Novel chemotherapeutic drug nano ADC based on antibody conjugation and preparation method and application thereof

Abstract

The invention discloses nanoparticles of an antibody chemotherapeutic drug such as doxorubicin and maytansine (DOX, DM1) based on an antibody conjugation new technology and a preparation method and an application thereof. Experimental results show that compared with a single antibody and a single drug, nanoparticles formed by self-assembling antibody-chemotherapeutic drug conjugated conjugates has a targeting property significantly enhanced, and has the drug toxic and side effects on bodies significantly reduced; the formed nanoparticles use enhanced permeability and retention effect (EPR) of tumor tissues in a composite mode to enhance intratumoral accumulation, enhances the bioavailability of the drug, at the same time, reduces the use dosage of the drug, and provides a high-efficiency and low-toxicity nano treatment mode for tumor targeted therapy.

Description

【Technical field】 [0001] The invention relates to the technical field of medicine, in particular to a novel antibody-coupled chemotherapeutic drug nano-ADC and its preparation method and application. 【Background technique】 [0002] Tumor is one of the three major diseases that seriously threaten human health today. The incidence of cancer in my country has reached 2 / 1,000, and the mortality rate is 1.5 / 1,000. Among them, lung cancer has the highest mortality rate, liver cancer ranks second, and gastric cancer ranks third. The treatment effect of malignant gastric cancer is poor, the late metastasis rate is high, and the prognosis is often poor. Conventional treatments such as radiotherapy, chemotherapy and surgery, which are commonly used in clinical practice, relieve the pain to a great extent and prolong the survival time; however, chemotherapy or radiotherapy cannot change the survival period of patients, even for cancers that are sensitive to the first chemotherapy For...

AI Technical Summary

Problems solved by technology

[0004] Although antibody-drug conjugates have certain advantages over single antibodies and chemotherapeutic drugs in terms of killing effect and reducing the toxicity of chemotherapeutic drugs, due to the different abundance of antigens expressed on the surface of different cells, a single antibody-drug conjugate The therapeutic effect of cells with relatively insufficient antigen expression is not satisfactory; and studies have shown that the number of effector molecules coupled to ADC affects the aggregation of ADC, antigen binding activity, clearance rate in blood circulation, activity and resistance. Receptivity, the number of coupled effector molecules is too small, which reduces the activity of ADC; on the contrary, too much will reduce the half-life and tolerance of ADC drugs in the blood, and at the same time affect the effective combination of antibodies and antigens; in addition, a single antibody- The accumulation of drug conjugates in tumors is low, chemically conjugated drugs are not stable enough in blood circulation, and the toxic side effects of released cytotoxic molecules on cells also make antibody-drug conjugates fail to achieve clinical expectations

[0005] The antibody-coupled chemotherapeutic drug nano-ADC of the present invention aims to utilize the hydrophilicity of the antibody and the hydrophobicity of the chemotherapeutic drug doxorubicin to self-assemble in a liquid phase environment into a hydrophobic chemotherapeutic drug core inside and a hydrophilic exterior. The outer shell of the antibody forms an immuno-chemotherapy nanosystem; the nanoimmuno-chemotherapy system not only retains the targeting of a single antibody and the strong lethality of chemotherapy drugs alone, but the immuno-chemotherapy nanosystem targets tumor cells in a multivalent manner , also significantly enhanced its antigen-antibody affinity, so that a large amount of doxorubicin can be effectively enriched into the tumor site, reducing the dosage of the drug, thereby reducing the damage of the drug to normal tissues and reducing the side effects of the drug. Not yet reported

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