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P-hydroxybenzoic acid mediated polymer micelle drug delivering system with brain targeting function

A technology of para-hydroxybenzoic acid and drug delivery system, which can be used in pharmaceutical formulations, anti-tumor drugs, drug combinations, etc., can solve the problems of brain-targeted polymer micelle drug delivery systems mediated by hydroxybenzoic acid, etc. Achieving good brain aggregation effect, improving therapeutic effect, and improving inhibitory effect

Active Publication Date: 2014-08-13
SHANGHAI WHITTLONG PHARMA INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

So far, there have been no literature reports on the preparation of p-hydroxybenzoic acid-mediated brain-targeted polymer micellar drug delivery system and its application in the treatment of brain tumors

Method used

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  • P-hydroxybenzoic acid mediated polymer micelle drug delivering system with brain targeting function
  • P-hydroxybenzoic acid mediated polymer micelle drug delivering system with brain targeting function
  • P-hydroxybenzoic acid mediated polymer micelle drug delivering system with brain targeting function

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1 Preparation of p-hydroxybenzoic acid-polymer micelles / DTX (p-HA-micelles / DTX)

[0063] 1) Preparation of p-hydroxybenzoic acid-polyethylene glycol-distearoylphosphatidylethanolamine (p-HA-PEG-DSPE)

[0064] Weigh an appropriate amount of p-HA, dissolve it in DMF, add a certain amount of NHS and EDC·HCl to activate for 3 h, centrifuge to get the supernatant; weigh an appropriate amount of NH 2 - PEG-DSPE in DMF, add the supernatant dropwise, then add 50 μL of DIEA, and stir overnight at room temperature. The above reaction solution was precipitated and centrifuged with glacial ether. After vacuum drying, the dried product was dispersed with double distilled water, purified by dialysis, and freeze-dried to obtain p-HA-PEG-DSPE as a white solid. use 1 Its structure was verified by H-NMR (500 MHz, CD 3 Cl) (eg figure 1 shown), the results show that: the compound has between 0.8-1.5ppm two The characteristic peak of stearyl phosphatidylethanolamine, the...

Embodiment 2

[0069] Example 2 BCECs cell uptake test of p-hydroxybenzoic acid-polymer micelles (p-HA-micelles)

[0070] 1) Preparation of p-hydroxybenzoic acid-polymer micelles / C6 (p-HA-micelles / C6)

[0071] The film-forming hydration method was used to prepare coumarin-6 (C6)-labeled mPEG-micelles, including the steps of: mixing mPEG-DSPE with 50 μg of fluorescent dye C6, vortexing for 1 min, and rotating to dryness at 37°C. The membrane was vacuum-dried to remove residual organic solvents, and 200 μL of HEPES (pH 7.4, 10 mmol / L) was added, vortexed for 10 min, shaken in a water bath at 37 °C for 2 h, and gel filtration chromatography was used, with G50 as filler and HEPES as The unloaded C6 was removed from the elution medium, and mPEG-micelles / C6 was obtained after passing through a 0.22 μm microporous membrane; using the same preparation process, the molar ratio of p-HA-PEG-DSPE to mPEG-DSPE was 5:95 , to prepare p-HA-micelles / C6, measure the content of C6 with a fluorescence spec...

Embodiment 3

[0076] Example 3 Animal experiment of intracerebral drug delivery of p-hydroxybenzoic acid-polymer micelles (p-HA-micelles)

[0077] 1) Distribution of p-hydroxybenzoic acid-polymer micelles / DiR in living tissues of mice

[0078] Preparation of p-HA-micelles / DiR separately 、m PEG-micelles / DiR polymer micelles, in which the amount of DiR was 15.6 μg, 100 μL / mouse was injected into the tail vein, and 10% chloral hydrate was injected at 1, 2, 4, 8, 12 and 24 hours after administration. The mice were anesthetized, and the fluorescence distribution in the mice was observed in the live animal imaging system. It can be seen from the distribution diagram that p-HA-micelles / DiR has obvious fluorescence distribution in the mouse brain, while mPEG-micelles / DiR has no fluorescence distribution in the brain, suggesting that p-HA-micelles / DiR can pass through p-hydroxybenzene Formic acid mediates crossing of the blood-brain barrier into the brain (eg Figure 4 shown).

[0079] 2) ...

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Abstract

The invention belongs to the technical field of high polymer material and pharmaceutical preparations, and particular to preparation of a p-hydroxybenzoic acid mediated polymer micelle drug delivering system with brain targeting function and application of the polymer micelle drug delivering system in the treatment of brain tumors. The polymer micelle drug delivering system with the brain targeting function is prepared by mixed construction of a brain targeting functional material and an amphipathic r polymer material, in-vivo and in-vitro activity evaluation results show that the p-hydroxybenzoic acid mediated polymer micelle drug delivering system can step over blood brain barrier to deliver drugs into the brain, can significantly increase the drug accumulation in the brain, and has the obvious antitumor effect, and compared with a common polymer micelle drug delivery system, the treatment effect of anticancer drugs on the brain tumor can be significantly improved.

Description

[0001] technical field [0002] The invention belongs to the technical field of polymer materials and pharmaceutical preparations, in particular to a p-hydroxybenzoic acid-mediated brain-targeted polymer micelle drug delivery system and a preparation method thereof, and the brain-targeted polymer micelle drug delivery system Application in the treatment of brain tumors. [0003] Background technique [0004] The prior art discloses that brain tumors are common malignant diseases of the central nervous system, including primary brain tumors and metastatic brain tumors. Since the tumor site is close to the patient's central nervous system, it is difficult to completely remove it with general clinical surgery and the tumor is prone to recurrence. In clinical practice, surgical resection of brain tumors combined with chemotherapy is usually used for the prevention and treatment of tumor recurrence. [0005] In the prior art, targeted drug delivery systems for the treatment of ...

Claims

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Application Information

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IPC IPC(8): A61K51/12A61K51/06A61K49/18A61K49/12A61K9/107A61K47/34A61K45/00A61P35/00
Inventor 陆伟跃张智新谢操魏晓丽李瑾孟庆刚
Owner SHANGHAI WHITTLONG PHARMA INST
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