Application of P-glycoprotein inhibitors in drug delivery system modified by DCDX

A glycoprotein inhibitor and drug delivery system technology, applied in the field of biopharmaceuticals, can solve the problems of low quality of life of patients, clean tumor resection, and lack of in-depth research.

Active Publication Date: 2019-05-31
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main treatment for brain tumor patients is surgical resection, supplemented by chemotherapy and radiotherapy. However, due to the infiltration and growth characteristics of the tumor, and the rich blood vessels and nerves in the brain, it is difficult to remove the tumor completely by surgery, and postoperative radiotherapy has serious side effects. As a result, the quality of life of patients is low, and chemotherapy drugs are difficult to cross the blood-brain barrier (BBB), which limits their efficacy
As a result, the mortality rate of patients remains high. For example, the 5-year survival rate of glioma is less than 5%. [1] The median survival time of brain metastases is less than half a year
However, in the prior art, how to improve the efficiency of drug-targeted treatment of tumors through the efflux function of P-gp has not been studied in depth.

Method used

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  • Application of P-glycoprotein inhibitors in drug delivery system modified by DCDX
  • Application of P-glycoprotein inhibitors in drug delivery system modified by DCDX
  • Application of P-glycoprotein inhibitors in drug delivery system modified by DCDX

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1D

[0053] Example 1 D Construction and characterization of CDX-liposome drug delivery system

[0054] This example discloses a DCDX-liposome drug delivery system construction and characterization method, which specifically includes the following steps:

[0055] (1) Preparation and characterization of membrane materials: first react DCDX-Cys with Mal-PEG-DSPE (phospholipid polyethylene glycol maleimide), freeze-dry to obtain DCDX-PEG-DSPE, then according to HSPC / Chol / mPEG2000 -DSPE / DCDX-PEG-DSPE (52:43:3:2, mol / mol) formula to prepare DCDX modified PEG (polyethylene glycol) liposome membrane material. The DCDX-PEG-DSPE that Mal-PEG-DSPE and above-mentioned steps obtain is dissolved in CDCl3, nuclear magnetic resonance instrument detects its nuclear magnetic spectrum, test result is as follows figure 1 shown. figure 1 Figure A in the middle is the 1H-NMR spectrum of Mal-PEG-DSPE, and Figure B is the 1H-NMR spectrum of DCDX-PEG-DSPE. Such as figure 1 As shown, Mal-PEG-DSPE show...

Embodiment 2

[0058] Embodiment 2 Verapamil to D Effect of CDX-Liposome Drug Delivery System on Brain Targeting

[0059] (1) In vivo / ex vivo near-infrared investigation of brain targeting effects: in order to detect P-gp and D The relationship between CDX-liposome accumulation in the brain, ICR mice were randomly divided into 3 groups: control group, D CDX-liposome set, D CDX-liposome+verapamil group. Specific operation: the three groups of ICR mice were injected with 100 liters into the tail vein respectively D CDX-Liposome / 3D, D CDX-liposome / 3D and normal saline, intraperitoneal injection of verapamil (15mg / kg) to one group of liposome-injected mice, and in vivo fluorescence detection by intravital imager at 12h, 24h and 48h respectively . After the detection, anesthetized with chloral hydrate, cardiac perfusion with normal saline, removed the brain tissue, and detected the fluorescence intensity of the brain tissue at 12h, 24h and 48h with an in vivo imager. The results were as fol...

Embodiment 3

[0061] Embodiment 3 verapamil to D Anti-glioma effect of CDX-liposome drug delivery system

[0062] (1) Construction of orthotopic glioma model mice: Take U87 cells in the logarithmic growth phase, digest and count the cells, suspend them with an appropriate amount of PBS buffer, and inoculate each nude mouse with 8×10 5 cells. Before the experiment, the nude mice were anesthetized with 8% chloral hydrate, fixed with a brain stereotaxic instrument, and the suspension cells were inoculated in the striatum (0.6 mm forward, 1.8 mm to the right, and 3 mm in depth) of the bregma, and regular observations were made. Status of nude mice after surgery.

[0063] (2) Efficacy test of antigenic glioma: the rats bearing orthotopic glioma were randomly divided into 4 groups (n=8), and injected with 100 g of D CDX-Liposome / Doxorubicin, Saline, Verapamil, 100M, D CDX-liposome / doxorubicin+verapamil, the single injection dose of verapamil was 15mg / kg, and the survival time of the model mice ...

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PUM

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Abstract

The invention belongs to the field of biological pharmacy, and relates to an application of P-glycoprotein inhibitors in a drug delivery system modified by DCDX. An amino acid sequence of the DCDX isshown in SEQ NO:1. According to the application of the P-glycoprotein inhibitors in the drug delivery system modified by the DCDX,the application proves that P-gp inhibitors can significantly increasethe amount of intracerebral accumulation and prolong the time of intracerebral accumulation of a liposome drug delivery system modified by the DCDX, and further proves that the P-gp inhibitors can significantly improve the effect of adriamycin liposome modified by the DCDX on brain glioma, therebyproviding a basis for the follow-up combination of the P-gp inhibitors and the liposome drug deliverysystem modified by the DCDX for the treatment of clinical brain diseases, especially brain tumors.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals and relates to a P-glycoprotein inhibitor D Application of CDX modified drug delivery system. Background technique [0002] Major brain diseases include brain tumors, Parkinson's disease, Alzheimer's disease, stroke, etc. Brain tumors include brain tumors in situ and brain metastases. The most common brain tumor in situ is glioma, which accounts for about 50% of primary malignant brain tumors; the most common brain metastases are breast cancer brain metastases (about 16%) and lung cancer brain metastases (about 20%). The main treatment for brain tumor patients is surgical resection, supplemented by chemotherapy and radiotherapy. However, due to the infiltration and growth characteristics of the tumor, and the rich blood vessels and nerves in the brain, it is difficult to remove the tumor by surgery, and postoperative radiotherapy has serious side effects. As a result, the quality of life of pa...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K31/277A61K31/704A61K9/127A61K47/42A61P35/00
Inventor 张雪梅陆伟跃谢为怡辛宏刘敏
Owner FUDAN UNIV
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