Tumor treatment nano-drug for targeting Trop2 protein on tumor cell surface and preparation method of tumor treatment nano-drug

A nano-drug and drug technology, applied in the field of tumor molecular biology, can solve the problems of limited application and therapeutic effect, limited effect, limited silencing effect, etc., to achieve easy clinical transformation, increase utilization rate, and reduce toxic and side effects Effect

Active Publication Date: 2021-07-27
SUN YAT SEN MEMORIAL HOSPITAL SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although this type of antibody conjugate can improve targeting, it also has defects. For example, when some antibodies are loaded with nanoparticles, the excessive molecular weight of the antibody will limit the number of monoclonal antibodies that can be placed on a single nanoparticle. resulting in a decrease in efficiency
In addition, the Fc domain in some antibodies may be immunogenic and cytotoxic, which may cause side effects
[0003] At the same time, even if the targeted antibody can be selected to achieve targeting, its effect is still limited. The specific site of the nanoparticle can not be based on the specificity of the tumor microenvironment to achieve responsive release of the main drug, that is, the application and therapeutic effect of this type of nanoparticle are still limited; take the main drug siRNA as an example, if the siRNA does not Enter the cytoplasm of a specific site and release it to act on the target gene, its utilization rate is obviously low, and the silencing effect is obviously limited

Method used

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  • Tumor treatment nano-drug for targeting Trop2 protein on tumor cell surface and preparation method of tumor treatment nano-drug
  • Tumor treatment nano-drug for targeting Trop2 protein on tumor cell surface and preparation method of tumor treatment nano-drug
  • Tumor treatment nano-drug for targeting Trop2 protein on tumor cell surface and preparation method of tumor treatment nano-drug

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Embodiment 1

[0063] Acquisition and Analysis of Uc003xsl.1

[0064] 1. Acquisition of Uc003xsl.1

[0065] The inventors of the present application collected 6 fresh breast cancer tissues from the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, including 3 TNBC and 3 Luminal breast cancer tissues. Then lncRNA sequencing was carried out by Illumina PE150 to analyze the expression of lncRNA in 6 fresh tissues of breast cancer, the sequencing heat map is as follows figure 1 As shown in A (left), 30 lncRNAs whose expression levels in TNBC tissues were up-regulated compared with Luminal tissues were screened out.

[0066] At the same time, in order to find out the biomarkers associated with TNBC metastasis, the inventors constructed a breast cancer lung metastasis model, collected highly metastatic MDA-MB-231 cells from the lung metastases of mice, and screened out the metastatic MDA-MB-231 cells by lncRNA sequencing. -MB-231 cells express 267 lncRNAs up-regulated compared with ordina...

Embodiment 2

[0075] Synthesis and structure analysis of PDSA

[0076] 1. Synthesis of PDSA

[0077] PDSA in this example is a high molecular polymer decomposed at a higher glutathione concentration. In this example, the "one-pot method" is used for large-scale preparation. The preparation process includes: (1) the fat Acid and triethylamine are mixed and dissolved, and the fatty diacids include succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, For all fatty diacids such as carbolic acid or tridecanedioic acid, the solvent used for mixing and dissolving is a strong polar solvent such as dimethylsulfoxide or dimethylformamide;

[0078] (2) Add Cystine dimethyl esterdihydrochloride dropwise to the mixed solution of fatty diacid and triethylamine under the condition of ice-salt bath. Then, after stirring the reaction at room temperature for 15 minutes to 4 hours, the precipitate in the reaction system wa...

Embodiment 3

[0083] Detection of Trop2 expression in breast cancer

[0084] 1. Gene expression detection of Trop2 in different breast cell lines

[0085] The inventors based on normal breast epithelial cell lines: MCF10A, HMEC; TNBC cell lines: MDA-MB-231, MDA-MB-436, MDA-MB-468, BT549; HER2+ breast cancer cell lines BT474, SKBR3; Luminal breast cancer cell lines Cancer cell lines T47D, MCF-7 and ZR751 were tested for Trop2 gene expression levels in different cells. The detection method was Western blot, and the detection results were as follows: Figure 9 As shown, it was found that Trop2 was highly expressed in breast cancer cell lines than normal breast epithelial cell lines MCF10A and HMEC, and the expression levels in TNBC cell lines MDA-MB-231, MDA-MB-436, MDA-MB-468 and BT549 The highest expression level was in HER2+ breast cancer cell lines BT474 and SKBR3, and the lowest expression level was in Luminal breast cancer cell lines T47D, MCF-7 and ZR751. The above results also indicate...

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Abstract

The invention relates to a tumor treatment nano-drug targeting Trop2 protein on the surface of a tumor cell and a preparation method thereof, the nano-drug is a novel nano-drug targeting Trop2 and responding to GSH, by loading a Trop2 antibody, tumor cells over-expressing Trop2 can be targeted, the nano-drug is enriched in tumor tissues, toxic and side effects on normal tissues and cells are reduced to the maximum extent, and high-concentration GSH in cytoplasm is responded, so that the nano-drug rapidly releases the main drug at the specific site cytoplasm, and interference to other biological processes is reduced. The nano-drug has long circulation time in blood, can improve the utilization rate of the main drug, prolongs the acting time of the main drug, and improves the treatment effect. The invention also discloses lnc RNA for promoting invasion and metastasis of TNBC, and provides an application of the lnc RNA in diagnosis and treatment of triple negative breast cancer, and siRNA of the lnc RNA can be used as a main drug of the nano-drug and is applied to treatment of triple negative breast cancer.

Description

technical field [0001] The invention relates to the field of tumor molecular biology, more specifically, relates to a tumor treatment nano-medicine targeting Trop2 protein on the surface of tumor cells and a preparation method thereof. Background technique [0002] In normal tissues, the microvascular endothelial gap is dense and has a complete structure, and macromolecular substances are not easy to penetrate the vessel wall; while solid tumor tissues are completely opposite, solid tumor tissues have selective high permeability and retention effect on macromolecular substances ( That is the EPR effect). The characteristics of solid tumor tissue just promote the selective distribution of the nano-particles encapsulating the main drug in tumor tissue, which increases the efficacy of the drug and reduces systemic side effects. However, although tumor tissue has an EPR effect on nanoparticles, studies have shown that this process is not efficient, and the number of nanoparticl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K47/68A61K31/713A61P35/00
CPCA61K47/6935A61K47/6851A61K31/713A61P35/00
Inventor 姚和瑞许小丁胡海许英李青剑任炜李俊微
Owner SUN YAT SEN MEMORIAL HOSPITAL SUN YAT SEN UNIV
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