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Targeted tumor cell mitochondria peptidyl nano-drug as well as preparation method and application thereof

A technology of tumor cells and nano-drugs, applied in the field of nano-biomedical materials, can solve the problems of limited promotion and application, low bioavailability, strong liver toxicity, etc., and achieve enhanced chemotherapy and radiotherapy sensitization efficacy, good biocompatibility , good repeatability

Active Publication Date: 2021-07-09
INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to its small molecular properties, the amount of LND reaching the tumor site is very small, showing low bioavailability and strong liver toxicity, which limits its clinical promotion and application.

Method used

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  • Targeted tumor cell mitochondria peptidyl nano-drug as well as preparation method and application thereof
  • Targeted tumor cell mitochondria peptidyl nano-drug as well as preparation method and application thereof
  • Targeted tumor cell mitochondria peptidyl nano-drug as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] The preparation of polypeptide nanofibers of tumor cell mitochondrial, the latter, that is, the latter is substituted with a fluorescent molecule NBD, in a period of the use of NBD fluorescence to demonstrate targeting of mitochondria, Taking LND-GFFYK-CYCLEN nanofibers as an example, the specific preparation steps are as follows:

[0043] (1) Synthesis LND-GffYk by FMOC solid phase synthesis, 0.1 mmol of crude product is dissolved in 1 ml DMSO, and the liquid phase synthesized by the cyclo vine rattan is allowed to activate the reaction liquid, and the reaction liquid pH to 8 is adjusted with Diea. ~ 9. After overnight reaction room temperature, 95% trifluoroacetate was removed from the protective group of the Wheel Fuji Ning. The purpose product LND-GFFYK-CYCLEN was obtained by reverse phase HPLC. The synthesis steps of the cyclic ringunning activated ester are as follows:

[0044] (1) Wheel ruthenne (6 g, 34.8 mmol) and DIEA (24 mL, 104.5 mmol) were dissolved in 40 ml DC...

Embodiment 2

[0050] The two polypeptide nano-assemblies prepared in Example 1 were characterized and evaluated by the mitochondrial targeting. figure 1 , Proceed as follows:

[0051] 1) Sippo the nano-assembly of 20 μL of Example 1 on the 300-mesh copper net, stand for 1 to 2 min, and the excess liquid was added to the copper sheet, and 20 μl of acetate is added to 1 ~ 2 min, filter paper. After sucking the excess liquid, it was placed in a desiccator overnight drying, and the micro morphology was observed using a transmissive electron microscope. Result figure 1 A and 1B) show that the micro-morphology of the two nano-assemblies prepared in Example 1 is nanofibers;

[0052] 2) Determination of the secondary structure of the two nano-assemblies prepared in Example 1 with a circular two chromatography (CD), attached figure 1 C Displays two nano-assemblies have the same secondary structure, ie, is composed of a β layer;

[0053] 3) Determination of Zeta potential values ​​of the two nano-assembl...

Embodiment 3

[0056] The LND-GFFYK-Cyclen nano drugs and free drugs prepared in Example 1 were evaluated in vitro to the growth inhibition effect of cancer cells and normal cells. The specific implementation steps are as follows:

[0057] 1) Take a few long-term MCF-7, 4T1, L929 and 3T3 cells, inoculated into a 96-well plate in 5,000 densities per well, and placed in an incubator for 18 h;

[0058] 2) Dilute the LND-PEP-CYCLEN nano drug, LND, Cyclen, LND and Cyclen mixture to a pre-set concentration and incubate 48 h with cells.

[0059]3) 10 μl of CCK-8 solution is added to each well under the prototyping conditions, and after continuous culture of 4 h, the absorbance value at 450 nm is detected by the enzyme syndrometer, calculating different concentrations of drugs in each group. The survival rate of the subsequent cells;

[0060] 4) figure 2 It is shown that peptide-cyber drug Lnd-Pep-cyclen can significantly increase the growth inhibitory ability of LND to cancer cells while reducing LND t...

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Abstract

The invention discloses a targeted tumor cell mitochondria peptidyl nano-drug as well as a preparation method and application thereof. The polypeptide derivative LND-GFFYK-cyclin is prepared by connecting a hydrophobic anti-cancer drug-lonidamine (LND) and a hydrophilic cycleanine (Cyclin) to a self-assembled short peptide sequence through covalent modification, and is a polypeptide derivative LND-GFFYK-cyclin. The product can be self-assembled to form a peptidyl nano-drug through intermolecular non-covalent interaction, is used for tumor specific and synergistic radiotherapy and chemotherapy, and has the characteristics of simple synthesis, high repeatability, good biocompatibility and large clinical transformation potential. Meanwhile, compared with free LND, the self-assembled peptidyl nano-drug obtained by the invention can significantly improve the selective killing effect of LND on tumor cells and the effect of radiotherapy and chemotherapy synergistic treatment by targeting mitochondria, and has good clinical transformation and application prospects.

Description

Technical field [0001] The present invention belongs to the field of nano bio-medicinal materials, and the method of preparation of peptide-based nanogenes targeting tumor cell mitochondrial and its application in enhancing the activity of cancer in vivo in vivo. Background technique [0002] At present, the combination of radiotherapy therapy is still a common method of clinical treatment of most cancers. Compared to single chemotherapy or radiotherapy, alcoholic treatment combined with treatment can improve the treatment efficacy to avoid tumor resistance and metastasis. However, it is limited to small molecular chemotherapeutic drugs or radiotherapy sensitizers lack of selectivity to tumor cells, and chemotherapy therapy is still unable to avoid severe toxic side effects from normal tissues and cells. Therefore, how to maximize the efficacy of radiotherapy anti-tumor and reduce its poisonous side effects, is one of the main problems faced by clinical chemotherapy treatment. ...

Claims

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Application Information

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IPC IPC(8): A61K47/64A61K47/69A61K31/4748A61K31/416A61P35/00A61P15/14B82Y5/00B82Y40/00C07K7/06C07K1/04
CPCA61K47/64A61K47/6931A61K31/4748A61K31/416A61P35/00A61P15/14B82Y5/00B82Y40/00C07K7/06A61K2300/00Y02P20/55
Inventor 刘鉴峰任春华郭庆祥杨翠红杨丽军黄帆高洁
Owner INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI
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