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Mixed medicament carrying micelle based on polyphosphoester, preparation method thereof and a mixed medicament carrying micelle modified by positive targeted group

An active targeting group, polyphosphate technology, applied in the direction of pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve the problem of PEG lack of active sites, slow drug release, difficult Targeted modification and other issues, to achieve excellent in vivo long-circulation effect, easy targeted modification, and good stability

Active Publication Date: 2017-10-27
HUAZHONG UNIV OF SCI & TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Active targeted modification can increase tumor cell endocytosis, but PEG lacks active sites, making it difficult to carry out targeted modification
At the same time, PEG is difficult to degrade in the human body, and the drug is released slowly after entering tumor cells

Method used

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  • Mixed medicament carrying micelle based on polyphosphoester, preparation method thereof and a mixed medicament carrying micelle modified by positive targeted group
  • Mixed medicament carrying micelle based on polyphosphoester, preparation method thereof and a mixed medicament carrying micelle modified by positive targeted group
  • Mixed medicament carrying micelle based on polyphosphoester, preparation method thereof and a mixed medicament carrying micelle modified by positive targeted group

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preparation example Construction

[0086] The present invention provides a method for preparing the mixed drug-loaded micelles described in the above scheme, comprising the following steps:

[0087] mixing polyphosphate-polylactic acid diblock copolymers, polyethylene glycol-polylactic acid diblock copolymers, hydrophobic chemotherapeutic drugs, organic basic compounds and organic solvents to obtain an oil phase;

[0088] adding the oil phase to water for emulsification to obtain an emulsion;

[0089] The organic solvent in the emulsion is removed to obtain the mixed drug-loaded micelles based on polyphosphate.

[0090] The present invention combines polyphosphate ester-polylactic acid two-block copolymer (PAEEP-PLLA), polyethylene glycol-polylactic acid two-block copolymer (PEG-PLLA), hydrophobic chemotherapeutic drug, organic basic compound and organic solvent Mix to obtain an oily phase. In the present invention, the mass ratio of the PEG-PLLA and PAEEP-PLLA is preferably (1-20):(1-5), more preferably (2-1...

Embodiment 1

[0112] Mix 1 mol of 2-chloro-2-oxo-1,3,2-dioxaphospholane, 0.9 mol of N-(tert-butoxycarbonyl)ethanolamine and 40 mol of tetrahydrofuran, and carry out substitution reaction at 0°C for 12 hours, After rotary evaporation of the solvent, vacuum drying at 60°C for 20 h under a vacuum of 0.03 atm to obtain 2-(N-(tert-butoxycarbonyl)ethanolamine)-2-oxo-1,3,2-dioxaphospha Cyclopentane (N-Boc-EAOP)

[0113] (2) Mix polylactic acid, N-Boc-EAOP and tetrahydrofuran, and carry out ring-opening polymerization at 60°C for 3 hours under the action of an organoaluminum catalyst to obtain an intermediate product;

[0114] (3) The intermediate product obtained in the step (2) is mixed with tetrahydrofuran and trifluoroacetic acid to carry out a deprotection reaction, and then the material obtained after the deprotection reaction is finished is precipitated with ether, filtered, and the obtained solid Vacuum drying at 40°C for 15 hours under a vacuum degree of 0.03atm to obtain PAEEP 12 -PLLA ...

Embodiment 2

[0118] Weigh respectively doxorubicin hydrochloride 8.2mg, PEG 83 -PLLA 70 (wherein the weight average molecular weight of PEG block is 5000, and the weight average molecular weight of PLLA block is 5000) 60.2mg and the PAEEP that embodiment 1 prepares 12 -PLLA 70 (wherein the weight-average molecular weight of the PAEEP block is 2000, and the weight-average molecular weight of the PLLA block is 5000) 40.2mg, be dissolved in the mixed solvent of 1mL chloroform and 0.5mL methanol together, and add 50 μ L triethylamine solution to dissolve doxorubicin hydrochloride After the element was completely dissolved, it was added dropwise into 15mL ultrapure water and ultrasonic emulsification was performed using a cell disruptor, maintaining a power of 200w for 5min to obtain a uniform and stable emulsion; the emulsion was placed at room temperature and stirred at 150rpm After 24 hours, the organic solvent was evaporated to obtain mixed drug-loaded micelles.

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Abstract

The invention provides a mixed medicament carrying micelle based on polyphosphoester, a preparation method thereof and a mixed medicament carrying micelle modified by a positive targeted group. A compound micelle consists of polyphosphoester-polylactic acid two segmented copolymers and polyethylene glycol-polylactic acid two segmented copolymers; the compound micelle with the same polylactic acid hydrophobic kernel and different hydrophilic shells is formed under the hydrophobic interaction of polylactic acid segments. The mixed medicament carrying micelle provided by the invention has the advantages of high hydrophilicity and high stability, is easy to perform targeted modification, has an in vivo long circulation effect, effects of facilitating of targeted cell endocytosis and in-cell medicament release, targeted modified mixed medicament carrying micelle can achieve a passive targeting effect and a positive targeting effect, so that the tumor treatment effect is further improved.

Description

technical field [0001] The invention relates to the technical field of biomedical materials, in particular to a polyphosphate-based mixed drug-loaded micelle, a preparation method thereof, and a mixed drug-loaded micelle modified by an active targeting group. Background technique [0002] Polymer micelles are a new type of nano-drug loading system developed in recent years, generally composed of amphiphilic diblock (hydrophilic-hydrophobic) polymers or triblock (hydrophilic-hydrophobic-hydrophilic) polymers In addition, there are also some grafted hydrophilic-hydrophobic polymers or ionic hydrophilic ionic copolymers. [0003] Active targeting mainly refers to endowing the drug or its carrier with the ability to actively bind to the target. The main means include using chemical or physical methods to probe molecules such as antibodies, polypeptides, sugar chains, and nucleic acid aptamers that can specifically bind to target molecules. Coupled to the surface of the drug or ...

Claims

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Application Information

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IPC IPC(8): A61K9/107A61K47/34A61K47/69A61K47/64A61P35/00A61K31/704
CPCA61K9/1075A61K31/704A61K47/34
Inventor 刘卫刘旭菡谭熙饶荣任园园许琦
Owner HUAZHONG UNIV OF SCI & TECH
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