A leukocyte membrane-modified paclitaxel targeted sustained-release liposome and preparation method thereof

Abstract

The invention discloses a paclitaxel-targeted sustained-release liposome modified by a leukocyte membrane and a preparation method thereof, and belongs to the technical fields of drug control releaseand biomaterials. The paclitaxel-targeted sustained-release liposome comprises a drug-loaded sustained-release liposome and the leukocyte membrane modifying the surface of the drug-loaded sustained-release liposome, wherein the drug-loaded sustained-release liposome is composed of paclitaxel, star-shaped cholic acid functionalized polylactic acid, soybean phospholipid and cholesterol. The star-shaped cholic acid functionalized polylactic acid with excellent biocompatibility is introduced into the paclitaxel sustained-release liposome, surface modification is performed by the leukocyte membrane, the prepared paclitaxel-targeted sustained-release liposome overcomes the toxic and side effects caused by a surfactant polyoxyethylene castor oil in a conventional paclitaxel injection liquid, andhas the advantages of excellent sustained-release effect, good tumor targeting property, long half-life period in vivo, high stability and good biocompatibility.

Description

technical field [0001] The invention belongs to the technical field of drug controlled release and biomaterials, and in particular relates to a leukocyte membrane-modified paclitaxel targeted slow-release liposome and a preparation method thereof. Background technique [0002] Paclitaxel is a diterpene compound extracted from Taxus genus Taxus, which has a unique anti-tumor effect. It can form stable microtubule bundles after combining with tubulin, inhibit the replication of cancer cells, and thus prevent cancer cells from Proliferation is a broad-spectrum and highly effective anticancer drug, mainly used for the treatment of ovarian cancer, breast cancer, melanoma, lung cancer, colorectal cancer, head and neck cancer, lymphoma, brain tumor and other cancers. [0003] However, due to the special physical and chemical properties and pharmacological effects of paclitaxel, there are still some shortcomings in clinical use, such as unsatisfactory curative effect and obvious tox...

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Problems solved by technology

[0003] However, due to the special physical and chemical properties and pharmacological effects of paclitaxel, there are still some shortcomings in clinical use, such as unsatisfactory curative effect and obvious toxic and side effects. The main problems are as follows: ① Poor solubility in water. Ethylene castor oil and the degradation products of polyoxyethylene castor oil in the body are likely to cause severe allergic reactions, neurotoxicity, nephrotoxicity and other adverse reactions. In order to overcome allergic reactions, dexamethasone should be given as a preventive drug before medication; It is a kind of cell cycle-specific drug, the tumor-inhibiting effect of continuous low-dose administration in vivo is more obvious than that of one-time pulse administration, so it should be prepared as a sustained-release preparation, while the current commercially available paclitaxel injections are all non-sustained-release preparations, which affect Efficacy; ③Targeted preparations can maximize the distribution of drugs to target organs to achieve the best curative effect, but have no effect on other normal tissues and organs, so as to achieve high efficiency and low toxicity, especially suitable for anticancer drugs. Commercially available paclitaxel injections are all non-targeting preparations, which affects its clinical application

[0004] Therefore, it has become a hotspot in paclitaxel drug research to find new formulations for the purpose of improving water solubility, delaying drug release, and increasing targeting effects, such as preparing paclitaxel into liposomes, nanoparticles, emulsions, clathrates, prodrugs, gels, etc. Liposomes are widely used as paclitaxel carriers because of their excellent biocompatibility, simple preparation process, and the ability to simultaneously load hydrophilic and hydrophobic drugs. There are still some shortcomings and problems that need to be solved urgently: ① traditional unmodified common liposomes are easily damaged by various proteins and enzymes in the blood, such as high-density lipoprotein is the main component of liposomes, and liposomes The protein is easy to fall off from the high-density lipoprotein and combine with the phospholipid in the liposome, which is easy to exchange with the phospholipid, resulting in the formation of holes in the liposome membrane and leakage of drugs; the complex formed by the combination of serum albumin and liposome phospholipid Liposomes will cause the reduction of liposome stability; liposomes in the blood will activate the complement system and form a complex that destroys the membrane, leading to the appearance of hydrophilic channels in the liposome membrane, causing drug leakage, and a large amount of water and electrolytes entering , and even cause liposome cracking; phospholipase in the blood can hydrolyze the phospholipids in the liposomes, leading to the destruction of the liposomes (the strength of the reaction is determined by the phospholipid structure); ② after the liposomes enter the blood circulation system , most of the unmodified liposomes are transported to the rich mononuclear phagocyte system such as the liver and spleen, and a small amount is taken up by the lung, bone marrow and kidney. The liver cell membrane receptors recognize the negatively charged phospholipids directly exposed on the surface, As a result, it is phagocytized by liver cells, resulting in a short residence time of ordinary liposomes in the systemic circulation; ③Unmodified traditional liposomes are not ideal for sustained release due to the destructibility of phospholipids, and the clinical efficacy is affected; ④ Unmodified traditional liposomes have unsatisfactory targeting and severe side effects, which seriously affect their clinical application

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