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Nanometer drug delivery system targeted for brain tumors and tumor stem cells thereof and preparation and application of nanometer drug delivery system

A tumor stem cell and nano-drug technology, applied in the field of nano-drug delivery carrier, can solve the problems of lack of specificity of signaling pathway, difficulty in targeted delivery, stem cell killing, etc., and achieve improved therapeutic effect, easy operation and good biocompatibility. Effect

Inactive Publication Date: 2019-08-30
SHANGHAI TONGREN HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the particularity of the anatomical location of the brain tumor, its highly invasive growth state, and the distribution of very few tumor stem cells, it is difficult to target delivery. At the same time, the targeted therapy for brain tumor stem cells involves a lack of specificity in some signaling pathways. It is easy to cause damage to other stem cells in the whole body (such as neural stem cells, hematopoietic stem cells, embryonic stem cells, etc.) during the treatment process, causing serious side effects

Method used

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  • Nanometer drug delivery system targeted for brain tumors and tumor stem cells thereof and preparation and application of nanometer drug delivery system
  • Nanometer drug delivery system targeted for brain tumors and tumor stem cells thereof and preparation and application of nanometer drug delivery system
  • Nanometer drug delivery system targeted for brain tumors and tumor stem cells thereof and preparation and application of nanometer drug delivery system

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Experimental program
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Embodiment 1

[0048] A method for preparing a nano-drug delivery vehicle targeting brain tumors and tumor stem cells, the steps are as follows:

[0049] (1): Synthesis of phospholipids carrying targeting molecules: the surface modified polypeptide (SEQ ID NO. 1) and aptamer (SEQ ID NO. 2) are connected to the COOH group of COOH-PEG2000-DSPE with EDC and NHS as linkers Above, the molar ratio is COOH-PEG2000-DSPE:EDC:NHS (N-hydroxysuccinimide)=0.03:1.25:2.1, mmol / mmol, incubate at room temperature and stir slowly for 8h. The sum of the molar amount of surface-modified polypeptide and aptamer is equal to the molar amount of COOH-PEG2000-DSPE.

[0050] (2): The targeted phospholipid prepared in step (1), DC-chol, and DOPE are dissolved in chloroform at a molar ratio of 1:2:0.03, and the dry film is formed by rotary evaporation at 40°C for 2 hours. Hydrate in HEPES (10mM, pH 7.4) buffer for 30min to make the final phospholipid concentration 20mg / mL. Sonicate the probe for 10min with ultrasonic probe...

Embodiment 2

[0056] (1): Synthesis of phospholipids carrying targeting molecules: the surface modified polypeptide (SEQ ID NO. 1) and aptamer (SEQ ID NO. 2) are thiolated and then linked to phosphatidylethanolamine-polyethylene glycol 2000-Malay On imide (MAL-PEG2000-DSPE), the target molecule is dissolved in 0.15mol / L borate+0.1mmol / L EDTA buffer (pH8.5), then 2-IT is added, and the reaction is incubated at room temperature for 60min. The solution was concentrated by ultrafiltration, the buffer was replaced with 0.1 mol / L PBS (pH 8.0), detected by Ellman reagent, and the feed ratio was 1:40 (mol / mol).

[0057] (2): Dissolve the targeted phospholipid prepared in step (1) with DC-chol, DOPE and other phospholipid components in chloroform at a molar ratio of 1:2:0.03, and vacuum rotary evaporate at 40°C for 2 hours. The dry film formed is in HEPES (10mM, pH 7.4) hydration in buffer for 30min to make the final phospholipid concentration 20mg / mL, ultrasonic probe ultrasonic for 10min, and then pa...

Embodiment 3

[0063] Characterize the particle size and apparent morphology of the targeted nanocarrier system.

[0064] (1) Use dynamic light scattering instrument (Zetasizer, Nano-ZS, Malvern, UK) to measure particle size distribution and surface potential. At the same time, the change of particle size of the prepared sample before and after adding 10% BSA was detected.

[0065] (2) Take an appropriate amount of the sample, drop it on a copper mesh covered with carbon film, negatively stain with 2.0% phosphotungstic acid, dry at room temperature for 0.5 h, and observe the external morphology of the liposome under a transmission electron microscope.

[0066] The experimental results are as Figure 2A~2D Shown. by Figure 2A~2D It can be seen that by combining DLS and TEM, it can be seen that the particle size of the system is uniformly dispersed. With the increase of the amount of plasmid, the particle size of the system increases and the ZETA potential decreases, but the particle size in 10 m...

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Abstract

The invention discloses a nanometer drug delivery system targeted for brain tumors and tumor stem cells thereof. The nanometer drug delivery system comprises tumor treatment drugs, a carrier frameworkand targeting molecules combined to the surface of the carrier framework, wherein the carrier framework is a cationic liposome; the targeting molecules at least comprise a first targeting molecule and a second targeting molecule, the first targeting molecule is surface modification polypeptide, and the second targeting molecule is an aptamer; and the tumor treatment drugs are selected from chemotherapy drugs and / or gene targeting drugs. The invention discloses a preparation method and application of the nanometer drug delivery carrier. The nanometer drug delivery carrier can carry and load target genes or chemotherapy drugs for cerebral tumor treatment, and through dimolecular modification, the targeting efficiency of the system is improved to 67% or above from 5% which is obtained underthe condition that modification is not performed.

Description

Technical field [0001] The present invention relates to a nano-medicine delivery carrier in the pharmaceutical field, in particular to a nano-medicine delivery carrier targeting brain tumors and tumor stem cells, and preparation and application thereof. Background technique [0002] In situ brain tumors there are blood brain barrier (BBB) ​​and blood tumor barrier (BTB). Low-grade brain tumors (grade Ⅰ, Ⅱ) have relatively poor new blood vessels, BBB has no destructive changes, and the enhanced permeability and retention effect (EPR) is not obvious. The main obstacle to drug delivery is BBB; high-grade brain tumors There are abundant new blood vessels (grade Ⅲ, Ⅳ), and a series of changes have taken place in the morphology of microvessels. There are worm-eaten cavities in the basement membrane, the fenestration structure and the expansion of tight junctions appear, the blood tumor barrier is created, and the EPR effect exists. The BTB / BBB barrier is a crucial barrier for drug the...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K47/18A61K47/24A61K47/28A61K47/42A61K47/26A61K31/337A61K48/00A61P35/00
CPCA61K9/1271A61K31/337A61K47/186A61K47/24A61K47/26A61K47/28A61K47/42A61K48/005A61P35/00
Inventor 孙西洋马俐君
Owner SHANGHAI TONGREN HOSPITAL
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