PH-responsive polyethylene glycol-anticarcinogen conjugate, and synthetic method and application thereof

Abstract

The invention discloses a pH-responsive polyethylene glycol-anticarcinogen conjugate, and a synthetic method and application thereof. After anticarcinogen molecules and polyethylene glycol are covalently linked through pH-sensitive phenylimide linkage, the conjugate is formed, wherein, anticarcinogen can be doxorubicin, epirubicin, daunorubicin, demethoxydaunorubicin or hydrochlorides of the above-mentioned anticarcinogens. The phenylimide linkage is stable under the condition of a normal physiological pH value but undergoes hydrolysis under the condition of a slightly acidic pH value, e.g., a solid tumor cell external pH value and a cell endosome and lysosome pH value; that is, the phenylimide linkage is sensitive to changes of pH values in a range of 7.4 to 4.5 or to below 4.5. The polyethylene glycol-anticarcinogen conjugate has amphiphilic nature and can form nanometer-scale micelle in a saline solution through self-assembly; the micelle can be used as a drug carrier to carry hydrophobic drugs and form a nanometer micelle preparation cladded with drugs, thereby realizing synergy therapy of a plurality of drugs.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a pH-responsive polyethylene glycol-anticancer drug bond based on a phenylimine bond and a synthesis method thereof, and the polyethylene glycol-anticancer drug The application of the bond as a drug carrier. Background technique [0002] Cancer seriously endangers human life and health. According to the statistics of the World Health Organization, 7.6 million people died of cancer in the world in 2005, and it is estimated that the number will reach 9 million in 2015 and 11.5 million in 2030. Cancer has been listed as the "No. 2 killer" (after cardiovascular disease) facing mankind (China Cancer, 2009, 18, 88-89). Due to the difficulty of early detection, its treatment has always been a difficult point in the medical field. At present, less than 10% of tumor patients can undergo preoperative chemotherapy and complete resection after radiotherapy, although about ...

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Problems solved by technology

At present, less than 10% of tumor patients can undergo preoperative chemotherapy and complete resection after radiotherapy, although about 90% of patients can receive radiotherapy, including radiofrequency or alcohol ablation, and administration of doxorubicin, 5-fluorouracil, etc. for systemic or arterial infusion. Injection, embolization and other chemotherapy treatments, these methods or drugs can indeed have a certain inhibitory or killing effect on tumor tissues or cells. However, when using traditional preparations to treat tumors, the drug-loading system cannot distinguish between normal tissues and tumors. Tissues, normal cells and tumor cells, so that the drug kills the cancer cells, but also brings serious damage to the normal cells of the human body. This is a serious problem that currently limits the dosage of drugs, therapeutic effects and quality of life of patients (Ann. Surg., 1999, 229, 790-800)

On the other hand, many new cancer drugs under development have good killing / inhibitory effects on tumor cells in vitro experiments, but most of the drugs have complex structures, poor stability, and low solubility in water (about 40% of the drugs are non-water-soluble). properties) (Drug Discovery, 2003, 2, 337 and references therein), new preparation systems are required to adapt to it, otherwise their clinical effects will be greatly limited

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