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Cross-linked mitochondrial targeting doxorubicin liposome and preparation method thereof

A technology of doxorubicin lipid and mitochondria, which is applied in the field of anti-tumor drug liposome and its preparation, can solve the problems of affecting anti-tumor effect, low carrier uptake rate, neurotoxicity, etc., and achieve good tumor tissue targeting, Avoid early release, long cycle effects

Active Publication Date: 2015-11-18
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The micellar drug-loading system has the function of targeting mitochondria, but there are the following problems in the process of delivering the drug doxorubicin to the mitochondria of tumor cells: (1) folic acid is a hydrophobic molecule, in an aqueous environment, according to the hydrophilic and hydrophobic properties, Folic acid molecules tend to be distributed in the hydrophobic core of micelles rather than in the hydrophilic outer layer of micelles, resulting in a low uptake rate of folic acid-modified carriers by cells and affecting the antitumor effect; (2) triphenylphosphine is An organophosphorus pesticide that is irritating to the eyes, upper respiratory tract, mucous membranes, and skin, and is neurotoxic
Therefore, the use of triphenylphosphine in medicinal materials has potential safety hazards
There is no report about doxorubicin liposomes with mitochondrial targeting function

Method used

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  • Cross-linked mitochondrial targeting doxorubicin liposome and preparation method thereof
  • Cross-linked mitochondrial targeting doxorubicin liposome and preparation method thereof
  • Cross-linked mitochondrial targeting doxorubicin liposome and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The doxorubicin liposome described in this example is composed of doxorubicin, soybean lecithin, cholesterol and cross-linkable mitochondria-targeting pegylated distearoylphosphatidylethanolamine (DSPE-PEG2000-KLA). The mass ratio of doxorubicin hydrochloride to soybean lecithin is 1:5. The molar ratio of soybean lecithin, cholesterol and DSPE-PEG2000-KLA is 50:47:3, and the structural formula of the DSPE-PEG2000-KLA is

[0040]

[0041] The preparation method is as follows:

[0042] (1) Preparation of DSPE-PEG2000-KLA

[0043] Distearoylphosphatidylethanolamine-polyethylene glycol 2000-maleimide (DSPE-PEG2000-Mal), polypeptide D-(KLAKLAK) 2 -C 5 And triethylamine as raw material, polypeptide D-(KLAKLAK) 2 -C 5 , triethylamine, the mol ratio of DSPE-PEG2000-Mal is 1:1:1;

[0044] Under nitrogen protection, DSPE-PEG2000-Mal, triethylamine and chloroform were mixed uniformly to obtain the first solution, and the amount of chloroform was such that the concentratio...

Embodiment 2

[0050] The doxorubicin liposome described in this example is composed of doxorubicin, egg yolk lecithin, cholesterol and mitochondria-targeted pegylated dimyristoylphosphatidylethanolamine (DMPE-PEG2000-KLA). The mass ratio of doxorubicin hydrochloride to egg yolk lecithin is 1:20. The molar ratio of egg yolk lecithin, cholesterol and DMPE-PEG2000-KLA is 90:2:8, and the structural formula of DMPE-PEG2000-KLA is

[0051]

[0052] The preparation method of described liposome is as follows:

[0053] (1) Preparation of DMPE-PEG2000-KLA

[0054] Dimyristoylphosphatidylethanolamine-polyethylene glycol 2000-maleimide (DMPE-PEG2000-Mal), polypeptide D-(KLAKLAK) 2 -C 5 And 4-dimethylaminopyridine as raw material, polypeptide D-(KLAKLAK) 2 -C 5 , 4-dimethylaminopyridine, the mol ratio of DMPE-PEG2000-Mal is 2:2:1;

[0055] Under nitrogen protection, mix DMPE-PEG2000-Mal, 4-dimethylaminopyridine, and dichloromethane evenly to obtain the first solution. The amount of dichlorometh...

Embodiment 3

[0061] The doxorubicin liposome described in this example is composed of doxorubicin, hydrogenated lecithin, cholesterol and mitochondria-targeted pegylated dipalmitoylphosphatidylethanolamine (DPPE-PEG2000-KLA). The mass ratio of the doxorubicin hydrochloride to the hydrogenated lecithin is 1:10. The molar ratio of hydrogenated lecithin, cholesterol and DPPE-PEG2000-KLA is 70:25:5, and the structural formula of DPPE-PEG2000-KLA is

[0062]

[0063] (1) Preparation of DPPE-PEG2000-KLA

[0064] Dipalmitoylphosphatidylethanolamine-polyethylene glycol 2000-maleimide (DPPE-PEG2000-Mal), polypeptide D-(KLAKLAK) 2 -C 5 And N, N-diisopropylethylamine as raw material, polypeptide D-(KLAKLAK) 2 -C 5 , N, the molar ratio of N-diisopropylethylamine, DPPE-PEG2000-Mal is 3:3:1;

[0065] Under the protection of nitrogen, mix DPPE-PEG2000-Mal, N,N-diisopropylethylamine, and dichloromethane evenly to obtain the first solution. The amount of dichloromethane in the first solution is to ...

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Abstract

The invention relates to a cross-linked mitochondrial targeting doxorubicin liposome. The cross-linked mitochondrial targeting doxorubicin liposome is composed of doxorubicin hydrochloride, phospholipid, cholesterol and a cross-linkable mitochondrial targeting pegylated phospholipid medicinal material, a mass ratio of doxorubicin hydrochloride to the phospholipid is 1:(5-20), a molar ratio of the phospholipid to cholesterol to the cross-linkable mitochondrial targeting pegylated phospholipid medicinal material is (50-90):(2-47):(3-8), the structural formula of the cross-linkable mitochondrial targeting pegylated phospholipid medicinal material is shown in the specification, and n in the structural formula is 10, 12, 14 or 16. The invention also provides a preparation method of the liposome. The cross-linked mitochondrial targeting doxorubicin liposome has the advantages of mitochondrial targeting, large absorbed quantity of tumor cells, and high safety.

Description

technical field [0001] The invention belongs to the technical field of medicine and its preparation, and in particular relates to an antitumor drug liposome and a preparation method thereof. Background technique [0002] Chemotherapy is one of the main ways to treat cancer, but the mortality rate of cancer patients after chemotherapy is still high. Multidrug resistance (MDR) is one of the main reasons for clinical chemotherapy failure. Doxorubicin is a commonly used drug in cancer chemotherapy, but the extensive use of chemotherapy drugs such as doxorubicin can easily lead to drug resistance in cells. The drug resistance of tumor cells can be divided into two categories: congenital and acquired. Studies have shown that changes in tumor cell genes or gene phenotypes lead to changes in apoptosis pathways, which eventually lead to the emergence of tumor innate drug resistance. Mitochondria are the "power factory" of the cell and also the "suicide arsenal", which can initiate...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K47/34A61K31/704A61P35/00
Inventor 李莉顾忠伟姜雷孙家维
Owner SICHUAN UNIV
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