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Methoxy polyethylene glycol-polyphosphate diblock copolymer and adriamycin bonding medicine thereof

A technology of polyethylene glycol monomethyl ether and polyphosphate doxorubicin, which is applied in drug combinations, antineoplastic drugs, and pharmaceutical formulations, can solve problems such as limited side group selection, side reactions, and interference with polymerization reactions, and achieve Simple preparation method, good stability and high reproducibility

Inactive Publication Date: 2013-04-24
UNIV OF SCI & TECH OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] However, the polymerization of phosphate esters also faces some limitations. If the side group-functionalized phosphate monomers are directly used to synthesize polyphosphate esters through polymerization, the choice of side groups is limited, and the functional groups can easily interfere with the polymerization reaction and cause Side reactions, so it is necessary to protect the related groups in the monomer, which makes the synthesis of the monomer difficult and increases the complexity of the synthetic route

Method used

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  • Methoxy polyethylene glycol-polyphosphate diblock copolymer and adriamycin bonding medicine thereof
  • Methoxy polyethylene glycol-polyphosphate diblock copolymer and adriamycin bonding medicine thereof
  • Methoxy polyethylene glycol-polyphosphate diblock copolymer and adriamycin bonding medicine thereof

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Embodiment 1

[0068] Embodiment 1, mPEG a -PAOOP b Synthesis and characterization of

[0069] 1. Synthesis and characterization of 2-allyloxy-2-oxo-1,3,2-dioxaphospholane (AOOP) cyclic phosphate monomer

[0070] (1) Synthesis of 2-chloro-2-oxo-1,3,2-dioxaphospholane (COP)

[0071] COP synthesis route such as figure 1 (A) shown. The specific steps for synthesizing COP are as follows: at 25°C, slowly add 301 mL of 3.25 mol / L ethylene glycol in dichloromethane to 300 mL of 3.26 mol / L phosphorus trichloride in dichloromethane. After the dropwise addition was completed, the reaction was continued for 0.5 hour, and the solvent was distilled off under normal pressure at 45°C. After obtaining the product twice in a row under reduced pressure distillation (20Pa), the product was dissolved in 500mL of benzene, and logically 3 days. 2 Until the reaction is complete, distillation under reduced pressure (20Pa) is performed again, and the fraction at 70°C is collected to obtain COP.

[0072] (2) S...

Embodiment 2

[0092] Embodiment 2, the synthesis and the characterization (mPEG a -PAOOP b -Cya-ADR-DMMA)

[0093] 1. Polyethylene glycol monomethyl ether-polyphosphate diblock copolymer (mPEG) with amino groups as side groups a -PAOOP b -Cya) synthesis and characterization

[0094] Synthetic route such as figure 1 (D) as shown in mPEG4 5 -b-PAOOP 75 As an example, at 25°C, take mPEG 45 -b-PAOOP 75 (200mg, 0.014mmol), mercaptoethylamine hydrochloride (0.375g, 3.15mmol, 300% of the double bond molar weight) and benzoin dimethyl ether (DMPA, 13.4mg, 0.05mmol, 5% of the double bond molar weight) Dissolve in 1.5 mL dry DMF. After bubbling nitrogen gas for 20 minutes, irradiate with 365nm ultraviolet light for 30 minutes, dialyze the product with distilled water for 48 hours at 4°C (molecular weight cut-off is 2000), and obtain polyethylene glycol monomethyl ether-polyphosphoric acid with side groups as amino groups after freeze-drying Ester polymer (mPEG 45 -PAOOP 75 -Cya, PPC). Pr...

Embodiment 3

[0101] Embodiment 3, mPEG a -PAOOP b -Cya-DMMA and mPEG a -PAOOP b -Biocompatibility of Cya-ADR-DMMA copolymer nanoparticles

[0102] 1. mPEG a -PAOOP b -Biocompatibility of Cya-DMMA nanoparticles

[0103] In this experiment, since ADR itself has the ability to kill cells, in order to eliminate the interference of ADR on the biocompatibility of the material, mPEG without doxorubicin bound to the side group was selected. a -PAOOP b -Cya-DMMA. The above materials were prepared as a 1 mg / mL nanoparticle solution and then diluted to 10.6-340 μg / mL. Determination of different concentrations of mPEG by MTT method a -PAOOP b - Cytotoxicity of Cya-DMMA copolymer nanoparticles. The specific test is: different concentrations of mPEG a -PAOOP b - After the Cya-DMMA nanoparticle solution was co-cultured with the MDA-MB-231 cells for 48 hours under the conditions of pH=7.4 and pH=6.8, respectively, the cell viability was measured. The survival rate of cells under different tr...

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Abstract

The invention discloses a macromolecular bonding medicine based on adriamycin. The active ingredient of the bonding medicine is nanoparticles formed by bonding of a polyphosphate polymer and adriamycin. Specifically, the polyphosphate polymer can be a methoxy polyethylene glycol-polyphosphate diblock copolymer with amino as the side group. The invention also provides a methoxy polyethylene glycol-polyphosphate copolymer with an amino side group and a method for synthesizing the copolymer. The polyphosphate adriamycin macromolecular bonding medicine provided in the invention can self-assemble to form nanoparticles with a particle size of about 30nm. Through the intrinsic scale effect of the nanoparticles and by combining a charge reversal technology, the nanoparticles can better concentrate in a tumor tissues and a cell, thus enhancing the targeting property of adriamycin on a tumor site. And the adriamycin bonded on a polyphosphate polymer chain can have responsiveness to a tumor tissue microenvironment, and can be rapidly released in the tumor tissue under a weakly acidic condition. And a good tumor cell-killing effect can be achieved.

Description

technical field [0001] The invention relates to a polyethylene glycol monomethyl ether-polyphosphate diblock copolymer and a polyphosphate doxorubicin macromolecule bonded drug prepared therefrom. Specifically, the general formula of the polyphosphate doxorubicin macromolecular bonded drug is mPEG a -PAOOP b - Cya-ADR-DMMA, wherein a=45-113, b=25-150. More specifically, the present invention synthesized mPEG 45 -PAOOP 25 -Cya-ADR-DMMA or mPEG 45 -PAOOP 75 -Cya-ADR-DMMA or mPEG 113 -PAOOP 150 -Cya-ADR-DMMA three kinds of doxorubicin macromolecule bonded drugs. The polyphosphate doxorubicin macromolecule-bonded drug provided by the present invention can self-assemble in an aqueous solution to form nanoparticles with a particle diameter of about 30 nm. Background technique [0002] Doxorubicin belongs to the anthracycline class of antibiotics and was first extracted and discovered by Italian scientists from a Streptomyces bacterium in the early 1960s. Since its discov...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K31/704C08G79/04A61P35/00
Inventor 王均杜金志孙春阳都小姣毛成琼
Owner UNIV OF SCI & TECH OF CHINA
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