Vesicle with anchoring and charge overturning functions and preparation and application thereof

Abstract

The invention provides a vesicle with anchoring and charge overturning functions as well as preparation and application of the vesicle. The vesicle is prepared through a series of reactions such as polymerization, ammonolysis, amidation and deprotection, and has excellent anchoring and charge overturning functions. The vesicles can be efficiently anchored to the surface of intracranial capillary endothelium through the anchoring peptide ApoE linked with the vesicles, under the action of GTT on the surface of BBB, specific chain segments on the surface of the vesicles can be cut off, amino groups are exposed, charges are remarkably increased, AMT-mediated endocytosis is promoted, the vesicles can efficiently penetrate through the BBB, and then the vesicles are further gathered at tumor positions under the targeting action of the ApoE peptide; the vesicles are sensitive to pH and enzyme, and can be expanded to 500 nm or above in a slightly acidic environment of a tumor site, so that the cavitation effect under the ultrasonic action is enhanced, and the penetration of a drug to the deep part of a tumor is promoted.

Description

technical field [0001] The invention belongs to the technical field of medicine. More specifically, it relates to a vesicle with anchoring and charge flipping functions and its preparation and application. Background technique [0002] Glioma is a primary malignant intracranial tumor with the characteristics of high recurrence rate, high mortality rate and low cure rate, and is considered to be one of the deadliest tumor diseases. According to the data provided by the International Agency for Research on Cancer, in 2020 alone, there will be 300,000 new patients and 250,000 deaths of brain and nervous system tumors worldwide, which shows the danger. Currently, the median survival period of adult glioma patients is only 1-1.5 years, mainly because the protective function of the blood-brain barrier (BBB) ​​hinders most drugs (100% Macromolecular drugs and more than 98% of small molecule drugs) enter the brain tissue, resulting in that even in today's highly developed medical ...

AI Technical Summary

Problems solved by technology

Currently, the median survival period of adult glioma patients is only 1-1.5 years, mainly because the protective function of the blood-brain barrier (BBB) ​​hinders most drugs (100% Large molecule drugs and more than 98% of small molecule drugs) enter the brain tissue, so that even in today's highly developed medical technology, researchers are still at a loss for brain diseases such as glioma

[0003] Different from drug molecules, the nutrients required by the brain, such as glucose, hormones, amino acids, vitamins, and insulin, can quickly pass through the BBB to meet the needs of normal physiological activities. There are three main ways to enter the brain tissue: (1 ) Carrier mediated transport system (carrier mediated transport, CMT), this mechanism mainly uses the endogenous carrier on the brain capillary endothelial cells to mediate some hydrophilic molecules with small molecular weight to quickly pass through the BBB to reach the brain tissue Most of the small molecular nutrients such as glucose, amino acids, hormones, etc. enter the brain tissue through this mechanism, so the drug molecules need to be modified to have similar molecular weight and molecular structure with amino acids, so that they can use this mechanism to enter the brain tissue. However, this kind of modification is very easy to inactivate the drug, and many drug molecules do not have the structural basis for chemical modification, which greatly limits their application (Tsuji, A., Small molecular drug transfer across the blood-brain barrier via carrier-mediated transport systems.NeuroRX, 2005, 2(1), 54-62.); (2) receptor mediated transport system (receptor mediated transport, RMT), which mainly uses circulating ligands and brain capillary endothelial cells The way of homologous transmembrane receptor binding promotes endocytosis, so that substances can reach the brain parenchyma. The currently discovered and commonly used receptors include insulin receptors, transferrin receptors, low-density lipoprotein receptors and lactoferrin Therefore, coupling drug-loaded nanocarriers with targeting ligands can promote the drug to cross the BBB, but the efficiency of drug crossing the BBB will be limited by the size of the nanocarrier and the number of receptors, successfully delivered through the RMT mechanism The efficiency to brain tissue is often not more than 1%, resulting in insufficient potential for its practical application (Wiley, D.T.; Webster, P.; Gale, A., et al., Transcytosis and brain uptake of transferrin-containing nanoparticles bytuning avidity to transferrin receptor. Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(21), 8662-8667.); (3) adsorption mediated transport system (adsorption mediated transport, AMT), the mechanism is through adsorption Acts to bind positively charged species to the negatively charged BBB On the surface, it triggers the endocytosis of cells, and then transports through the BBB through the vesicles in endothelial cells and enters the brain parenchyma. However, most cell membranes in the human body are negatively charged, and positively charged nanoparticles are easily absorbed by other cells during blood circulation. Cellular uptake, bringing toxicity risk, namely cationic toxicity (Iqbal, A.; Ahmad, I.; Khalid, M.H., et al., Nanoneurotoxicity to nanoneuroprotection using biological and computational approaches. Journal of Environmental Science and Health, Part C, 2013, 31 (3), 256-284.)

[0004] It can be seen that the application of the existing three BBB crossing mechanisms has great limitations. Therefore, it is necessary to develop a drug delivery system that can efficiently cross the BBB for the treatment of glioma.

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