirubicin, epoetin alfa, erythropoietin, epoetin, levamisole tablets, estradiol preparations, 17-β-estradiol, estramustine sodium phosphate, ethinyl estradiol, amifostine, hydroxyphosphoric acid, vancomycin Bifu, etoposide, fadrozole, tamoxifen preparations, filgrastim, finasteride, firaprestin, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine nucleoside monophosphate, 5-fluorouracil, fluoxymesterone, flutamide, formestan, 1-β-D-arabinofuranosylcytosine-5'-stearoyl phosphate, fotemustine, fulvestrant, gamma globulin, gemcitabine, gemtuzumab, imatinib mesylate, carmustine rice paper capsules, goserelin, granisiron hydrochloride, histrelin, andmeixin, hydrocortisone, erythro-hydroxynonyl adenine, hydroxyurea, tentan isobetumomab, idarubicin, ifosfamide, interferon α, interferon-α2, interferon α-2A, interferon α-2B, interferon α-nl, Interferon α-n3, interferon β, interferon γ-la, interleukin-2, intron A, Iressa, irinotecan, Kateri, lentinan sulfate, letrozole, leucovorin, leuprorelin acetate, levomizole, levofolinic acid calcium salt, levothyroxine sodium, levothyroxine sodium preparations, lomustine, lonidamine, dronabinol, nitrogen mustard, methylcobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen, 6-mercaptopurine, mesna, methotrexate, methyl aminolevulinate, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, trilostane, liposomal doxorubicin citrate, nedaplatin, pegfilgrastim, oprelleukin, neupogen,Nilutamide, tamoxifen, NSC-631570, recombinant human interleukin 1-β, octreotide, ondansetron hydrochloride, dehydrocortisone oral solution, oxaliplatin, paclitaxel, prednisone sodium phosphate preparation, pegaspargase, PEGASYS, pentostatin, lysin, pilocarpine hydrochloride, pilocarpine, plicamycin, porfimer sodium, prednimustine, stiprenisolone, prednisone, premarin, procarbazine, recombinant human erythropoietin, raltitrexed, libi, etidronate rhenium-186, rituximab, dextrin-A, romotide, pilocarpine hydrochloride tablets, octreotide, sarmustine, semustine, sizoran, sobuzosine, sodium methylprednisolone, pafosic acid, stem cell therapy, streptozocin, strontium-89 chloride , levothyroxine sodium, tamoxifen, tamsulosin, tasofenamin, tastolactone, taxotere, tesifazines, temozolomide, teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyroid-stimulating hormone, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, retinoic acid, methotrexate tablets, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, eufodine, uridine, valrubicin, veseratinone, vinblastine, vincristine, vinblastine, vinorelbine, virulizine, dexrazoxane, statins ester, zofran, paclitaxel protein-stabilized formulation, acolbifene, interferon r-lb, affinita k, aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, BAY43-9006, Avastin, CCI-779, CDC-501, Celebrex, cetuximab, clenatol, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, exitecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafamib , miproxifene, minocycline, MS-209, liposome MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, noratriptide, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, sodium bromoglutamate, PN-401, QS-21, quasi-sea, R-154, raloxifene, ranpirnase, 13-cis retinoic acid, satraplatin, ciocalcitol, T-138067, tarceva, paclitaxel docosahexaenoic acid, thymosin αl, gazofurin, tipifarnib, tirapazamine, TLK-286, toremifene, trans-MID-lo7R, vaspuda, vapreotide, vatalanib, verteporfin, vinflunine,Z-100 and zolephos acid or a combination thereof.

[0131] The drug for preventing and / or treating tumors of the present invention can be used in non-human mammals or humans.

[0132] The pharmaceutically acceptable excipients or carriers used in the drug for preventing and / or treating tumors of the present invention refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity.

[0133] "Compatibility" here means that the components in the composition can be blended with the active ingredients of the present invention (film-breaking polyesters or nanoparticles thereof represented by formula (I) to (V)) and with each other without significantly reducing the efficacy of the active ingredients.

[0134] The pharmaceutically acceptable excipients used in the drug for preventing and / or treating tumors of the present invention include, but are not limited to, one or more of the following materials: at least one of solvents, excipients, fillers, extenders, binders, humectants, disintegrants, solubilizers, absorption accelerators, adsorbents, diluents, solubilizers, emulsifiers, lubricants, wetting agents, suspending agents, flavoring agents and fragrances.

[0135] Examples of pharmaceutically acceptable excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0136] There is no particular limitation on the administration of the active ingredient or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.

[0137] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

[0138] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients:

[0139] (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;

[0140] (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic;

[0141] (c) humectants, for example, glycerin;

[0142] (d) disintegrating agents, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

[0143] (e) a buffering solvent, for example, paraffin;

[0144] (f) absorption accelerators, for example, quaternary ammonium compounds;

[0145] (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate;

[0146] (h) adsorbents, for example, kaolin; and

[0147] (i) Lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffering agent.

[0148] The solid dosage forms can also be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes.

[0149] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and spices.

[0150] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances.

[0151] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0152] The present invention is further described in the following examples, but the examples are not intended to limit the scope of protection of the present invention.

[0153] In the following examples, a polyester having an unsaturated carbon-carbon bond in the side group is obtained by ring-opening polymerization of anhydride and epoxy monomer, and then a series of pH-sensitive film-breaking polyester polymer materials having the structure shown in formula (I) are synthesized by a click reaction of the unsaturated carbon-carbon bond and the thiol group of the polyester and aminothiol. The reaction formula is as follows:

[0154]

[0155] The polymerization reaction was synthesized with reference to the preparation method of related literature (Li, H.; Zhao, J.; Zhang, G., Self-Buffering Organocatalysis Tailoring Alternating Polyester. Acs Macro Letters 2017, 6 (10), 1094-1098.).

[0156] Among them, the initiator (mPEG) required for the polymerization reaction can be purchased directly from the market, and it needs to be dehydrated with toluene before use; the epoxy monomer required can be purchased directly from the market, and it needs to be dehydrated with calcium hydride and then distilled under reduced pressure to remove water before use; the acid anhydride can be purchased directly from the market, and it is generally purified and dehydrated by sublimation and recrystallization before use.

[0157] Among them, the aminothiol required for the click reaction, namely C6A, C7A, and DPA, needs to be synthesized by the ring-opening reaction of ethylene oxide and secondary amine. The specific reaction steps refer to the relevant literature (Hao, J.; Kos, P.; Zhou, K.; Miller, JB; Xue, L.; Yan, Y.; Xiong, H.; Elkassih, S.; Siegwart, DJ, Rapid Synthesis of a Lipocationic Polyester Library via Ring-Opening Polymerization of Functional Valerolactones for Efficacious siRNA Delivery. Journal of the American Chemical Society 2015, 137 (29), 9206-9209.).

[0158] The structural formulas of the synthesized C6A, C7A, and DPA are as follows:

[0159]

[0160] NMR spectra Figure 1-Figure 3 As shown, the successful synthesis of aminothiol hydrochloride was confirmed.

[0161] Embodiment 1:

[0162] 1. Preparation and characterization of film-breaking polyester polymer materials in which the initiator is a methoxy polyethylene glycol group with a molecular weight of 2000, R2, R3 and the carbon atom connected to it form a benzene ring, and R4 and R5 are different hydrophobic groups

[0163] This example prepares film-breaking polyester polymer materials containing different types of tertiary amine groups when the initiator molecular weight is 2000 methoxy polyethylene glycol and the hydrophobic monomer is phthalic anhydride. These polymer materials can be synthesized by the following ring-opening polymerization of phthalic anhydride and glycidyl propargyl ether, and then modified with tertiary amines of different structures by click reaction, and the reaction equation is as follows:

[0164]

[0165] Wherein, R4 and R5 together with the nitrogen atom connected thereto form the following group:

[0166]

[0167] The specific synthesis steps are as follows:

[0168] In a glove box, the initiator, phthalic anhydride, glycidyl propargyl ether and phosphazene ligand P1-tert-butyl (t-BuP1) in a molar ratio of 1:30:45:0.5 were added to the reaction vessel in sequence, and the mixture was heated and sealed at 100°C for 4-6 hours. After the reaction was completed, a trace amount of acetic acid was added to terminate the reaction, and then a small amount of dichloromethane was added to dissolve it, and the reaction solution was dropped into cold ether for precipitation to obtain an orange-yellow high molecular polymer.

[0169] The polymer and aminothiol hydrochloride were dissolved in N, N-dimethylformamide (DMF) respectively, wherein the carbon-carbon triple bond of the polymer side group: the thiol feed ratio was 1:6, and nitrogen was introduced for 15 minutes after mixing evenly, and 20-50 mg of the DMF solution of the photoinitiator 2, 2-dimethoxy-2-phenylacetophenone (DMPA) was added, and nitrogen was continued to be introduced for 15 minutes, and then stirred for reaction under 365nm ultraviolet light for 3 hours. After the reaction was completed, a dialysis bag with a molecular weight cutoff of 3500 was used for dialysis in ultrapure water at 4°C for 24 hours. Finally, the liquid in the dialysis bag was freeze-dried and stored at low temperature.

[0170] The abbreviations of the macromolecular film-breaking polyester polymer prepared in this example and the reactants are shown in Table 1. Among them, GPE refers to glycidyl propargyl ether, PA refers to phthalic anhydride, C6A refers to aminothiol with a six-membered ring tertiary amine as a side group, the reactant C7A refers to aminothiol with a seven-membered ring tertiary amine as a side group, and the reactant DPA refers to aminothiol with a dipropyl tertiary amine as a side group.

[0171] Table 1

[0172]

[0173] The NMR spectrum of the obtained macromolecular broken film polyester polymer is as follows Figure 4-Figure 5 As shown, the synthesis of high molecular weight film-breaking polyester was confirmed. Figure 4 The integrated area ratio of the proton peak b belonging to the polyethylene glycol segment, the proton peak c belonging to the benzene ring of the anhydride portion, and the proton peak e belonging to the epoxy segment was used to obtain the degree of polymerization and confirm that the structural formulas are as follows:

[0174]

[0175]

[0176] 2. Preparation of film-breaking polyester polymer nanoparticles in which R1 is a methoxy polyethylene glycol group with a molecular weight of 2000, R2, R3 and the carbon atom connected thereto form a benzene ring, and R4 and R5 are different hydrophobic groups

[0177] The specific operation of the film-breaking polyester polymer synthesized in this embodiment to self-assemble into nanoparticles in water is as follows: take 50mg of polymer material in a 5mL sample bottle, add 1.5mL DMF to fully dissolve for standby use. Take another 4.5mL of sterile water in a 25mL round-bottom flask sterilized in advance, place it on a magnetic stirring table, stir at a speed of RPM=600r / min, and add the DMF solution of the polymer material dropwise into the round-bottom flask using a pipette. After continuing to stir at a speed of RPM=400r / min for 15min, use a dialysis bag with a molecular weight cutoff of 3500 to dialyze in 4L ultrapure water at 4°C for 24 hours, change the water every 1 hour for the first 6 hours, and change the water every 6 hours for the last 18 hours. After dialysis, take out and quantify with a pipette and store in a 4°C refrigerator. Use a particle size potentiometer to test the particle size and potential of the obtained product.

[0178] 3. R1 is a methoxy polyethylene glycol group with a molecular weight of 2000, R2, R3 and the carbon atom connected to it form a benzene ring, and R4 and R5 are membrane-breaking polyester polymer materials with different hydrophobic groups at different pH values.

[0179] The film-breaking polyester polymer material prepared in this embodiment is dissolved in an acidic solution containing 150mM NaCl, all tertiary amines are protonated, and then the free hydrogen ions are neutralized with alkali, and the protonation degree and pKa (ionization equilibrium constant) of the corresponding polymer material are calculated by monitoring the change of the solution pH. The specific operation is as follows: Take 10mg of polymer material in a 20mL sample bottle, add HCl aqueous solution (10mL, 0.01M) to dissolve it into a clear solution. Add 1-10μL of 1MNaOH aqueous solution each time, and use a pH meter to monitor and record the change of solution pH until the pH reaches 11. The two extreme points of the first-order derivative of the pH titration curve are determined as complete protonation (Protonation degree = 1) and complete non-protonation (Protonation degree = 0). When the protonation rate is 0.5, it proves that the molar amount of the protonated part of the polymer material in the solution system is the same as that of the non-protonated part. According to the definition of the dissociation equilibrium constant (pKa), the protonation rate of the polymer material equal to 0.5 is defined as the pKa of the polymer material. The results are as follows Figure 6 As shown in Table 2, the protonation degree of this type of polymer undergoes a significant jump with pH, ​​and as the hydrophobicity of the tertiary amine increases, the pKa of the polymer decreases.

[0180] Table 2

[0181]

[0182]

[0183] 4. Cytotoxicity of membrane-breaking polyester polymer materials in which R1 is a methoxypolyethylene glycol group with a molecular weight of 2000, R2, R3 and the carbon atom connected thereto form a benzene ring, and R4 and R5 are different hydrophobic groups at the characteristic pH of normal tissues and tumor tissues

[0184] The cytotoxicity of the series of polymer materials prepared in this example at the characteristic pH of normal tissues and tumor tissues was studied by cytotoxicity. The MTT method (methyl thiazolyl salt microenzyme reaction colorimetric method) was used to evaluate the killing effect of the drug on tumor cells under two conditions of pH 7.4 and pH 6.8. The DMEM culture medium was adjusted to pH = 6.8 using a 6 mol / L HCl solution for later use. Mouse pancreatic cancer cells Panc02 (purchased from ATCC) were cultured in a DMEM culture medium containing 10% (v / v) fetal bovine serum. At pH 7.4 and pH 6.8, different concentrations of the membrane-breaking polyester polymer material nanoparticles prepared in this example were mixed with cells (concentration of 1×10 5 / mL) for incubation, and after culturing for 4 hours or 24 hours at 37℃ in a carbon dioxide incubator, discard the original culture medium, add MTT (0.5mg / mL, 100μL) solution, and continue to culture for 2-4 hours at 37℃ in a carbon dioxide incubator. Carefully aspirate the culture medium, add 100μLDMSO to each well, and shake at a low speed on a shaker for 10 minutes to fully dissolve the crystals. Use an enzyme marker to test the OD 490nm absorbance value.

[0185] Test results such as Figure 7 As shown. Figure 7 It can be seen that the cytotoxicity of the materials at pH 7.4 and 6.8 has a certain correlation with the pKa of the materials and their corresponding protonation rates: 2k-PG-C6 and 2k-PG-C7 materials have relatively obvious toxicity at pH 7.4 and pH 6.8. Relatively speaking, the toxicity of 2k-PG-DP materials at pH 7.4 and 6.8 is relatively low. The cytotoxicity of the three materials at pH 6.8 is stronger than that at pH 7.4.

[0186] Through this example, it can be found that: as the hydrophobicity of the tertiary amine increases, the pKa of the material decreases, and the cytotoxicity at pH 7.4 and pH 6.8 decreases. When the tertiary amine is C6A or C7A, the pKa of the material is between 6.8 and 7.4, and it has a strong cell killing ability in the slightly acidic environment of the tumor (pH = 6.8). When the tertiary amine is DPA, due to being too hydrophobic, the pKa of the material is far below 6.8, and the toxicity is low under the slightly acidic conditions of the tumor.

[0187] Embodiment 2:

[0188] 1. Preparation and characterization of film-breaking polyester polymer materials in which the initiator is a methoxy polyethylene glycol group with a molecular weight of 2000, R4, R5 and the nitrogen atom connected thereto form a tertiary amine group of a six-membered ring, and R2 and R3 are different hydrophobic groups

[0189] This example prepares a polymer material containing different types of hydrophobic groups when the initiator is methoxy polyethylene glycol with a molecular weight of 2000 and the tertiary amine is a six-membered ring structure. These polymer materials can be synthesized by the following ring-opening polymerization of anhydride and glycidyl propargyl ether, and then modified with the six-membered ring tertiary amine by click reaction, and the reaction equation is as follows:

[0190]

[0191] Among them, R2 and R3 are: phenyl and H (phenyl succinic anhydride), n-butyl and H (butyl succinic anhydride), n-octyl and H (n-octyl succinic anhydride), or R2, R3 and the carbon atoms connected thereto form a benzene ring (phthalic anhydride).

[0192] The specific synthesis steps are as follows:

[0193] In a glove box, add initiator, anhydride, glycidyl propargyl ether, t-BuP1 to the reaction vessel in sequence, heat and seal at 100-120°C for 1-3 days. After the reaction is completed, add a trace amount of acetic acid to terminate the reaction. For phthalic anhydride and phenyl succinic anhydride, the purification steps are as follows: add a small amount of dichloromethane to dissolve, drop the reaction solution into cold ether to precipitate, and obtain an orange-yellow polymer material. For butyl succinic anhydride and n-octyl succinic anhydride, the purification steps are as follows: use a dialysis bag with a molecular weight cutoff of 3500 to dialyze in DMF for 12 hours, change DMF 4 times; then dialyze in 4L ultrapure water for 24 hours, change the water every 1 hour for the first 6 hours, and change the water every 6 hours for the next 18 hours. Finally, freeze-dry the liquid in the dialysis bag and store it at low temperature.

[0194] The polymer and aminothiol hydrochloride were dissolved in N, N-dimethylformamide (DMF) respectively, wherein the carbon-carbon triple bond of the polymer side group: the thiol feed ratio was 1:6, and nitrogen was introduced for 15 minutes after mixing evenly, and 20-50 mg of the DMF solution of the photoinitiator 2, 2-dimethoxy-2-phenylacetophenone (DMPA) was added, and nitrogen was continued to be introduced for 15 minutes, and then stirred for reaction under 365nm ultraviolet light for 3 hours. After the reaction was completed, a dialysis bag with a molecular weight cutoff of 3500 was used for dialysis in ultrapure water at 4°C for 24 hours. Finally, the liquid in the dialysis bag was freeze-dried and stored at low temperature.

[0195] The abbreviations of the polymers of the film-breaking polyester polymer material prepared in this embodiment and the reactants are shown in Table 3. Among them, GPE refers to glycidyl propargyl ether, PA refers to phthalic anhydride, PSA refers to phenyl succinic anhydride, BSA refers to butyl succinic anhydride, NOSA refers to n-octyl succinic anhydride, and C6A refers to aminothiol with a six-membered ring tertiary amine as a side group.

[0196] Table 3

[0197]

[0198]

[0199] The NMR spectrum of the obtained broken film polyester polymer is as follows: Figure 8-Figure 9 As shown, the synthesis of film-breaking polyester polymer was confirmed. Figure 8 The corresponding degree of polymerization was analyzed by the nuclear magnetic integration and the position of the hydrogen atom proton signal peak: for the material with PA anhydride as the polymerization monomer, the degree of polymerization was obtained by the integrated area ratio of the proton peak b belonging to the polyethylene glycol segment, the proton peak 1 belonging to the anhydride part of the benzene ring, and the proton peak d belonging to the epoxy part; for the material with PSA anhydride as the polymerization monomer, the degree of polymerization was obtained by the integrated area ratio of the proton peak b belonging to the polyethylene glycol segment, the proton peak 2 belonging to the anhydride part, and the proton peak d belonging to the epoxy part. Its degree of polymerization; for materials with BSA anhydride as the polymerization monomer, the degree of polymerization is obtained by the integrated area ratio of the proton peak b belonging to the polyethylene glycol segment, the proton peaks 5 and 6 belonging to the anhydride part, and the proton peak g belonging to the epoxy part; for materials with NOSA anhydride as the polymerization monomer, the degree of polymerization is obtained by the integrated area ratio of the proton peak b belonging to the polyethylene glycol segment, the proton peaks 10 and 11 belonging to the anhydride part, and the proton peak g belonging to the epoxy part, and the structural formulas are confirmed to be as follows:

[0200]

[0201]

[0202] 2. Preparation of film-breaking polyester polymer nanoparticles in which the initiator is a methoxy polyethylene glycol group with a molecular weight of 2000, R4, R5 and the nitrogen atom connected thereto form a tertiary amine group of a six-membered ring, and R2 and R3 are different hydrophobic groups

[0203] The experimental method is the same as that in Example 1.

[0204] 3. The initiator is a methoxy polyethylene glycol group with a molecular weight of 2000, R4, R5 and the nitrogen atom connected to it form a tertiary amine group of a six-membered ring, and R2 and R3 are different hydrophobic groups. The protonation of the membrane-breaking polyester polymer material at different pH

[0205] The experimental method is the same as that in Example 1.

[0206] The results are as follows Fig.10 As shown in Table 4, the protonation degree of this type of polymer undergoes a significant jump with pH, ​​and as the hydrophobicity of the hydrophobic group increases, the pKa of the polymer decreases.

[0207] Table 4

[0208] Material pKa Protonation rate (pH 6.8) Protonation rate (pH7.4) 2k-PG-C6 7.35 92％ 29％ 2k-PS-G-C6 7.09 89％ 7％ 2k-BS-G-C6 7.09 88.5％ 6％ 2k-NOS-G-C6 6.93 78.3％ 8％

[0209] 4. The initiator is a methoxy polyethylene glycol group with a molecular weight of 2000, R4, R5 and the nitrogen atom connected to it form a tertiary amine group with a six-membered ring, and R2 and R3 are different hydrophobic groups. Cytotoxicity of membrane-breaking polyester polymer materials at characteristic pH of normal tissues and tumor tissues

[0210] The experimental method is the same as that in Example 1.

[0211] Test results such as Fig.11 shown.

[0212] Depend on Fig.11 It can be seen that the membrane-breaking polyester polymer materials with different hydrophobic structures all showed strong cytotoxicity at pH 6.8; while at pH 7.4, the toxicity of 2k-PS-G-C6, 2k-BS-G-C6 and 2k-NOS-G-C6 decreased successively.

[0213] Through this embodiment, it can be found that: as the hydrophobicity of the anhydride monomer increases, the pKa of the material decreases, and the cytotoxicity decreases under normal physiological conditions (pH = 7.4), but there is no obvious effect in the slightly acidic environment of the tumor (pH = 6.8), and both have strong tumor cell killing ability.

[0214] Embodiment 3:

[0215] 1. Preparation and characterization of film-breaking polyester polymer materials using different initiators, R2 and R3 are phenyl and H, R4, R5 and the nitrogen atom connected to them form a six-membered ring or a seven-membered ring of tertiary amine groups

[0216] This embodiment prepares a film-breaking polyester polymer material initiated by different initiators, wherein R2 and R3 are phenyl and H, and R4, R5 and the nitrogen atom connected thereto form a six-membered ring or a seven-membered ring of a tertiary amine group. These polymer materials can be synthesized by the following ring-opening polymerization method of phenyl succinic anhydride and glycidyl propargyl ether, and then modified by a six-membered ring tertiary amine or a seven-membered ring tertiary amine by a click reaction, and the reaction equation is as follows:

[0217]

[0218] Wherein, R1 is selected from:

[0219] Wherein, R4 and R5 together with the nitrogen atom connected thereto form the following group:

[0220]

[0221] The specific synthesis steps are as follows:

[0222] In a glove box, add initiator, phenylsuccinic anhydride, glycidyl propargyl ether, and t-BuP1 to the reaction vessel in sequence, heat at 120°C and react in a sealed manner for 1-7 days. After the reaction is completed, add a trace amount of acetic acid to terminate the reaction. Then add a small amount of dichloromethane to dissolve, and drop the reaction solution into cold ether for precipitation to obtain an orange-yellow polymer material.

[0223] The polymer and aminothiol hydrochloride were dissolved in N, N-dimethylformamide (DMF) respectively, wherein the carbon-carbon triple bond of the polymer side group: the thiol feed ratio was 1:6, and nitrogen was introduced for 15 minutes after mixing evenly, and 20-50 mg of the DMF solution of the photoinitiator 2, 2-dimethoxy-2-phenylacetophenone (DMPA) was added, and nitrogen was continued to be introduced for 15 minutes, and then stirred for reaction under 365nm ultraviolet light for 3 hours. After the reaction was completed, a dialysis bag with a molecular weight cutoff of 3500 was used for dialysis in ultrapure water at 4°C for 24 hours. Finally, the liquid in the dialysis bag was freeze-dried and stored at low temperature.

[0224] The abbreviations of the polymers of the film-breaking polyester polymer material prepared in this example and the reactants are shown in Table 5.

[0225] Table 5

[0226]

[0227] The NMR spectrum of the obtained broken film polyester polymer material is as follows: Figure 12-14 As shown, the synthesis of film-breaking polyester polymer was confirmed. Fig.12 The NMR integral and the position of the hydrogen atom proton signal peak were used to obtain the degree of polymerization through the integrated area ratio of the proton peak b belonging to the polyethylene glycol segment, the proton peak e belonging to the anhydride part, and the proton peak g belonging to the epoxy part, and the structural formula was confirmed as follows:

[0228]

[0229]

[0230] 2. Preparation of film-breaking polyester polymer nanoparticles using different initiators, R2 and R3 are phenyl and H, R4, R5 and the nitrogen atom connected thereto form a six-membered ring or a seven-membered ring of tertiary amine groups

[0231] The experimental method is the same as that in Example 1.

[0232] 3. Protonation of membrane-breaking polyester polymer materials at different pH values ​​using different initiators, where R2 and R3 are phenyl and H, and R4, R5 and the nitrogen atoms connected to them form a six-membered ring or a seven-membered ring of tertiary amine groups

[0233] The experimental method is the same as that in Example 1.

[0234] The results are as follows Fig.15 As shown in Table 6, the mPEG chain length has no significant effect on the pKa of the membrane-breaking polyester material.

[0235] Table 6

[0236] Material pKa Protonation rate (pH 6.8) Protonation rate (pH7.4) 2k-PS-G-C6 7.09 89％ 7％ 2k-PS-G-C7 6.94 85.4％ 5％ 5k-PS-G-C6 7.12 83％ 17％ 5k-PS-G-C7 6.98 86％ 11％

[0237] 4. Using different initiators, R2 and R3 are phenyl and H, and R4, R5 and the nitrogen atom connected to them form a six-membered ring or a seven-membered ring of tertiary amine groups. Cytotoxicity of membrane-breaking polyester polymer materials at the characteristic pH of normal tissues and tumor tissues

[0238] The experimental method is the same as that in Example 1.

[0239] Test results such as Fig.16 shown.

[0240] Depend on Fig.16 It can be seen that with the increase of mPEG chain length, the cytotoxicity of the membrane-permeable polyester material at pH 6.8 increased, and the cytotoxicity at pH 7.4 decreased.

[0241] Through this example, it can be found that increasing the length of the mPEG chain can reduce the cytotoxicity of the membrane-breaking polyester at pH 7.4, increase the cytotoxicity of the membrane-breaking polyester material at pH 6.8, and improve the selectivity of the membrane-breaking polyester material.

[0242] Embodiment 4:

[0243] 1. Preparation and characterization of film-breaking polyester polymer materials with methoxypolyethylene glycol with a molecular weight of 5000 as the initiator, R2 and R3 with different hydrophobic structures, and R4, R5 and the nitrogen atom connected thereto forming a six-membered ring or a seven-membered ring of tertiary amine groups

[0244] In this embodiment, a film-breaking polyester polymer material is prepared in which the initiator is methoxy polyethylene glycol with a molecular weight of 5000, R2 and R3 are different hydrophobic structures, and R4, R5 and the nitrogen atom connected thereto form a six-membered ring or a seven-membered ring tertiary amine group. These polymer materials can be synthesized by the following ring-opening polymerization method of anhydride and epoxy monomer, and then modified by a click reaction for a six-membered ring tertiary amine or a seven-membered ring tertiary amine, and the reaction equation is as follows:

[0245]

[0246] Among them, R2 and R3 are: n-butyl and H (butyl succinic anhydride), n-octyl and H (n-octyl succinic anhydride), or R2, R3 and the carbon atoms connected thereto form a benzene ring (phthalic anhydride).

[0247] Wherein, R4 and R5 together with the nitrogen atom connected thereto form the following group:

[0248]

[0249] The specific synthesis steps are as follows:

[0250] In a glove box, add initiator, anhydride, epoxy monomer, t-BuP1 to the reaction vessel in sequence, heat and seal at 100-120°C for 1-5 days. After the reaction is completed, add a trace amount of acetic acid to terminate the reaction. For phthalic anhydride, the purification steps are as follows: add a small amount of dichloromethane to dissolve, drop the reaction solution into cold ether to precipitate, and obtain an orange-yellow polymer material. For butyl succinic anhydride and n-octyl succinic anhydride, the purification steps are as follows: use a dialysis bag with a molecular weight cutoff of 3500 to dialyze in DMF for 12 hours, and change DMF 4 times; then dialyze in 4L ultrapure water for 24 hours, change the water every 1 hour for the first 6 hours, and change the water every 6 hours for the next 18 hours. Finally, freeze-dry the liquid in the dialysis bag and store it at low temperature.

[0251] The polymer and aminothiol hydrochloride were dissolved in N, N-dimethylformamide (DMF) respectively, wherein the molar ratio of carbon-carbon double bond: thiol in the polymer side group was 1:6, and the molar ratio of carbon-carbon triple bond: thiol was also 1:6. After mixing evenly, nitrogen was introduced for 15 minutes, and 20-50 mg of DMF solution of photoinitiator 2,2-dimethoxy-2-phenylacetophenone (DMPA) was added, and nitrogen was continued to be introduced for 15 minutes, and then stirred for reaction under 365nm ultraviolet light for 3 hours. After the reaction was completed, a dialysis bag with a molecular weight cutoff of 3500 was used for dialysis in ultrapure water at 4°C for 24 hours. Finally, the liquid in the dialysis bag was freeze-dried and stored at low temperature.

[0252] The abbreviations of the polymers of the film-breaking polyester polymer material prepared in this example and the reactants are shown in Table 7.

[0253] Table 7

[0254]

[0255]

[0256] The NMR spectrum of the obtained broken film polyester polymer material is as follows: Figure 17-Figure 22 As shown, the synthesis of film-breaking polyester polymer was confirmed. Figure 17-Figure 22 The corresponding degree of polymerization was analyzed by the nuclear magnetic integration and the position of the hydrogen atom proton signal peak: for the material with PA anhydride as the polymerization monomer, the degree of polymerization was obtained by the integrated area ratio of the proton peak b belonging to the polyethylene glycol segment, the benzene ring proton peak 1 belonging to the anhydride part, and the proton peak d belonging to the epoxy part; for the material with BSA anhydride as the polymerization monomer, the degree of polymerization was obtained by the integrated area ratio of the proton peak b belonging to the polyethylene glycol segment, the proton peaks 2 and 3 belonging to the anhydride part, and the proton peak g belonging to the epoxy part; for the material with NOSA anhydride as the polymerization monomer, the degree of polymerization was obtained by the integrated area ratio of the proton peak b belonging to the polyethylene glycol segment, the proton peaks 7 and 8 belonging to the anhydride part, and the proton peak g belonging to the epoxy part, and the structural formulas were confirmed as follows:

[0257]

[0258]

[0259]

[0260] 2. Preparation of film-breaking polyester polymer nanoparticles with methoxy polyethylene glycol with a molecular weight of 5000 as an initiator, R2 and R3 with different hydrophobic structures, and R4, R5 and the nitrogen atom connected thereto forming a six-membered ring or a seven-membered ring of a tertiary amine group

[0261] The experimental method is the same as that in Example 1.

[0262] 3. Protonation of membrane-breaking polyester polymer materials with methoxypolyethylene glycol with a molecular weight of 5000 as initiator, R2 and R3 with different hydrophobic structures, and R4, R5 and the nitrogen atoms connected to them forming a six-membered ring or a seven-membered ring of tertiary amine groups at different pH values

[0263] The experimental method is the same as that in Example 1.

[0264] The results are as follows Fig.23 As shown in Table 8, when an epoxy compound containing a double bond is used as a polymerization monomer, the pKa of the obtained film-breaking polyester material is significantly lower than that of an epoxy compound containing a triple bond.

[0265] Table 8

[0266] Material pKa Protonation rate (pH 6.8) Protonation rate (pH7.4) 5k-PA-C6 6.88 74％ 10％ 5k-PA-C7 6.72 27％ 7％ 5k-BS-A-C6 6.67 29％ 9％ 5k-BS-A-C7 6.45 32％ 20％ 5k-NOS-A-C6 6.34 27％ 15％ 5k-NOS-A-C7 6.34 30％ 13％ 5k-PG-C6 7.20 89％ 10％ 5k-PG-C7 7.10 96％ 12％ 5k-BS-G-C6 7.08 87％ 9％ 5k-BS-G-C7 6.92 91％ 11％ 5k-NOS-G-C6 7.00 82％ 16％ 5k-NOS-G-C7 6.77 40％ 14％

[0267] 4. Cytotoxicity of membrane-breaking polyester polymer materials with methoxypolyethylene glycol with a molecular weight of 5000 as initiator, R2 and R3 with different hydrophobic structures, and R4, R5 and the nitrogen atoms connected to them forming a six-membered ring or a seven-membered ring of tertiary amine groups at the characteristic pH of normal tissues and tumor tissues

[0268] The experimental method is the same as that in Example 1.

[0269] Test results such as Fig.24 and Fig.25 shown.

[0270] Depend on Fig.24 and Fig.25 It can be seen that when epoxy compounds containing double bonds and epoxy compounds containing triple bonds are used as polymerization monomers, the cytotoxicity of the obtained membrane-breaking polyester nanoparticles at pH 6.8 is higher than that at pH 7.4, and both have good selectivity.

[0271] 5. The in vivo toxicity of a membrane-breaking polyester polymer material in which methoxypolyethylene glycol with a molecular weight of 5000 is used as an initiator, R2 and R3 are different hydrophobic structures, and R4, R5 and the nitrogen atom connected thereto form a tertiary amine group with a six-membered ring or a seven-membered ring.

[0272] The toxicity of membrane-breaking polyester polymer materials was studied in mice by testing the maximum lethal dose (MTD). A total of 60 5-week-old ICR female mice (purchased from Hunan Shrek Jingda Experimental Animal Co., Ltd.) were divided into 12 groups with similar average weights, with 5 mice in each group. The corresponding materials were 5k-PA-C6, 5k-PA-C7, 5k-BS-A-C6, 5k-BS-A-C7, 5k-NOS-A-C6, 5k-NOS-A-C7, 5k-PG-C6, 5k-PG-C7, 5k-BS-G-C6, 5k-BS-G-C7, 5k-NOS-G-C6, and 5k-NOS-G-C7. Each material was dosed starting from 100 mg / kg body weight, and the same dose was administered to one ICR female mouse. If no experimental animal died after 24 hours, the administration continued. If a dead experimental mouse occurred, the dose was reduced by 10 mg / kg and administered again until all mice did not die at the dose. The maximum dose without death of mice was recorded as the maximum tolerated dose of ICR mice, and a graph was plotted, as shown in the figure below. Fig.26As shown: Using double-bond epoxy compounds as polymerization monomers, the resulting film-breaking polyester materials have lower in vivo toxicity than triple-bond epoxy compounds. Among them, the MTD of 5k-PA-C7, 5k-BS-A-C6, 5k-BS-A-C7, 5k-NOS-A-C6, and 5k-NOS-A-C7 is greater than 100 mg / kg.

[0273] Through this example, it can be found that: using double-bond-containing epoxy compounds as polymerization monomers, the obtained membrane-breaking polyester material has higher cell-selective killing ability and lower in vivo toxicity compared with epoxy compounds containing triple bonds.

[0274] Example 5: Study on the physical and chemical properties of 5k-PA-C7 film-breaking polyester polymer nanoparticles

[0275] Take the 5k-PA-C7 membrane-breaking polyester polymer material nanoparticles prepared in Example 4, take 100 μL of the nanoparticle solution with a concentration of 5 mg / mL, dilute it to 1 mL with a PB salt solution of the corresponding pH, and put it into the potential / particle size test cell of the nanoparticle size analyzer, and use a nanoparticle size and Zeta potential meter to characterize the particle size and potential of the nanoparticles. Fig. 27 As shown in a and b, as the pH decreases, the potential gradually increases, and the particle size does not change much. Under acidic conditions, more tertiary amine structures in the nanoparticles are transformed into positively charged, forming cationic regions with more positive potential.

[0276] Example 6: Verification study on the mechanism of action of 5k-PA-C7 membrane-breaking polyester polymer material in killing cells

[0277] (1) This example further studies whether the cellular endocytosis of 5k-PA-C7 membrane-permeable polyester nanoparticles affects its killing effect on Panc02 cells. Cells were treated with endocytosis inhibitors or co-incubated at 4°C. Fig.28 As shown in a, under pH 7.4 and 6.8 conditions, Panc02 cells and 5k-PA-C7 nanoparticles were placed at 4°C for 30 minutes, and then incubated for 4 hours to detect cell survival rate. Cells and nanoparticles were incubated at 37°C as a control. The results showed that the change in temperature did not affect the killing effect of 5k-PA-C7 nanoparticles on cells. Since low temperature can inhibit the cell endocytosis effect, it can be inferred that 5k-PA-C7 does not work through the classical endocytosis pathway. In addition, Fig.28 As shown in Figure b, pre-treatment of cells with different endocytosis inhibitors and then co-incubation with 5k-PA-C7 nanoparticles did not affect the killing effect of 5k-PA-C7 nanoparticles, which was consistent with the killing effect of the control group. This further proves that the killing of cells by 5k-PA-C7 is not affected by endocytosis. In addition, Fig.28 As shown in Figure d, pre-treatment of cells with different death inhibitors and then co-incubation with 5k-PA-C7 nanoparticles did not affect the killing effect of 5k-PA-C7 nanoparticles, which was consistent with the killing effect of the control group.

[0278] (2) Panc02 cells expressing GFP on the cell membrane and mCherry in the cytoplasm were plated one day in advance, with 18,000 cells per well, and cultured overnight in a 37°C, CO2 incubator to allow the cells to adhere to the wall and grow. 160 μg / mL of 5k-PA-C7 nanoparticles were prepared with DMEM complete medium (containing 10% fetal bovine serum and 1% double antibody) of different pH values, and then the original medium in the well plate was discarded and treated with 5k-PA-C7 nanoparticles for 2 hours. The test was performed using a high-content instrument, such as Fig.28 As shown in c and e, 5k-PA-C7 nanoparticles can cause the release of intracellular proteins in a short time, and from the bright field images, cells die under acidic conditions.

[0279] The above results prove that 5k-PA-C7 does not kill cells by common death pathways, such as apoptosis and pyroptosis, but works by destroying the cell membrane structure.

[0280] Example 7: In vivo tumor inhibition experiment of 5k-PA-C7 membrane-breaking polyester polymer material

[0281] The tumor suppressive effect of 5k-PA-C7 was tested in vivo using an orthotopic C57 mouse breast cancer model (E0771 cells). The procedure was as follows:

[0282] Female mice (C57BL / 6, 6-8 weeks old) were injected with 1×10 6 E0771 cell suspension (100 μL) was added to establish an orthotopic breast cancer model. 3 (Tumor volume = length × width × width / 2), and administration (5k-PA-C7: 30 mg / kg) was performed via the tail vein. A negative control group was set up, and only an equal volume of PBS solution was injected. The tumor size was measured using a vernier caliper, and the mouse body weight was recorded. Fig.29 As shown in the figure, according to the tumor growth curve, the growth of tumor volume in the 5k-PA-C7 nanoparticle group mice was significantly slower than that in the PBS group. At the same time, after the mice underwent the entire treatment cycle, there was no difference in the weight of the mice in the experimental group and the PBS control group, and the treatment process did not cause the mice to lose weight.

[0283] Example 8: In vivo tumor inhibition experiment of 5k-PA-C7 membrane-breaking polyester polymer material combined with anti-PD-1 antibody

[0284] The tumor inhibitory effect of 5k-PA-C7 combined with anti-programmed death receptor 1 (PD-1) antibody (anti-PD-1) was verified by in vivo experiments in C57 mouse colorectal cancer subcutaneous tumor model (MC38 cells). The operation is as follows:

[0285] Female mice (C57BL / 6, 6-8 weeks old) were injected subcutaneously on the back with 1×10 6 100 μL of MC38 cell suspension was added to establish a subcutaneous colorectal cancer tumor model. 3 (Tumor volume = length × width × width / 2), anti-PD-1 (0.75 mg / kg), or anti-PD-1 (0.75 mg / kg) + 5k-PA-C7 (30 mg / kg) membrane-breaking polyester nanoparticles were administered via the tail vein. A negative control group was set up, and only an equal volume of PBS solution was injected. The tumor size was measured using a vernier caliper and the mouse body weight was recorded. Fig.30 As shown in the figure, according to the tumor growth curve, the growth of tumor volume in the mice in the combination group was significantly slower than that in the anti-PD-1 group. At the same time, after the mice underwent the entire treatment cycle, there was no difference in the weight of the mice in the experimental group and the PBS control group, and the treatment process did not cause the mice to lose weight. By weighing the ex vivo tumor, it can be found that the mice in the combination group were lighter than those in the anti-PD-1 group, and the weight of the ex vivo tumor in the combined medication group was the smallest. The ex vivo tumor weight is consistent with the results of the tumor growth curve.

[0286] Embodiment 9:

[0287] 1. Preparation and characterization of film-breaking polyester polymer materials with different degrees of polymerization, in which the initiator is a methoxy polyethylene glycol group with a molecular weight of 5000, R2, R3 and the carbon atom connected to it form a benzene ring, and R4, R5 and the nitrogen atom connected to it form a tertiary amine group with a seven-membered ring

[0288] This example uses the method of Example 4 to synthesize and characterize a series of 5k-(P)nA-(C7)m with different degrees of polymerization. The specific NMR characterization is as follows Figure 31-Figure 32 As shown, according to Fig.31 The corresponding degree of polymerization was analyzed by the nuclear magnetic integration and the position of the hydrogen atom proton signal peak: the degree of polymerization was obtained by the integrated area ratio of the proton peak b belonging to the polyethylene glycol segment, the proton peak c belonging to the anhydride part of the benzene ring, and the proton peak e belonging to the epoxy part, and the structural formula was confirmed as follows:

[0289]

[0290] 2. Preparation of film-breaking polyester polymer nanoparticles with different polymerization degrees, wherein the initiator is a methoxy polyethylene glycol group with a molecular weight of 5000, R2, R3 and the carbon atom connected thereto form a benzene ring, and R4, R5 and the nitrogen atom connected thereto form a tertiary amine group with a seven-membered ring

[0291] The experimental method is the same as that in Example 1.

[0292] 3. Cytotoxicity of membrane-breaking polyester polymer materials with different polymerization degrees at characteristic pH of normal tissue and tumor tissue, in which the initiator is a methoxy polyethylene glycol group with a molecular weight of 5000, R2, R3 and the carbon atom connected to it form a benzene ring, and R4, R5 and the nitrogen atom connected to it form a tertiary amine group with a seven-membered ring

[0293] The experimental method is the same as that in Example 1.

[0294] Test results such as Fig.33 shown.

[0295] Depend on Fig.33 It can be seen that the molecular weight of the membrane-breaking polyester material has little effect on its cytotoxicity at pH 6.8 and pH 7.4, and has little effect on its selective killing ability.

[0296] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the following embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0297] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A film-breaking polyester having a structure shown in formula (I): in, R1 is selected from the group consisting of: the residue of methoxypolyethylene glycol with the hydroxyl group removed; R2 and R3 are independently selected from: H, aryl, alkyl, or R2, R3 and the carbon atom to which they are connected together form a cycloalkyl, cycloalkene, cycloalkynyl or aryl group; Each R4 and R5 are independently selected from: C1-C6 alkyl, or R4, R5 and the nitrogen atom to which they are attached together form a 5-10 membered heterocycloalkyl; R6 is selected from: H, alkyl, Each R is selected from: an alkylene group; n and m are each independently an integer of 1-200.

2. The film-breaking polyester according to claim 1, characterized in that Each R is independently selected from: C1-C6 alkylene.

3. The film-breaking polyester according to claim 2, characterized in that Each R is independently selected from the group consisting of methylene, ethylene, and propylene.

4. The film-breaking polyester according to claim 1, characterized in that R1 is selected from: Where x is 1-200.

5. The film-breaking polyester according to claim 4, characterized in that x is 40-120.

6. The film-breaking polyester according to claim 5, characterized in that x is 40-48 or 108-116.

7. The film-breaking polyester according to claim 5, characterized in that R1 is selected from:

8. The film-breaking polyester according to claim 1, characterized in that R2 and R3 are independently selected from: H, C6-C 10 Aryl, C1-C 20 Alkyl, or R2, R3 and the carbon atom to which they are attached together form a C3-C8 cycloalkyl, C3-C8 cycloalkene, C3-C8 cycloalkyne or C6-C 10 Aryl.

9. The film-breaking polyester according to claim 8, characterized in that R2 and R3 are independently selected from: H, phenyl, C4-C 12 Alkyl, or R2, R3 and the carbon atom to which they are attached together form a phenyl group.

10. The film-breaking polyester according to claim 9, characterized in that R2 is selected from: H, phenyl, C6-C 10 Alkyl, R3 is H; or R2, R3 and the carbon atom to which they are attached together form a phenyl group.

11. The film-breaking polyester according to claim 10, characterized in that R2 is selected from: H, phenyl, n-butyl, n-octyl, R3 is H; or R2, R3 and the carbon atom to which they are connected together form a phenyl group.

12. The film-breaking polyester according to claim 1, characterized in that Each R4 and R5 is independently selected from: C1-C3 alkyl, or R4, R5 and the nitrogen atom to which they are connected together form a 5-8 membered heterocycloalkyl.

13. The film-breaking polyester according to claim 12, characterized in that R4, R5 and the nitrogen atom to which they are connected together form the following group:

14. The film-breaking polyester according to claim 1, characterized in that R6 is selected from: H, C1-C 10 alkyl, 15. The film-breaking polyester according to claim 1, characterized in that It has a structure as shown in the following formula (II) or formula (III):

16. The film-breaking polyester according to claim 1, characterized in that It has a structure shown in the following formula (IV) or formula (V): Wherein, x is 40-48, and R2 is selected from: C8-C 10 Alkyl, R3 is H.

17. The film-breaking polyester according to claim 1, characterized in that It has a structure shown in the following formula (IV) or formula (V): Wherein, x is 108-116; R2 is selected from: H, phenyl, C6-C 10 Alkyl, R3 is H; or R2, R3 and the carbon atom to which they are attached together form a phenyl group.

18. The film-breaking polyester according to any one of claims 1 to 17, characterized in that: n and m are independently 20-180.

19. The film-breaking polyester according to claim 18, characterized in that n and m are independently 25-35, or 35-45, or 45-55, or 52-62, or 60-70, or 80-90, or 95-105, or 165-180.

20. The film-breaking polyester according to claim 1, characterized in that Selected from the following polymers:

21. A film-breaking polyester nanoparticle, characterized in that: It is formed by self-assembly of an organic solution of the film-breaking polyester according to any one of claims 1 to 20 in an aqueous medium.

22. A method for preparing the film-breaking polyester nanoparticles according to claim 21, characterized in that: The method comprises the following steps: dissolving the membrane-breaking polyester in an organic solvent, then adding the obtained solution dropwise into water under stirring, continuing stirring, and removing the solvent by low-temperature dialysis to obtain the membrane-breaking polyester nanoparticles.

23. The method for preparing film-broken polyester nanoparticles according to claim 22, characterized in that: The organic solvent is N,N-dimethylformamide; and / or, The ratio of the film-breaking polyester, the organic solvent and the water is 45 mg to 55 mg: 1 to 2 mL: 4 to 6 mL.

24. The method for preparing film-broken polyester nanoparticles according to claim 22, characterized in that: The preparation method of the membrane-breaking polyester nanoparticles comprises the following steps: dissolving the membrane-breaking polyester in N,N-dimethylformamide at a ratio of 45 mg to 55 mg: 1.5 mL, then adding the obtained solution dropwise into water under stirring at a speed of 400 to 800 rpm, continuing stirring at a speed of 200 to 600 rpm for 8 to 20 minutes, dialyzing in water using a dialysis bag with a molecular weight cutoff of 3400 to 3600 to remove the solvent, and obtaining the membrane-breaking polyester nanoparticles.

25. The method for preparing film-broken polyester nanoparticles according to claim 24, characterized in that: The dialysis temperature is 0°C-5°C, the dialysis time is 24 hours, the water is changed every 0.8-1.2 hours in the first 6 hours, and the water is changed every 5-7 hours in the next 18 hours.

26. Use of the membrane-breaking polyester according to any one of claims 1 to 20 in the preparation of a drug for preventing and / or treating tumors.

27. Use of the membrane-broken polyester nanoparticles according to claim 21 in the preparation of drugs for preventing and / or treating tumors.

28. Use of the membrane-perturbing polyester according to any one of claims 1 to 20 in combination with an immune checkpoint inhibitor in the preparation of a drug for preventing and / or treating tumors.

29. Use of the membrane-breaking polyester nanoparticles according to claim 21 in combination with immune checkpoint inhibitors in the preparation of drugs for preventing and / or treating tumors.

30. The use according to claim 28 or 29, characterized in that The immune checkpoint inhibitor is a PD-1 inhibitor.

31. The use according to any one of claims 26 to 29, characterized in that: The tumor is pancreatic cancer, melanoma, colorectal cancer, lung cancer, tongue squamous cell carcinoma, cervical cancer, ovarian cancer, osteosarcoma, liver cancer, breast cancer, bladder cancer, and ovarian epithelial cancer.

32. A drug for preventing and / or treating tumors, characterized in that: The composition is prepared from active ingredients and pharmaceutically acceptable excipients, wherein the active ingredients include the film-breaking polyester according to any one of claims 1 to 20 and / or the film-breaking polyester nanoparticles according to claim 21.

33. A combined drug for preventing and / or treating tumors, characterized in that: Its active ingredients include: Component 1: the film-breaking polyester according to any one of claims 1 to 20, and / or the film-breaking polyester nanoparticles according to claim 21; and Component 2: anti-tumor drugs other than component 1; The component 1 and the component 2 are respectively independent administration units, or the component 1 and the component 2 together form a combined administration unit.

34. The combined drug for preventing and / or treating tumors according to claim 33, characterized in that: The component 2 is an immune checkpoint inhibitor.

35. The combined drug for preventing and / or treating tumors according to claim 34, characterized in that: The immune checkpoint inhibitor is a PD-1 inhibitor.

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