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CN112535678A - Trituzumab-linked maytansine nanoparticle composition - Google Patents

Trituzumab-linked maytansine nanoparticle composition Download PDF

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CN112535678A
CN112535678A CN202011577826.6A CN202011577826A CN112535678A CN 112535678 A CN112535678 A CN 112535678A CN 202011577826 A CN202011577826 A CN 202011577826A CN 112535678 A CN112535678 A CN 112535678A
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plga
maytansine
terminated peg
trastuzumab
maleimide
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倪玲
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Yantai University
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    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5169—Proteins, e.g. albumin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The invention provides a trastuzumab-connected maytansine nanoparticle composition, which contains a blend of maytansine, a methoxy-terminated lactide-glycolide copolymer and a maleimide-terminated lactide-glycolide copolymer, wherein the first methoxy-terminated lactide-glycolide copolymer has high intrinsic viscosity, and the second maleimide-terminated lactide-glycolide copolymer has low intrinsic viscosity. And the maytansine nanoparticles are connected with trastuzumab targeting ligands. The nanoparticles prepared according to the embodiment of the invention have round and smooth appearance and sustained release effect, and compared with nanoparticles not connected with a targeting ligand, the nanoparticles connected with trastuzumab can enter tumor cells more.

Description

Trituzumab-linked maytansine nanoparticle composition
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a maytansine nanoparticle composition connected with trastuzumab.
Background
Breast cancer is one of the most common malignant tumors of women, and seriously harms the physical and mental health and life of the women. The incidence of the cancer is related to heredity, the incidence of the cancer accounts for 7% -10% of all malignant tumors, and the cancer is in a trend of rising year by year, becomes the highest incidence of the malignant tumors of female suffering, and is the cause of cancer death of the sixth female after lung cancer, gastric cancer, liver cancer, esophageal cancer and colorectal cancer. By 2008, a total of 169452 newly-developed invasive breast cancers and 44908 deaths from breast cancer have occurred in china. By 2021, the number of chinese breast cancer patients will be as high as 250 ten thousand.
In recent years, with the deepening and development of molecular biology research, a tumorigenesis mechanism is introduced into the molecular field, and the discovery of various tumor molecular markers provides important values for differential diagnosis and treatment of breast cancer and the like. It was found that the HER2 gene is amplified or overexpressed in many human tumors and is closely related to resistance to tumor therapy and prognosis. The positive rate of HER2 in breast cancer is 25-30% by immunohistochemical detection.
With the deep understanding of the mechanism of tumor development and biological properties, new drugs and their applications have been developed for specific biological pathways directed to tumor progression, and this therapeutic modality has become a targeted therapy. The monoclonal antibody can identify cell antigens, improve the tumor killing rate and reduce systemic side effects, and becomes the development trend of the molecular targeted drug market at present. Trastuzumab, a trade name of herceptin, was approved by the FDA in 1998, is suitable for HER2 positive metastatic breast cancer patients who have rapid metastasis and are difficult to be cured, and has good curative effects.
Maytansine, also known as maytansine, is a natural ansa-macrolide antibiotic with anti-tumor therapeutic action, and is a highly effective mitotic inhibitor. It was found that maytansine prevents tubulin polymerization by specifically binding to tubulin of mitotic cells, ultimately inhibiting metaphase mitosis. Clinical preliminary experiments show that the maytansine has very obvious tumor inhibition effect on tumors such as breast cancer, and the drug effect is 100-fold and 1000-fold higher than that of vinblastine. However, the maximum tolerated dose is very low and, beyond the tolerated dose, has strong toxic side effects. Therefore, there is an urgent clinical need to develop a novel targeted delivery system for maytansine to overcome the above-mentioned drawbacks. Intensive studies were conducted on the trastuzumab maytansine co-delivery system for HER2 positive breast cancer therapy. The co-delivery system wraps the maytansine in the nanoparticles, and the trastuzumab is connected to the surface of the carrier through a connecting molecule to serve as a targeting ligand. The specific combination of the ligand and the cancer cell surface receptor realizes the fixed-point release of the medicine, so that the medicine is maintained at the treatment concentration for a long time.
Disclosure of Invention
A trastuzumab-linked maytansine nanoparticle composition comprising: the active ingredient maytansine, a polymer mixture comprising methoxy-terminated PEG-PLGA and maleimide-terminated PEG-PLGA, and the targeting ligand trastuzumab; the weight content of the active ingredient in the pharmaceutical composition is 0.1-5%, the weight content of the polymer mixture in the pharmaceutical composition is 95-99.9%, and the connection rate of the targeting ligand is 10-90%.
Preferably, the methoxy-terminated PEG-PLGA has a high intrinsic viscosity of 0.4-0.8 dl/g; the maleimide-terminated PEG-PLGA has a low intrinsic viscosity of 0.1 to 0.35 dl/g.
Preferably, the weight ratio of the methoxy-terminated PEG-PLGA to the maleimide-terminated PEG-PLGA is (50-150): 1-20).
Preferably, the molar ratio of lactide to glycolide of the methoxy-terminated PEG-PLGA is 65: 35-90: 10; the molar ratio of lactide to glycolide of the maleimide-terminated PEG-PLGA is 50: 50-75: 25.
Preferably, the weight average molecular weight of the methoxy-terminated PEG-PLGA is 45,000-155,000; the weight average molecular weight of the maleimide-terminated PEG-PLGA is 3,500-55,000.
Preferably, the polymer mixture is present in the pharmaceutical composition in an amount of 95% to 99.9% by weight.
Preferably, the linkage rate of the targeting ligand is 10-90%.
Preferably, the maytansine is present in an amount of 2.5% by weight; the weight content of the polymer mixture in the pharmaceutical composition is 97.5%; the weight ratio of the methoxy-terminated PEG-PLGA to the maleimide-terminated PEG-PLGA is 95: 5; the molecular weight of the methoxy-terminated PEG-PLGA is 70,000-85,000, the intrinsic viscosity is 0.4-0.8 dl/g, and the molar ratio of lactide to glycolide is 75: 25; the molecular weight of the maleimide-terminated PEG-PLGA is 20,000-35,000, the intrinsic viscosity is 0.1-0.35 dl/g, and the molar ratio of lactide to glycolide is 50: 50; the connection rate of the targeting ligand is 40-60%.
The invention provides a trastuzumab-linked maytansine nanoparticle composition, which comprises an active ingredient and a polymer mixture, wherein the active ingredient is selected from maytansine; the drug polymer mixture comprises methoxy-terminated PEG-PLGA and maleimide-terminated PEG-PLGA; the targeting ligand is selected from trastuzumab; the weight content of the active ingredients in the pharmaceutical composition is 0.1-5%, preferably 0.2-4%, and more preferably 0.4-3%; the content of the PEG-PLGA terminated by methoxy group and the PEG-PLGA terminated by maleimide group in the pharmaceutical composition is 95 to 99.9 percent, preferably 96 to 99.8 percent, and more preferably 97 to 99.6 percent; the connection rate of the targeting ligand is 10-90%.
The nanoparticles disclosed herein mean spherical particles of a drug uniformly dissolved and/or dispersed in a polymeric material, have a particle size ranging from 50 to 500nm, and are generally prepared as suspensions for injection.
Two PEG-PLGA are first PEG-PLGA with a high intrinsic viscosity and a methoxyl end capping and a second PEG-PLGA with a low intrinsic viscosity and a maleimide end capping, wherein the high intrinsic viscosity is 0.4 to 0.8dl/g, preferably 0.5 to 0.7dl/g, and more preferably 0.55 to 0.65 dl/g; the low intrinsic viscosity is 0.1 to 0.35dl/g, preferably 0.1 to 0.3dl/g, and more preferably 0.2 to 0.3 dl/g. The weight ratio of the high intrinsic viscosity methoxy-terminated PLGA to the low intrinsic viscosity maleimide-terminated PLGA is (50-150): 1-20), preferably (70-100): 3-10, more preferably 95: 5.
The intrinsic viscosity of PLGA was determined as follows: PLGA was formulated into a solution of about 0.5% (w/v) in chloroform and the intrinsic viscosity of PLGA was measured at 30 ℃ using a Cannon-Fenske glass capillary viscometer.
The two PEG-PLGAs may also be a first high molecular weight methoxy-terminated PEG-PLGA and a second low molecular weight maleimide-terminated PEG-PLGA, having a high molecular weight of 45,000 to 155,000, preferably 65,000 to 100,000, more preferably 70,000 to 85,000; the low molecular weight is 3,500 to 55,000, preferably 4,500 to 40,000, and more preferably 20,000 to 35,000. The weight ratio of the high molecular weight PEG-PLGA to the low molecular weight PEG-PLGA is (50-150): 1-20), preferably (70-100): 3-10, more preferably 95: 5; the molar ratio of lactide to glycolide in the high molecular weight PEG-PLGA is 65: 35-90: 10, preferably 75: 25; the molar ratio of lactide to glycolide in the low molecular weight PEG-PLGA is 50: 50-75: 25, preferably 50: 50. The term "molecular weight" as used herein refers to "weight average molecular weight", simply referred to as "molecular weight".
For convenience of description, hereinafter, the molar ratio of lactide to glycolide in PEG-PLGA and the intrinsic viscosity of PLGA are indicated in parentheses after PLGA. For example, "PEG-PLGA (75/25, 0.6A)" means a lactide-glycolide copolymer having a lactide to glycolide molar ratio of 75:25, an intrinsic viscosity of 0.6dl/g and a methoxy end group.
In particular, the weight ratio of methoxy-terminated PEG-PLGA (75/25, 0.6A) having high intrinsic viscosity to maleimide-terminated PEG-PLGA (50/50, 0.25A) having low intrinsic viscosity in the present invention is preferably 95: 5.
Specifically, in the nano-drug composition of the present invention, the preferred weight content of maytansine is 2.5% and the weight content of methoxy-terminated and maleimide-terminated PEG-PLGA is 97.5%, the weight ratio of the two PEG-PLGAs is 95: and 5, the molecular weights of the two PEG-PLGAs are respectively 70,000-85,000 and 20,000-35,000, the intrinsic viscosities of the two PEG-PLGAs are respectively 0.55-0.65 dL/g and 0.2-0.3 dL/g, and the molar ratios of lactide to glycolide in the two PEG-PLGAs are respectively 75:25 and 50: 50.
The "drug loading" used in the present invention is the actual drug loading, and is calculated according to the following equation: the drug loading rate is [ the amount of the drug in the nanoparticle/(the amount of the drug in the nanoparticle + the amount of the polymer in the nanoparticle) ] × 100%.
The maytansine nanoparticles of the present invention can be prepared by conventional methods, such as emulsion-solvent evaporation, nano-precipitation, and the like.
Emulsion-solvent evaporation method: dissolving maytansine and PEG-PLGA in proper organic solvent, injecting the organic solvent into water-soluble polymer water phase solution for dispersion and emulsification, volatilizing the organic solvent, washing the residue and filtering to obtain the microsphere. The organic solvent may be selected from halogenated hydrocarbons (e.g., dichloromethane, chloroform, ethyl chloride, or trichloroethane, etc.), ethyl acetate, ethyl formate, diethyl ether, cyclohexane, benzyl alcohol, or combinations thereof. The water-soluble polymer can be selected from at least one of polyvinyl alcohol (PVA), sodium carboxymethylcellulose (CMC-Na), polyvinylpyrrolidone (PVP), sodium polymethacrylate, and sodium polyacrylate, or their combination. The dispersion emulsification can be carried out with mechanical stirring or by means of a static mixer.
Nano precipitation method: weighing a certain amount of methoxy-terminated PEG-PLGA and maleimide-terminated PEG-PLGA, dissolving in an organic solvent to serve as an organic phase, using ultrapure water as a water phase, slowly dripping the organic phase into the water phase under the condition of ice-water bath, and performing magnetic stirring to volatilize and remove the organic solvent to obtain the nanoparticles.
The monoclonal antibody is connected by adding a monoclonal antibody solution under a proper concentration of the nanoparticles, and stirring for a certain time in an ice water bath to obtain the monoclonal antibody-connected nanoparticles.
The invention also provides the application of the trastuzumab-linked maytansine nanoparticles in preparing an anti-breast cancer medicament, wherein the breast cancer is HER2 positive metastatic breast cancer, and the treatment of patients who have received trastuzumab and a taxane separately or jointly.
Has the advantages that:
the technical scheme provides a novel active targeting preparation drug delivery system taking maytansine as a drug, and provides a novel targeting therapeutic drug for treating HER2 positive breast cancer.
Drawings
FIG. 1 is a transmission electron micrograph of maytansine nanoparticles and trastuzumab-linked maytansine nanoparticles of example 4.
Fig. 2 is a photograph showing the in vitro release of maytansine solution and maytansine nanoparticles in example 4.
Detailed Description
As described herein, various embodiments relate to pharmaceutical compositions comprising: the active component is maytansine; comprises a first methoxy-terminated lactide-glycolide copolymer and a second maleimide-terminated lactide-glycolide copolymer, wherein the weight content of active ingredients in the pharmaceutical composition is 0.1-5%, preferably 0.2-4%, more preferably 0.4-3%. The weight content of the polymer blend in the pharmaceutical composition is 95-99.9%, preferably 96-99.8%, more preferably 97-99.6%. The connection rate of the targeting ligand is 10-90%. The pharmaceutical composition exists in the form of nanoparticles.
In the pharmaceutical composition of one embodiment of the present invention, the polymer blend is composed of a methoxy-terminated lactide-glycolide copolymer and a maleimide-terminated lactide-glycolide copolymer.
In the pharmaceutical composition of one embodiment of the invention, the methoxyl-terminated lactide-glycolide copolymer has high intrinsic viscosity of 0.4-0.8 dl/g, preferably 0.5-0.7 dl/g, and more preferably 0.55-0.65 dl/g; the maleimide-terminated lactide-glycolide copolymer has a low intrinsic viscosity of 0.1-0.35 dl/g, preferably 0.1-0.3 dl/g, and more preferably 0.2-0.3 dl/g; the weight ratio of the methoxyl-terminated lactide-glycolide copolymer to the second non-terminated lactide-glycolide copolymer is (50-150): 1-20, preferably (70-100): 3-10, and more preferably 95: 5; the molar ratio of lactide to glycolide in the methoxy-terminated lactide-glycolide copolymer is 65: 35-90: 10, preferably 75: 25; the molar ratio of lactide to glycolide of the maleimide-terminated PEG-PLGA is 50: 50-75: 25, preferably 50: 50.
In another embodiment of the pharmaceutical composition of the present invention, the methoxy-terminated lactide-glycolide copolymer has a weight average molecular weight of 45,000 to 155,000, preferably 65,000 to 100,000, more preferably 70,000 to 85,000; the weight average molecular weight of the maleimide-terminated PEG-PLGA is 3,500-55,000, preferably 4,500-40,000, and more preferably 20,000-35,000. The weight ratio of the methoxyl-terminated lactide-glycolide copolymer to the maleimide-terminated lactide-glycolide copolymer is (50-150): 1-20, preferably (70-100): 3-10, and more preferably 95: 5; the molar ratio of lactide to glycolide in the methoxy-terminated lactide-glycolide copolymer is 65: 35-90: 10, preferably 75: 25; the molar ratio of lactide to glycolide of the maleimide-terminated PEG-PLGA is 50: 50-75: 25, preferably 50: 50.
In a preferred embodiment of the present invention, the pharmaceutical composition comprises 2.5% maytansine by weight, 97.5% polymer blend by weight, and the weight ratio of methoxy-terminated PEG-PLGA to maleimide-terminated PEG-PLGA is 95:5, the molecular weight of the methoxy-terminated PEG-PLGA is 70,000-85,000, the molecular weight of the maleimide-terminated PEG-PLGA is 20,000-35,000, the intrinsic viscosity of the methoxy-terminated PLGA is 0.55-0.65 dl/g, the viscosity of the maleimide-terminated PEG-PLGA is 0.2-0.3 dl/g, and the molar ratio of lactide to glycolide in the methoxy-terminated PEG-PLGA is 75:25 and the molar ratio of lactide to glycolide in the maleimide-terminated PEG-PLGA is 50: 50.
the invention also provides application of the maytansine pharmaceutical composition in preparation of a medicine for treating breast cancer, wherein the breast cancer mainly refers to HER2 positive breast cancer.
The invention will be further illustrated by the following examples and test examples, which are not intended to limit the scope of the invention in any way.
Example 1
Weighing 57mg of methoxy-terminated PEG-PLGA and 3mg of maleimide-terminated PEG-PLGA, dissolving in 3ml of acetone, adding 600 mu l of maytansine solution with the concentration of 3.33mg/ml, uniformly mixing in a vortex manner to obtain an organic phase, slowly dripping the organic phase into the water phase under the conditions of ice water bath and magnetic stirring (the rotating speed is 324rpm), and completely volatilizing the organic solvent to obtain the maytansine nanoparticles. The drug loading of the microspheres was 3.0% and the particle size D50 was 120 nm.
Example 2
Weighing 57mg of methoxy-terminated PEG-PLGA and 3mg of maleimide-terminated PEG-PLGA, dissolving in 3ml of acetone, adding 450 mu l of maytansine solution with the concentration of 3.33mg/ml, uniformly mixing in a vortex manner to obtain an organic phase, slowly dripping the organic phase into the water phase under the conditions of ice water bath and magnetic stirring (the rotating speed is 324rpm), and completely volatilizing the organic solvent to obtain the maytansine nanoparticles. The drug loading was 2.3% and the particle size D50 was 90 nm.
Example 3
Weighing 57mg of methoxy-terminated PEG-PLGA and 3mg of maleimide-terminated PEG-PLGA, dissolving in 3ml of acetone, adding 300 mul of maytansine solution with the concentration of 3.33mg/ml, uniformly mixing in a vortex manner to obtain an organic phase, slowly dripping the organic phase into the water phase under the conditions of ice water bath and magnetic stirring (the rotating speed is 324rpm), and completely volatilizing the organic solvent to obtain the maytansine nanoparticles. The drug loading was 1.5% and the particle size D50 was 123 nm.
Example 4
8.87mg of methoxy-terminated PEG-PLGA, 0.47mg of maleimide-terminated PEG-PLGA, and 69. mu.l of maytansine solution with the concentration of 3.33mg/mL were weighed at room temperature, and 2.0mL of acetone was added for ultrasonic dissolution to obtain an organic phase. Slowly dropwise adding the organic phase into 10mL of ultrapure water (under the condition of ice-water bath) under magnetic stirring, removing the ice-water bath after one hour of the ice-water bath, and carrying out magnetic stirring for 2-3 hours at normal temperature to completely volatilize the organic solvent. To obtain the maytansine nanoparticles. And (3) concentrating the nanoparticles by using a 100k ultrafiltration tube, and performing ultrafiltration until the volume of the nanoparticles is 1mL, wherein the concentration condition is 3500rpm at 4 ℃ for 12 min. After the concentration is finished, the nanoparticle concentrated solution is placed in a small beaker, 10mL of trastuzumab solution (dissolved in 0.01mol/L phosphate buffer solution with pH7.4 and the concentration is about 4.3544ug/mL) is immediately added, the mixture is protected from light, and after the mixture is magnetically stirred in an ice-water bath for one hour, the reaction is continued for 8 hours at room temperature. Thus obtaining the maytansine nano-particle connected with the trastuzumab. After the reaction, 1.0mL of the mixture is centrifuged (4 ℃, 4000rpm, 45min), and the supernatant is taken and operated according to the BCA kit instruction to detect the concentration of the free monoclonal antibody, so as to obtain the monoclonal antibody connection rate. The drug loading of the obtained nanoparticles is 1.5%, the granularity D50 is 123nm, and the monoclonal antibody connection rate is 60%.
Dropping 1 drop of maytansine nanoparticle solution on a copper mesh, fixing, sucking the redundant liquid around the copper mesh with filter paper, dyeing with phosphotungstic acid solution (1%), sucking the redundant dyeing liquid with filter paper, and drying. The morphology of the maytansine nanoparticles was observed by transmission electron microscopy. The results are shown in FIG. 1. As can be seen from FIG. 1, the nanoparticles are regular spherical particles, the particle size distribution is uniform, and no agglomeration or adhesion occurs.
The in vitro release characteristics of maytansine nanoparticles were investigated by membrane dialysis. Putting 1.5ml maytansine nanoparticle solution into a dialysis bag (molecular cut-off is 8000-14000), putting the dialysis bag into 40ml PBS (pH7.4) buffer solution containing 0.5% Tween 80, setting shaking table conditions at 37 ℃ and 130rpm, and taking 1ml of dialysate and simultaneously supplementing release media with the same temperature and volume at 0.5h, 1h, 2h, 4h, 8h, 24h, 32h, 48h, 72h and 96 h. The maytansine content of the dialysate was determined by HPLC. And calculating the cumulative release degree of the maytansine nanoparticles and drawing a cumulative release curve. The results are shown in FIG. 2. As can be seen from FIG. 2, the maytansine solution can be completely released within 12h, and the cumulative release amount reaches 93.82% +/-2.26%. The maytansine nanoparticles (DM1-NPs, TMAB-DM1-NPs) can realize the slow release of the medicine, and the cumulative release amount in 72 hours is 89.12% +/-2.32% and 82.32% +/-1.21% respectively. In vitro release experiments show that the slow release effect can be achieved by taking the high-molecular PEG-PLGA as a carrier to entrap the maytansine. The target TMAB modified nanoparticles have no influence on the release of the drug.
And observing the uptake condition of the nanoparticles connected with the trastuzumab and the nanoparticles not connected with the trastuzumab by the tumor cells by using a laser confocal microscope. Breast cancer cells BT-474(HER2+) at logarithmic growth phase were seeded in 24-well plates. The well plate was placed in a cell incubator for 48 hours and the cells attached to the wall. Then, nanoparticles connected with the nanoparticle solution trastuzumab and nanoparticles not connected with the monoclonal antibody (the nanoparticles are marked by Nile red) are added and cultured for a period of time respectively. The drug-containing medium was discarded, washed, fixed with paraformaldehyde, washed again, incubated with hoechst33342, and finally the cells were washed 3 times with cold PBS. And (3) inverting the cell slide on a glass slide, and observing the uptake position of the nanoparticles in the cells under a confocal microscope. The results show that with increasing time more and more nanoparticles (red) are distributed around the blue nucleus, also indicating that the nanoparticles are mainly distributed in the cytoplasm after being taken up by the cells. The density of nanoparticle distribution around the nuclei showed that TMAB-NPs were greater than NPs. The trastuzumab modified nanoparticles are proved to have good targeting property and higher tumor permeability.

Claims (8)

1.一种连接曲妥珠单抗的美登素纳米粒组合物，其特征在于，所述美登素纳米粒组合物包含：活性成分美登素，聚合物混合物和靶向配体曲妥珠单抗；所述聚合物混合物包含甲氧基封端的PEG-PLGA和马来酰亚胺基封端的PEG-PLGA；所述活性成分在药物组合物中的重量含量为0.1％～5％，所述聚合物混合物在药物组合物中的重量含量为95％～99.9％，所述靶向配体的连接率为10％～90％。1. A maytansine nanoparticle composition linked to trastuzumab, characterized in that the maytansine nanoparticle composition comprises: active ingredient maytansine, polymer mixture and targeting ligand trast beadzumab; the polymer mixture comprises methoxy-terminated PEG-PLGA and maleimide-terminated PEG-PLGA; the weight content of the active ingredient in the pharmaceutical composition is 0.1% to 5%, The weight content of the polymer mixture in the pharmaceutical composition is 95%-99.9%, and the linking ratio of the targeting ligand is 10%-90%. 2.根据权利要求1所述的连接曲妥珠单抗的美登素纳米粒组合物，其特征在于，所述甲氧基封端的PEG-PLGA具有0.4～0.8dl/g的特性黏度；所述马来酰亚胺基封端的PEG-PLGA具有0.1～0.35dl/g的特性粘度。2. The trastuzumab-linked maytansine nanoparticle composition according to claim 1, wherein the methoxy-terminated PEG-PLGA has an intrinsic viscosity of 0.4-0.8 dl/g; The maleimide-terminated PEG-PLGA has an intrinsic viscosity of 0.1-0.35 dl/g. 3.根据权利要求2所述的连接曲妥珠单抗的美登素纳米粒组合物，其特征在于，所述甲氧基封端的PEG-PLGA与所述马来酰亚胺基封端的PEG-PLGA的重量比为(50～150):(1～20)。3. The maytansine nanoparticle composition linked to trastuzumab according to claim 2, wherein the methoxy-terminated PEG-PLGA and the maleimido-terminated PEG The weight ratio of -PLGA is (50～150):(1～20). 4.根据权利要求3所述的连接曲妥珠单抗的美登素纳米粒组合物，其特征在于，所述甲氧基封端的PEG-PLGA的丙交酯与乙交酯的摩尔比为65:35～90:10；所述马来酰亚胺基封端的PEG-PLGA的丙交酯与乙交酯的摩尔比为50:50～75:25。4. The trastuzumab-linked maytansine nanoparticle composition according to claim 3, wherein the mol ratio of lactide and glycolide of the methoxy-terminated PEG-PLGA is 65:35-90:10; the molar ratio of lactide to glycolide of the maleimide-terminated PEG-PLGA is 50:50-75:25. 5.根据权利要求1或2所述的连接曲妥珠单抗的美登素纳米粒组合物，其特征在于，所述甲氧基封端的PEG-PLGA的重均分子量为45,000～155,000；所述马来酰亚胺基封端的PEG-PLGA的重均分子量为3,500～55,000。5. The trastuzumab-linked maytansine nanoparticle composition according to claim 1 or 2, wherein the weight-average molecular weight of the methoxy-terminated PEG-PLGA is 45,000-155,000; The weight-average molecular weight of the maleimide-terminated PEG-PLGA is 3,500-55,000. 6.根据权利要求5所述的连接曲妥珠单抗的美登素纳米粒组合物，其特征在于，聚合物混合物在所述药物组合物中的重量含量为95％～99.9％。6 . The trastuzumab-linked maytansine nanoparticle composition according to claim 5 , wherein the weight content of the polymer mixture in the pharmaceutical composition is 95% to 99.9%. 7 . 7.根据权利要求6所述的连接曲妥珠单抗的美登素纳米粒组合物，其特征在于，所述靶向配体的连接量率为10％～90％。7 . The trastuzumab-linked maytansine nanoparticle composition according to claim 6 , wherein the targeting ligand has a linking amount ratio of 10% to 90%. 8 . 8.根据权利要求7所述的连接曲妥珠单抗的美登素纳米粒组合物，其特征在于，所述美登素的重量含量为2.5％；所述聚合物混合物在所述药物组合物中的重量含量为97.5％；所述甲氧基封端的PEG-PLGA与马来酰亚胺基封端的PEG-PLGA的重量比为95：5；所述甲氧基封端的PEG-PLGA的分子量为70,000～85,000，特性粘度为0.4～0.8dl/g，丙交酯与乙交酯的摩尔比为75:25；所述马来酰亚胺基封端的PEG-PLGA的分子量为20,000～35,000，特性粘度为0.1～0.35dl/g，丙交酯与乙交酯的摩尔比为50:50；所述靶向配体的连接量率为40～60％。8. The trastuzumab-linked maytansine nanoparticle composition according to claim 7, wherein the weight content of the maytansine is 2.5%; the polymer mixture is in the drug combination The weight content is 97.5%; the weight ratio of the methoxy-terminated PEG-PLGA to the maleimide-terminated PEG-PLGA is 95:5; The molecular weight is 70,000～85,000, the intrinsic viscosity is 0.4～0.8dl/g, the molar ratio of lactide to glycolide is 75:25; the molecular weight of the maleimide-terminated PEG-PLGA is 20,000～35,000 , the intrinsic viscosity is 0.1-0.35 dl/g, the molar ratio of lactide to glycolide is 50:50; the linking ratio of the targeting ligand is 40-60%.
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