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Docetaxel micelle nano-drug as well as preparation method and application thereof

A docetaxel and micellar nanotechnology, which is applied in drug combination, drug delivery, pharmaceutical formulation, etc., can solve the problem that the prolongation of patient survival does not meet expectations, and achieve the reduction of enrichment, increase of solubility, and increase of cycle time Effect

Active Publication Date: 2021-10-08
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

PEG-PLA-based nano-medicines Genexol-PM and Nanoxel-PM have entered the clinic, but it should be pointed out that although these nano-medicines have reduced toxicity in clinical treatment, the prolongation of patient survival has not reached expectations

Method used

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  • Docetaxel micelle nano-drug as well as preparation method and application thereof
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  • Docetaxel micelle nano-drug as well as preparation method and application thereof

Examples

Experimental program
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Effect test

Synthetic example

[0031] Synthesis Example Synthesis of polymers is a conventional method

[0032] PEG-P(LA-DTC) was synthesized by ring-opening polymerization of DTC and LA in anhydrous DCM with PEG as macroinitiator and DBU as catalyst. For example, stir MeO-PEG-OH (0.4 g, 200 μmol), DTC (0.14 g, 7.1 mmol), and LA (0.2 g, 13.9 mmol) in DCM (10 mL) in a glove box under nitrogen atmosphere until completely dissolved. DBU (30 mg, 2 mmol) was added under stirring, then the reactor was sealed and transferred out of the glove box, and placed in an oil bath at 37°C for 3 hours to react. Then the reaction solution was added dropwise to a 20-fold excess of cold anhydrous ether to precipitate, after centrifugation, it was dissolved with acetonitrile, and the precipitation was repeated twice. The obtained PEG-P (LA-DTC) was vacuum-dried for 24 hours to obtain a light yellow Lumpy solid. Yield: 76%. polymer through 1 H NMR and GPC measure relative molecular weight and molecular weight distribution. ...

Embodiment 1

[0041] Example 1 Preparation and Characterization of DTX Micellar Nanomedicine

[0042] PEG 2k -P(LA 1k -DTC 0.7k ), cRGD-PEG 2k -PLA 1.7k and DTX were dissolved in PEG350 at concentrations of 200 mg / mL, 50 mg / mL and 100 mg / mL to configure three mother solutions. After mixing evenly according to the designed ratio, take 0.05mL of the mixed solution and heat it to 60°C and inject it into 0.95mL phosphate buffer (PB, 10 mM, pH 7.4) preheated to 60°C to obtain a uniform and clear gel. The beam solution cRGD-MDTX is a surface-coupled cRGD, PEG-P (LA-DTC)-based disulfide cross-linked, small-sized DTX micellar nanomedicine.

[0043] By changing the ratio of the three mother solutions, a series of micelles with different cRGD density and DTX drug loading can be obtained. Among them, cRGD-PEG-PLA and PEG-P (LA-DTC) are mixed according to the molar ratio of 0 / 100, 2.5 / 97.5, 5 / 95, and 10 / 90, and the cRGD surface density can be obtained as 0, 2.5%, 5%, respectively. % and 10% mice...

Embodiment 2

[0056] Example 2 Cellular uptake experiment of DTX micellar nanomedicine

[0057] PC3 cells were used. In the flow cytometry (FACS) test, first spread 2 mL of PC3 cells in a 6-well plate (3×10 5 cells / well) for 24 hours. After adding 200 µL of Cy5-MDTX, 2.5% cRGD / Cy5-MDTX, 5% cRGD / Cy5-MDTX or 10% cRGD / Cy5-MDTX and incubating for 4 hours, the medium and micelles were removed. After washing with PBS, add 0.25% (w / v) trypsin and 0.03% (w / v) EDTA to digest to a single cell suspension, centrifuge the cell suspension at 1000 rpm for 3 minutes, wash with PBS twice, and finally suspend the cells In 500 µL PBS, the fluorescence intensity of cell-associated Cy5 was detected by FACS. MCF-7 cells were used as negative control. In confocal laser microscopy (CLSM) testing, PC3 cells were plated in 24-well plates (3.0 × 10 5 cells / well) for 24 hours. Then add 200 µL of 5% cRGD / Cy5-MDTX or Cy5-MDTX and continue to culture for 4 hours. After removing the culture medium, fix with 4% form...

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Abstract

The invention discloses a docetaxel (DTX) micelle nano-drug as well as a preparation method and application thereof. The preparation method comprises the following steps: dissolving a polymer in oligomeric ethylene glycol to obtain a polymer mother solution; dissolving dTX in the oligomeric ethylene glycol to obtain a DTX mother solution; mixing the polymer mother solution with the DTX mother solution to obtain a mixed solution of the DTX, the polymer and the oligomeric ethylene glycol; and mixing the mixed solution of the DTX, the polymer and the oligomeric ethylene glycol with a buffer solution to obtain the DTX micelle nano-drug. Compared with a free drug, the nano-drug prepared by loading the chemotherapeutic drug can increase the solubility of the free hydrophobic drug, increase the circulation time of the drug, change the biological distribution of the drug, reduce the enrichment of normal tissues and the like, can quickly release the DTX in cells, has long blood circulation time, high tumor enrichment amount and deep tumor penetrability, and achieves targeted therapy and efficient inhibition on prostatic cancer.

Description

technical field [0001] The invention belongs to nano-medicines, in particular to docetaxel (DTX) micellar nano-medicines and its preparation method and application. Background technique [0002] Currently, chemotherapy is the main treatment for castration-resistant prostate cancer (CRPC). However, chemotherapy drugs generally have low bioavailability, high toxicity and side effects, and poor curative effect. The vigorous development of nanomedicine provides a way of thinking for the treatment of CRPC. However, drug delivery for tumor therapy faces many obstacles, including insufficient blood circulation time, low accumulation in tumor tissue, difficulty in penetrating deep into tumor tissue, and difficulty in being specifically endocytosed by tumor cells; researchers have developed multiple A multifunctional drug delivery system to overcome these challenges. However, the design of complex multifunctional delivery systems not only makes the synthesis of polymers time-consu...

Claims

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Application Information

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IPC IPC(8): A61K9/107A61K47/34A61K47/10A61K47/18A61K47/62A61K47/60A61K47/69A61K31/337A61P35/00
CPCA61K9/1075A61K47/34A61K47/10A61K47/183A61K47/62A61K47/60A61K47/6907A61K31/337A61P35/00
Inventor 孟凤华闫文成郭贝贝倪大伟钟志远
Owner SUZHOU UNIV
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