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Combined drug-loading micelle of targeted integrin receptor and preparation method thereof

An integrin receptor, drug-loaded micelle technology, which is applied in pharmaceutical formulations, medical preparations with inactive ingredients, and medical preparations containing active ingredients, can solve the problems of low drug loading in the micelle system, and achieve The effect of increasing drug loading and improving therapeutic index

Active Publication Date: 2014-05-21
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The application of polymer materials to prepare micellar carriers for the delivery of anti-tumor drugs has become a hot spot in the research of drug delivery systems in recent years, but there is still the defect of low drug loading in micellar systems, and combined drug loading can make up for the drug loading of micelles Low defect, while exerting the respective effects and synergistic effects of drugs

Method used

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  • Combined drug-loading micelle of targeted integrin receptor and preparation method thereof
  • Combined drug-loading micelle of targeted integrin receptor and preparation method thereof
  • Combined drug-loading micelle of targeted integrin receptor and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 Preparation of amphiphilic block copolymer Pluronic-COOH with active group carboxyl

[0042] Put 0.01M Pluronic and 400ml acetone in a round-bottomed flask, slowly heat up until the solution is clear, let cool to room temperature, add 17ml Jones reagent, magnetically stir overnight at room temperature, add 5mL isopropanol to quench the reaction. Add 12.6g of activated carbon and continue to stir for 2h, heat to 40°C, suction filter while hot to obtain a clear solution, evaporate under reduced pressure to obtain a white viscous substance, add precooled n-hexane to precipitate a solid, and dry in vacuo to obtain carboxylated Pluronic ( Pluronic-COOH). The purity of the product was analyzed by gel permeation chromatography (GPC). 1 The molecular weight of the product was calculated from the peak area ratio of the proton in the methylene group in the H-NMR spectrum.

Embodiment 2

[0043] Embodiment 2 prepares Pluronic-DOX

[0044] Weigh 7.4mM of Pluronic-COOH in the above Example 1, and dissolve it in 20ml of N,N-dimethylformamide at room temperature. 1 g EDC and 2 g NHS were added to the solution of Pluronic-COOH. After reacting for 15 minutes, 2.8ml of 2-mercaptoethanol, 3.48g of DOX and 10mg of triethylamine were added, and stirring was continued at room temperature for 12h under nitrogen protection. After the reaction, dialyze with deionized water in the dark for 2 days (MWCO 3500), and freeze-dry the concentrated solution to obtain Pluronic-DOX. pass 1 The product was verified by H-NMR spectrum; the absorbance was measured by UV-Vis spectrophotometry, and the molar connection rate of DOX was calculated.

Embodiment 3

[0045] Embodiment 3 prepares the amphiphilic copolymer modified with RGD peptide

[0046] (1) Preparation of Pluronic-NHS by activating the carboxyl group with NHS:

[0047] Weigh 0.053mM of Pluronic-COOH, 22mg of DCC and 12.2mg of NHS in the above-mentioned Example 1 and dissolve them in 5ml of chloroform, and react at room temperature for 24h under nitrogen protection. After the reaction was completed, the solvent was removed under reduced pressure and precipitated with cold ether. The precipitate was vacuum-dried to constant weight to obtain Pluronic-NHS. The product is verified by 1H-NMR spectrum;

[0048] (2) Preparation of c(RGDyK)-Pluronic by cyclic RGD peptide (c(RGDyK)) modified amphiphilic copolymer;

[0049] Take the Pluronic-COOH 0.0053mM in the above (1) and dissolve it in 1ml of N,N-dimethylformamide to obtain solution A; take 6.3mg (0.01mM) of c(RGDyK) peptide and dissolve it in 0.1M HEPES, Solution B is obtained. Solution B was added dropwise to solution A...

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Abstract

The invention belongs to the technical field of biological medicines, and relates to a combined drug-dosing micelle of a targeted integrin receptor and a preparation method thereof. Pluronic COOH which is modified by a terminal carboxyl is synthesized, and RGD (arginine-glycine-aspartic acid) polypeptides are connected with carboxyl by amido bonds to obtain a RGD polypeptide-modified Pluronic copolymer (RGD-Pluronic); and after copolymerization of drug doxorubicin (DOX) and Pluronic, another drug PTX (paclitaxel) is coated and loaded by a thin-film hydration method to prepare a mixed micelle (RGD-FP-DP). According to the preparation method, drug loading capacity of the micelle can be improved, the drug concentration of anti-tumor drugs in a target site can be increased, accumulation of the anti-tumor drugs in a non target site can be reduced, and the therapeutic index of the drugs can be effectively improved.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a combined drug-loaded micelle targeting integrin receptors and a preparation method thereof. Background technique [0002] The prior art discloses that tumor tissue is different from normal tissue in that it has rich blood vessels, wide space between blood vessel walls, poor structural integrity, and lack of lymphatic drainage. Therefore, drug-loaded nanoparticles can be enriched in tumor tissue through the EPR effect. However, studies have found that after the nanoparticles enter the circulatory system, they are mainly taken up by the mononuclear phagocyte system (MPS), causing the drug to accumulate in the liver, spleen and lungs, which not only reduces the therapeutic index of the drug, but also causes damage to these organs. severe toxic side effects. Constructing a tumor-targeted drug delivery system, reducing the damage of anti-tumor drugs to normal organs...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K31/704A61K9/10A61P35/00A61P31/00A61K31/337A61K47/34A61K47/42A61K47/18
Inventor 方晓玲陈彦佐沙先谊
Owner FUDAN UNIV
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