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A kind of multifunctional imaging cross-linked stable nanometer drug-loaded micelles and its preparation method

A drug and carrier technology, which is applied in the field of preparation of acid-sensitive nanomicelles, can solve the problems of sudden release of drugs, inability to release drugs completely, and reduced cycle time, so as to overcome poor stability and targeting, instability and High toxicity and side effects, improved stability and dilution resistance

Inactive Publication Date: 2019-02-05
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This process is very complicated and faces many challenges: 1. After being diluted by blood, the stability is reduced, the circulation time in the body is reduced, and a large number of polymers aggregate or degrade, causing the drug to fail to reach the tumor site and release early
2. Hydrophilic materials such as polyethylene glycol (PEG) can prevent the carrier from being absorbed non-specifically by proteins and avoid being cleared by the immune system, but it will hinder the endocytic efficiency of cells
3. When the carrier enters the tumor cells, the drug may be released suddenly or cannot be released quickly and effectively
4. The drug-loaded carrier entering the tumor cells cannot completely release the drug
After the micelles are administered, they will be diluted during blood circulation, and the micelles will automatically dissociate when the concentration is lower than its critical micelle concentration (CMC), resulting in a lower effective drug concentration reaching the tumor site

Method used

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  • A kind of multifunctional imaging cross-linked stable nanometer drug-loaded micelles and its preparation method
  • A kind of multifunctional imaging cross-linked stable nanometer drug-loaded micelles and its preparation method
  • A kind of multifunctional imaging cross-linked stable nanometer drug-loaded micelles and its preparation method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Amphiphilic drug carrier mPEG-S-Trityl-Cys-Dopa, represented by formula I:

[0066]

[0067] where n=9;

[0068] The mPEG-S-Trityl-Cys-Dopa is the abbreviation of polyethylene glycol monomethyl ether-S-trityl-L-cysteine-dopamine.

[0069] n can also be 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25.

[0070] In the present invention, dopamine is introduced into the carrier in the form of amidation, which is equivalent to the introduction of catechol functional groups, and Fe is added under the condition of pH 7.4 3+ Cross-linked with catechol to prepare carrier cross-linked micelles mPEG-S-Trityl-Cys-Dopa-Fe 3 + , the carrier cross-linked drug-encapsulated micelles mPEG-S-Trityl-Cys-Dopa-Fe were prepared by encapsulating the anticancer drug doxorubicin (DOX) by dialysis 3+ / DOX. This prodrug micelle itself is stable in the blood circulation, and effectively releases drugs under the acidic microenvironmental conditions in tumor cells to achie...

Embodiment 2

[0076]The preparation method of amphiphilic drug carrier mPEG-S-Trityl-Cys-Dopa is characterized in that it comprises the following steps:

[0077] (1) 1.1 g of S-trityl-L-cysteine ​​(II), di-tert-butyl dicarbonate (Boc 2 O) 1.0g and 19mL of 2N aqueous sodium hydroxide solution, react at room temperature for 24h, after the reaction is completed, lower to room temperature, slowly add 1mol / L HCl to adjust the pH to = 2, extract the aqueous layer with dichloromethane, combine the organic layers with distilled water Wash with water until the pH is 7, add anhydrous sodium sulfate to the organic layer to dry and remove water, collect the filtrate by suction filtration, and rotary evaporate the filtrate to remove the extractant to obtain white foamy solid amino-protected-S-trityl-L-cysteine (N-Boc-S-Trityl-Cys) (III);

[0078] The nuclear magnetic and mass spectral data of this compound (III) are as follows: 1 H NMR (CDCl 3 ,400MHz):δ7.21-7.41(m,15H,S-trityl-H),4.91(d,1H,CONH),3.9...

Embodiment 3

[0089] The preparation method of amphiphilic drug carrier mPEG-S-Trityl-Cys-Dopa is characterized in that it comprises the following steps:

[0090] (1) 1.1 g of S-trityl-L-cysteine ​​(II), di-tert-butyl dicarbonate (Boc 2 (0) 1.0 g and 19 mL of 2N aqueous sodium hydroxide solution were reacted at room temperature for 24 hours. After the reaction was completed, the temperature was lowered to room temperature, and 1 mol / L HCl was slowly added dropwise to adjust the pH to = 1. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with distilled water. When the pH was 7, the organic layer was dried by adding anhydrous sodium sulfate to remove water, the filtrate was collected by suction filtration, the filtrate was rotary evaporated to remove the extractant, and a white foamy solid amino-protected-S-trityl-L-cysteine ​​( N-Boc-S-Trityl-Cys) (III);

[0091] (2) Formula (III) compound 1.3g, catalyst 1-hydroxybenzotriazole 0.8g and dehydr...

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Abstract

The present invention discloses multifunctional imaging cross-linked stable nanometer drug-loading micelles and a preparation method thereof. The preparation method comprises: adding 200 mg of an amphiphilic drug carrier mPEG-S-Trityl-Cys-Dopa and a hydrophobic anti-cancer drug to an organic solvent, dissolving, and carrying out dialysis by using a dialysis bag to remove free Fe<3+>; carrying out centrifugation, and filtering the supernatant by using a 0.45 [mu]m microporous filtration membrane; and carrying out freeze drying on the filtrate, wherein the freeze-dried product is the multifunctional imaging cross-linked stable nanometer drug-loading micelles mPEG-S-Trityl-Cys-Dopa-Fe<3+> / hydrophobic anti-cancer drug. According to the present invention, the obtained nanometer micelles have the stability and the pH-sensitivity, and can be visible by MRI, can break through the single-function mode of the traditional drug delivery system, can integrate the MRI imaging function and the drug carrier function, and can achieve the synchronous diagnosis and treatment of cancers.

Description

technical field [0001] The invention relates to a functional nano-carrier with imaging and active molecule delivery functions, in particular to a method for preparing cross-linked and stable acid-sensitive nano-micelles visible in magnetic resonance imaging (MRI). Background technique [0002] Cancer has been one of the major challenges to human health in this century. At present, many cancers are usually diagnosed in the middle and late stages clinically, but commonly used methods such as surgery, radiation therapy, and chemotherapy are not effective for advanced cancers. Therefore, early diagnosis and treatment of cancer are of great significance. MRI can detect slight changes between normal tissue and tumor tissue, and has become one of the important methods for early diagnosis of cancer. However, traditional MRI contrast agents have poor stability and poor targeting in blood, which limits their effective diagnosis of tumors. Chemotherapy is a commonly used method to tr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C323/60C07C319/20C08G65/334A61K9/107A61K49/12A61K47/34A61K31/704A61P35/00
CPCA61K9/1075A61K31/704A61K47/183A61K49/126C07C319/20C07C323/60C08G65/3348C07C323/59
Inventor 赵燕军王征李漫辛科霆
Owner TIANJIN UNIV
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