Folate-targeted reduction sensitive drug-carrying polymer nano-micelle as well as preparation method and application thereof

A drug-loaded polymer and folic acid targeting technology, which is applied in drug combinations, pharmaceutical formulations, anti-tumor drugs, etc., can solve the problems of tumor cell recurrence or metastasis, uneven heat distribution, and difficulty in killing cancer cells, and achieve the goal of overcoming In vivo instability and ease of clearance, prolongation of circulation time, effects of long circulation properties

Inactive Publication Date: 2018-09-04
INST OF BIOMEDICAL ENG CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the heat distribution inside the tumor is uneven, and it is difficult to kill all cancer cells with simple heat therapy, and the surviving tumor cells may cause recurrence or metastasis

Method used

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  • Folate-targeted reduction sensitive drug-carrying polymer nano-micelle as well as preparation method and application thereof
  • Folate-targeted reduction sensitive drug-carrying polymer nano-micelle as well as preparation method and application thereof
  • Folate-targeted reduction sensitive drug-carrying polymer nano-micelle as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Synthesis of PCL-ss-PEG-ss-PCL.

[0044] A synthesis method of reduction-sensitive amphiphilic triblock copolymer (PCL-ss-PEG-ss-PCL) based on PCL 3750 -ss-PEG 7500 -ss-PCL 3750 The synthetic method of is example, comprises the following steps:

[0045] (1) Accurately weigh 1g of Py-ss-PEG 7500 -ss-Py (purchased from Beijing Jiankai Technology Co., Ltd.) was dissolved in 12 mL of dimethyl sulfoxide (DMSO). After fully dissolved, add 25 μL mercaptoethanol and 20 μL acetic acid. The reaction was carried out under magnetic stirring at 25 °C for 24 h. After the reaction, the reaction mixture was transferred to a dialysis bag of MWCO8000-14000Da, and placed in distilled water for dialysis for 24 h. Then lyophilized to obtain pure white powder product HO-SS-PEG 7500 -SS-OH.

[0046] (2) Accurately add 1 g of purified ε-caprolactone monomer and 1 g of HO-ss-PEG 7500 -ss-OH In the polymerization tube, add a drop of stannous octoate as a catalyst. The reaction system w...

Embodiment 2

[0054] A method for preparing reduction-sensitive polymer micelles (DINPs) co-encapsulating DOX and ICG, comprising the following steps:

[0055] (1) First transfer doxorubicin hydrochloride and ICG to hydrophobicity respectively: add 1% (mass percentage of material) doxorubicin hydrochloride to methanol solution containing triethylamine (20 μL triethylamine / 1 mg doxorubicin) , react at room temperature for 20 hours under magnetic stirring; mix ICG and tetrabutylammonium iodide (1:5.72 mass ratio) in dichloromethane, and react at room temperature for 20 hours under magnetic stirring.

[0056] (2) Fully dissolve PCL-ss-PEG-ss-PCL in the organic solvent dichloromethane, then add desalted doxorubicin and transhydrophobic ICG solution and mix well, remove the organic solvent with a rotary evaporator, and make it in eggplant-shaped A uniform film is formed on the inner wall of the bottle, and the residual dichloromethane is blown dry with nitrogen, and placed in a vacuum drying ove...

Embodiment 3

[0074] Study on drug release of FA-DINPs in vitro

[0075] The samples prepared in (3) of Example 2 were divided into 12 groups and released in MWCO 8000-14000Da dialysis bags. The release liquids were PBS (pH 7.4) and 10mM GSH PBS (pH 7.4). The release liquids were 20 mL, placed on a shaker, and shaken at 37°C at 120 rpm. After a certain period of time, all the release liquids were taken out to measure the drug content, and the same volume was added. of fresh release fluid. The laser irradiation group needs to use 1 W / cm before putting into the dialysis bag 2 The 808 nm laser was pre-irradiated for 5 min.

[0076] see release result image 3 , indicating that the release of doxorubicin in FA-DINPs was affected by the reduction of the release fluid and laser irradiation. After 2 days of incubation, FA-DINPs released 21.59 % and 48.77 % of doxorubicin in PBS (pH 7.4) and 10 mM GSH PBS (pH 7.4), respectively; The DOX released in PBS (pH 7.4) and 10mM GSH PBS (pH 7.4) were 2...

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Abstract

The invention relates to a folate-targeted reduction sensitive drug-carrying polymer nano-micelle as well as a preparation method and application thereof. The delivery carrier is prepared by taking anamphiphilic triblock copolymer PCL-ss-PEG-ss-PCL as a material, and a chemotherapeutic drug adriamycin amycin and a photosensitizer indocyanine green are entrapped in a hydrophobic core of the micelle. Besides, phospholipid DSPE-PEG-NH2 with an active group is introduced into the preparation process, the DSPE end of the phospholipid has strong hydrophobic property and is inserted into the hydrophobic PCL core of the polymer micelle, the flexible hydrophilic PEG long chain exists on the outer surface of the micelle, FA with a targeting effect is connected to a PEG active distal end of the surface of the polymer micelle, and functions of active tumor targeting and reduction response drug release are integrated. The folate-targeted reduction sensitive drug-carrying polymer nano-micelle disclosed by the invention has the advantages of being small in particle size, high in dispersion property, high in drug loading capacity and encapsulation efficiency and excellent in photothermal conversion effect, can realize reduced trigger drug release, fluorescence imaging of tumor sites, tumor targeting drug delivery and chemotherapy-photothermal combination therapy and improve the tumor inhibition effect, and has wide application prospects in the targeted combination therapy aspect of tumors.

Description

technical field [0001] The invention relates to a folic acid-targeted reduction-sensitive drug-loaded polymer nanomicelle and its preparation method and application, in particular to a targeted polymer micelle mediated by folic acid and capable of reducing the response to the tumor microenvironment, which can efficiently The inner core of the polymer micelle contains chemotherapeutic drugs and photosensitizers, and has long-term circulation characteristics, can enter tumor cells efficiently, and realizes reduction-sensitive triggered drug release and combined chemotherapy-photothermal therapy of tumors. Background technique [0002] Polymer micelle was developed 30 years ago. It is a thermodynamically stable colloidal solution formed by spontaneous assembly of amphiphilic polymers in selective solvents due to intermolecular hydrogen bonds, electrostatic interactions and van der Waals forces. A shell structure in which the hydrophilic blocks form the outer shell and the hydro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K47/10A61K47/24A61K47/34A61K47/22A61K31/704A61K41/00A61P35/00C08G63/664C08G65/334C08G65/332
Inventor 张琳华朱敦皖胡春艳秦玉黄晨露
Owner INST OF BIOMEDICAL ENG CHINESE ACAD OF MEDICAL SCI
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