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Small-particle-size drug-loaded micelle for actively targeting alpha v beta 3 integrin receptor tumor cells and preparation method of small-particle-size drug-loaded micelle

An integrin receptor, drug-loaded micelle technology, applied in anti-tumor drugs, pharmaceutical formulations, medical preparations with non-active ingredients, etc., can solve the problem of low targeting function or targeting efficiency, and unsatisfactory anti-tumor effect , insufficient targeting function, etc., to achieve good biocompatibility, good tumor penetration, and good anti-tumor efficacy.

Inactive Publication Date: 2020-02-21
INNER MONGOLIA MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The drug-loaded liposomes or nanoparticles reported in the literature that can target the αvβ3 integrin receptor have problems such as insufficient targeting function after the carrier is modified by the targeting peptide due to its large particle size or mass, that is, the so-called pony (Little horses are targeting peptides) pull carts (carts are liposomes or nanoparticles with larger particle sizes), specifically, liposomes or nanoparticles that reach the tumor site, due to their larger mass or volume The reason is that its targeting function or targeting efficiency is not high, and eventually it cannot enter tumor cells through receptor-mediated endocytosis, resulting in unsatisfactory anti-tumor effects

Method used

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  • Small-particle-size drug-loaded micelle for actively targeting alpha v beta 3 integrin receptor tumor cells and preparation method of small-particle-size drug-loaded micelle
  • Small-particle-size drug-loaded micelle for actively targeting alpha v beta 3 integrin receptor tumor cells and preparation method of small-particle-size drug-loaded micelle
  • Small-particle-size drug-loaded micelle for actively targeting alpha v beta 3 integrin receptor tumor cells and preparation method of small-particle-size drug-loaded micelle

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1. Preparation of small-sized drug-loaded micelles targeting tumor cells with high expression of αvβ3 integrin receptors

[0030] 1. Synthesis of Guided Compounds

[0031] Weigh a certain amount of actively esterified distearoylphosphatidylethanolamine-polyethylene glycol-NHS and cRGDfK peptide powder (molar ratio is 2:1~3:1), dissolve them in anhydrous N,N-dimethylformaldehyde In base formamide. After the powder is completely dissolved, the polypeptide solution is first transferred to an eggplant-shaped bottle, and the distearoylphosphatidylethanolamine-polyethylene glycol-NHS solution is added dropwise to the polypeptide solution under magnetic stirring. After mixing evenly, an appropriate amount of triethylamine was added to adjust the pH of the reaction solution to 8.0-9.0, and the mixture was reacted at room temperature for 24 hours under protection from light and nitrogen. During the reaction, the progress of the reaction was followed by thin layer chrom...

Embodiment 2

[0034] Example 2. Targeting evaluation of cRGDfK-PM small size micelles to B16 tumor cells in vitro

[0035] 1. The uptake of PM and cRGDfK-PM by B16 cells was measured by confocal laser. B16 cells were inoculated in different confocal small dishes respectively, incubated overnight until the cells were completely adhered to the wall, discarded the culture medium, and washed three times with phosphate buffer; The PM and cRGDfK-PM preparations (final concentration of nodrocetin: 10 μg / ml) were used to observe the uptake situation in real time by confocal laser at 37° C. And draw the relationship curve between the intracellular fluorescence intensity and the uptake time. The result is as image 3 As shown, cRGDfK-PM had significantly higher uptake speed and uptake than PM within 800S after the start of uptake.

[0036] 2. The uptake of QU-PM and cRGDfK-PM by B16 cells was measured by flow cytometry.

[0037] B16 cells were inoculated in 12-well plates, incubated overnight and...

Embodiment 3

[0038] Example 3. In vivo targeting and tumor tissue penetration evaluation of cRGDfK-PM small-sized micelles. A nude mouse model bearing B16 tumor was established. There are cRGDfK-PM micelles and PM micelles of Dir. Such as Figure 5 As shown, at 1h and 24h after injection, the in vivo distribution of the near-infrared fluorescent probe DiR micelles was detected by the in vivo imaging system. That is, there is obvious accumulation, indicating that the ability of cRGDfK-PM small-sized drug-loaded micelles targeting tumor cells with high expression of αvβ3 integrin receptors to target tumors is significantly enhanced. After the in vivo imaging was completed, the nude mice were killed suddenly, and the tumors of the nude mice were removed, and the intratumoral fluorescence distribution of the nude mice was continued to be observed with the in vivo imaging system, as shown in Figure 6 The shown cRGDfK-PM micelles significantly promoted the accumulation and penetration in the ...

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Abstract

The invention discloses a small-particle-size drug-loaded micelle for actively targeting alpha v beta 3 integrin receptor high-expression tumor cells and a preparation method of the small-particle-size drug-loaded micelle. The micelle comprises drug-loaded micelles, the surface of the drug-loaded micelle is modified by an alpha v beta 3 integrin receptor high-affinity ligand overexpressed on the surface of a tumor cell, aiming at the defects of insufficient targeting property and the like of antitumor drugs, a small-particle-size drug delivery system (the average particle size is about 15 nm)capable of targeting the high-expression tumor cells of the alpha v beta 3 integrin receptor is designed and constructed, PDI (0.2) is used for achieving the purposes that a medicine actively targetsspecific tumor cells and can be rapidly and effectively taken by the cells, the medicine effect of the medicine is brought into play to a greater extent, and the distribution of the medicine in the whole body and toxic and side effects caused by the distribution are reduced.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical preparations and tumor treatment, in particular to a drug-loaded micelle actively targeting tumor cells with high expression of αvβ3 integrin receptors and a preparation method thereof. Background technique [0002] Malignant tumors have always plagued human health. According to the latest statistics from the World Health Organization in 2018, there were about 18.08 million new cancer patients in the world in 2018. At present, there is no chemical drug or natural drug to cure cancer. Chemotherapy drugs are not selective. These drugs can kill tumor cells as well as normal cells, so they will have serious side effects. For example, paclitaxel can inhibit bone marrow, and doxorubicin can cause severe Cardiotoxicity, etc. Therefore, the development of anticancer drug preparations with less systemic toxicity and active targeting function is of great significance for tumor treatment. [0003] I...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K47/62A61K47/24A61K31/352A61P35/00
CPCA61K31/352A61K47/24A61K47/62A61K47/6909A61P35/00
Inventor 徐鹏程贾海涛王海生
Owner INNER MONGOLIA MEDICAL UNIV
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