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Survivin dual inhibitor loaded ferritin nanoparticles as well as preparation method and application thereof

A nanoparticle and inhibitor technology, applied in the field of medicine, can solve the problems of inability to effectively inhibit Survivin protein, systemic toxicity, etc., and achieve the effect of being suitable for large-scale continuous production and simple preparation method.

Active Publication Date: 2020-08-18
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

An important deficiency is systemic toxicity caused by nonspecific cellular uptake of high-dose YM155
On the other hand, although YM155 can inhibit the transcription level of Survivin, it cannot effectively inhibit the turnover of Survivin protein in tumor cells.

Method used

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  • Survivin dual inhibitor loaded ferritin nanoparticles as well as preparation method and application thereof
  • Survivin dual inhibitor loaded ferritin nanoparticles as well as preparation method and application thereof
  • Survivin dual inhibitor loaded ferritin nanoparticles as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1. Construction of recombinant plasmids and expression and purification of recombinant proteins

[0042] Reagents and kits: Premix Taq DNA polymerase, Pyrobest DNA polymerase, restriction enzymes (Ned I, Xho I), protein molecular weight standard Premixed Protein Marker (Low), protein loading buffer 4×Protein SDS PAGE Loading Buffer, DNA marker was purchased from Treasure Bioengineering Co., Ltd. (Dalian). Isopropyl-B-D-thiogalactopyranoside (IPTG) and kanamycin were purchased from Sigma-Aldrich (USA), and SPSepharose FF cation exchange columns were purchased from GE (USA). Other biochemical reagents belong to domestic conventional analytical reagents.

[0043] Strains and plasmids: E.coli DH5α and BL21(DE3) (Invirogen, USA) were used as plasmid cloning and expression strains respectively, the recombinant plasmid pET-24a-TmSm was constructed in our laboratory, and pGEM-FTH1 was purchased from Beijing Yiqiao Shenzhou Biotechnology Co., Ltd. Ltd., pET-24a(+) was ...

Embodiment 2

[0092] Example 2. Preparation and characterization of nanoparticles loaded with YM155

[0093] Reagents: YM155 and doxorubicin (DOX) were purchased from Aladdin Biochemical Technology Co., Ltd., and the Bradford method protein concentration determination kit was purchased from Sangon Bioengineering Co., Ltd. (Shanghai). Other biochemical reagents belong to domestic conventional analytical reagents.

[0094] Reagent preparation: related solutions were prepared with reference to the reagents in Example 1.

[0095] Preparation of YM155-loaded nanoparticles

[0096] UV-Vis full-wavelength scanning: Before choosing whether to denature ferritin with acid or alkali, the stability of the embedded substance YM155 in acid-base media was analyzed by UV-Vis spectroscopy. Dilute 1 mL of YM155 standard solution (100 μmol / L) with PBS (pH=2 and 12) to 10 mL, and use PBS as a blank control, and perform full-wavelength scanning in the range of 200-800 nm with a UV-visible spectrophotometer. ...

Embodiment 3

[0108] Example 3. Detection of anti-tumor activity in vivo and in vitro of FTS / YM155NPs

[0109] Reagents and kits: MTT, penicillin and streptomycin mixed solution, DMSO were purchased from Beijing Suolaibao Company; RPMI-1640 medium, fetal bovine serum, and trypsin were purchased from Gibco Company (USA); anti-survivin monoclonal antibody ( Rabbit origin), anti-MMP2 monoclonal antibody (rabbit origin), anti-βactin monoclonal antibody (mouse origin), goat anti-rabbit / goat anti-mouse IgG-HRP secondary antibody were purchased from Proteintech Group (USA). Other biochemical reagents belong to domestic conventional analytical reagents.

[0110] Cell lines and animals:

[0111] Human lung adenocarcinoma cell A549 and human pancreatic cancer cell Capan-2, cultured at 37°C, 5% CO 2 Concentration, the medium is RPMI1640 medium (containing 10% fetal bovine serum). Balb / c-nu female nude mice (4-6 weeks old, 20±2g) were purchased from Shanghai Slack Experimental Animal Co., Ltd.

[0...

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Abstract

The invention discloses Survivin dual inhibitor-loaded ferritin nanoparticles as well as a preparation method and application thereof, and application of a Survivin dual inhibitor combined medicine inpreparation of a medicine for treating tumors. The dual inhibitor comprises a small molecule inhibitor YM155 and a protein inhibitor TmSm. The obtained nanoparticles are of a nanocage spherical structure and are free of adhesion, small in particle size, narrow in range, convenient for intravenous injection and good in targeting effect. The nanoparticles can be effectively cut by MMP-2 secreted bycancer cells to release TmSm protein, actively targets the cancer cells through TfR1 on the surfaces of the cancer cells, and releases YM155 in cell nucleuses. The Survivin dual inhibitor-loaded ferritin nanoparticles can realize the synergistic inhibition of Survivin transcription and protein level and obtain a strong anti-tumor effect.

Description

technical field [0001] The present invention relates to the technical field of medicine, more specifically, relates to the preparation of drugs containing Survivin dual inhibitors, or ferritin nanoparticles loaded with Survivin dual inhibitors and their application as tumor treatment drugs. Background technique [0002] Cancer is a major public health problem worldwide, and chemotherapy, radiotherapy and surgery are the key methods of current cancer treatment. However, conventional chemotherapy is often accompanied by serious side effects in cancer treatment because it cannot specifically kill tumor cells. Furthermore, the development of drug resistance in cancer leads to unsatisfactory results of monotherapy for cancer. Therefore, combination therapy has emerged as a novel approach to cancer therapy, which enhances anticancer effects through potential synergy. Common combination therapy strategies include chemotherapeutic drugs, anticancer metals, gene drugs, and therapeu...

Claims

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Application Information

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IPC IPC(8): A61K47/64A61K47/65A61K47/69A61K38/17A61K31/497A61P35/00
CPCA61K47/644A61K47/65A61K47/6949A61K47/6929A61K38/1709A61K31/497A61P35/00A61K2300/00
Inventor 马兴元胡发彪郑文云晏婷郭伟刘畅张瑞环
Owner EAST CHINA UNIV OF SCI & TECH
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