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Nano micelle of biodegradable macromolecular-bonding Pt(IV) anti-cancer medicament and preparation method thereof

A technology of biodegradable and anticancer drugs, which is applied in the direction of antineoplastic drugs, drug combinations, and pharmaceutical formulations, and can solve problems such as failure to meet the use requirements

Active Publication Date: 2011-07-13
吉林市博禹祥实工贸有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Zhang Lianfang and others synthesized platinum (IV) containing ketone functional groups on the vertical axis, and connected it to PEG-PLGA with terminal amino groups through Schiff bases to synthesize acid-sensitive platinum (IV) polymer bonded drugs, but Since platinum (IV) is connected with two PEG-PLGA chains with a molecular weight of 10,000, the platinum content in the bond is only 1.05% (Zhang L., ACS Nano, 2010, 4(1), 251-258), Obviously can not meet the requirements of clinical use

Method used

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  • Nano micelle of biodegradable macromolecular-bonding Pt(IV) anti-cancer medicament and preparation method thereof
  • Nano micelle of biodegradable macromolecular-bonding Pt(IV) anti-cancer medicament and preparation method thereof
  • Nano micelle of biodegradable macromolecular-bonding Pt(IV) anti-cancer medicament and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Embodiment 1: the preparation of polyethylene glycol-b-polyester block polymer:

[0084] With ε-caprolactone as the cyclic ester monomer, 10 g of polyethylene glycol monomethyl ether with a molecular weight of 5000 was selected as the initiator, dissolved in 50 mL of toluene, and subjected to azeotropic distillation for 1 hour to remove residual water. Add 5gε-caprolactone, then add 100μL of 10% (w / w) stannous octoate toluene solution, stir evenly, heat to 120°C, polymerize for 12 hours and cool to room temperature, dissolve the polymer with 50mL chloroform, and then use 500mL Precipitate the polymer with a methanol / ether mixture with a volume ratio of 1:2; dissolve the precipitated polymer with 50 mL of chloroform, and then use 500 mL of a methanol / ether mixture with a volume ratio of 1:2 for precipitation; the product was vacuum-dried at room temperature for 12 hours. Calculate the polymerization yield by weighing. use 1 The HNMR method determines the molecular weig...

Embodiment 2

[0088] Example 2: Azidation of terminal hydroxyl groups of polyethylene glycol-b-polyester

[0089] Add 10g (1.4mmol) EG to a 500mL reaction flask 5000 -b-PCL 2280 And 0.4mL triethylamine, dissolved with 100mL chloroform under stirring. The reaction flask was cooled in an ice bath at 0°C, and 3.6 mL of 10% (w / v) sulfonyl chloride (CH 3 SO 2 Cl) in chloroform solution, after the reaction was carried out for 4 hours, the reaction product was poured into 500 mL of methanol / ether mixture (volume ratio 1:2) to precipitate a white solid.

[0090] Dissolve the precipitate in 100 mL of N,N-dimethylformamide (DMF), add 1.0 g NaN 3 , stirred at room temperature for 3 days. The solvent was then removed in vacuo, filtered, precipitated, and dried in vacuo to obtain the azidation product MPEG 5000 -b-PCL 2280 -N 3 .

[0091] The kind of polymer and methanesulfonyl chloride, triethylamine consumption, the consumption of sodium azide and the reaction time are listed in Table 3, and ...

Embodiment 3

[0094] Embodiment 3: the terminal azido group of polyethylene glycol-b-polyester is reduced to the terminal amino group, prepares MPEG-b-PES-NH 2 Methods

[0095] MPEG 5000 -b-PCL 2280 -N 3 As an example, the specific operation of the catalytic hydrogenation reaction is as follows: suspend 4g of polyethylene glycol-b-polyester with terminal azidation in a mixed solvent of 50mL of methanol and 300mL of tetrahydrofuran, transfer it to a hydrogenation autoclave, and add Pd(OH) supported on activated carbon 2 Palladium carbon catalyst Pd(OH) with a mass content of 10% 2 / C 600mg, feed hydrogen to make the hydrogen pressure reach 2.5MPa, maintain this pressure and keep constant temperature 50°C, and react for 24 hours. Release the material after pressure release, remove the catalyst by filtration, remove the solvent by evaporation, dissolve with 100mL chloroform, and precipitate 500mL methanol / ether (volume ratio 1:2) mixed solution to obtain MPEG-b-PCL-NH 2 White product, yi...

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Abstract

The invention relates to a nano micelle of a biodegradable macromolecular-bonding Pt(IV) anti-cancer medicament and a preparation method thereof. The structural formula of the anti-cancer medicament is defined in the specification, wherein the biodegradable macromolecule is tri-block copolymer, namely polyethylene glycol-b-polyester-b-polylysine; and tetravalency platinum coordination compound Pt(IV) is connected with a side amino on the block of polylysine on a macromolecular carrier through alpha, omega-polyethylene glycol. The carrier is non-toxic and is water-soluble, thus being convenient for reacting with the platinum(IV) coordination compound in water phase; a nano micelle form can be formed through self assembly; a platinum(IV) coordination compound is reduced to platinum(II), namely, cis-platinum, Carboplatin or Oxaliplatin, and the anti-cancer effect is known; the synthesis of the nano micelle is easy; the reduction potential of platinum(IV) is low, so that the platinum(IV) can be rapidly reduced to platinum(II) in cancer cells to take treatment effect; and the platinum(IV) is connected to the side chain of the macromolecule rather than the end of a chain, a macromolecular chain can be connected with multiple platinum(IV)s, and the content of platinum can be as high as 10-20%.

Description

technical field [0001] The invention relates to amphiphilic biodegradable macromolecule-bonded Pt (IV) anticancer drug nanomicelles and a preparation method thereof, and belongs to the field of chemically synthesized new drugs and preparations thereof. Background technique [0002] Since the discovery of cisplatin's anticancer activity in 1967, the research and application of platinum-based metal anticancer drugs have been greatly developed. Thousands of platinum series compounds have been screened successively, dozens of them have entered clinical research, and several have been approved to enter the market. [0003] Cis-dichlorodiammine platinum (II), also known as "cisplatin" (Cisplatin, figure 1 A), is a non-cell cycle-specific anticancer drug, which is cytotoxic and can combine with DNA to form cross bonds, destroy the replication function of DNA, and cause cell apoptosis. Clinical practice has proved that cisplatin has a strong broad-spectrum anti-cancer effect, has ...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/282A61K33/24A61P35/00A61K47/60
Inventor 景遐斌郑勇辉肖海华柳时胡秀丽齐若谷黄宇彬
Owner 吉林市博禹祥实工贸有限公司
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