Maleimide-polyglutamic acid-aspartic acid polymer and composite thereof, preparation methods for maleimide-polyglutamic acid-aspartic acid polymer and composite thereof, and application of maleimide-polyglutamic acid-aspartic acid polymer and composite thereof

A technology of maleimide and maleimide group, applied in the field of biomedicine, can solve the problems of lack of active targeting function and inability to directly couple ligands, etc.

Active Publication Date: 2012-08-01
SHANGHAI INST OF BIOLOGICAL PROD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above-mentioned γ-polyglutamic acid and γ-polyglutamic acid-aspartic acid carriers cannot be directly coupled with ligands, nor have active targeting functions.

Method used

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  • Maleimide-polyglutamic acid-aspartic acid polymer and composite thereof, preparation methods for maleimide-polyglutamic acid-aspartic acid polymer and composite thereof, and application of maleimide-polyglutamic acid-aspartic acid polymer and composite thereof
  • Maleimide-polyglutamic acid-aspartic acid polymer and composite thereof, preparation methods for maleimide-polyglutamic acid-aspartic acid polymer and composite thereof, and application of maleimide-polyglutamic acid-aspartic acid polymer and composite thereof
  • Maleimide-polyglutamic acid-aspartic acid polymer and composite thereof, preparation methods for maleimide-polyglutamic acid-aspartic acid polymer and composite thereof, and application of maleimide-polyglutamic acid-aspartic acid polymer and composite thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Embodiment 1 Preparation of acid type γ-polyglutamic acid-aspartic acid

[0081] Gamma-polyglutamic acid was prepared by fermentation of Bacillus licheniformis ATCC 9945a, and the reference [Haifeng Ye et al. Biomaterial 27 5958-5965] was slightly modified. Inoculate the fermentation medium (maltose 50 g l -1 , yeast extract 10 g·l -1 , sodium glutamate 30 g·l -1 , NaCl 10g·l -1 , KH 2 PO 4 5g·l -1 ,MgSO 4 ·7H 2 O 0.5g·l -1 ), 37 0 C, 220 rpm -1 Shake flasks were incubated for 72 hours. After the fermentation is finished, dilute the fermentation broth 4 times with distilled water, adjust the pH of the fermentation broth to 2.0-3.0 with hydrochloric acid, 12000 r min -1, Centrifuge for 30 minutes to remove the bacterial precipitate, then adjust the pH of the supernatant to 7.0-8.0, then add 3 times the volume of ice-cold absolute ethanol, stir to obtain the γ-polyglutamic acid precipitate, and re-dissolve the precipitate in distilled water, Remove insolub...

Embodiment 2

[0085] Embodiment 2 The preparation method of maleimide-polyglutamic acid-aspartic acid polymer

[0086] Reaction scheme 1:

[0087] Take the acid-type γ-polyglutamic acid-aspartic acid (PGA-Asp, 37 mg) prepared in Example 1 above, dissolve it in dimethyl sulfoxide solution (DMSO, 10 ml), add 1-hydroxybenzene Triazole (HOBt, 80mg) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC, 120mg), drop 150 μL of triethylamine and N-(2 -Aminoethyl)-6-maleimidocaproamide solution (400 mg, dissolved in 1 ml DMFO), stirred at 37°C under nitrogen protection for 72 hours. Add 15 times the volume of diethyl ether to the reaction system solution to terminate the reaction, shake vigorously, the mixed solution is divided into upper and lower layers, and the lower layer liquid is light yellow. The lower liquid was collected, added an equal volume of phosphate buffer (pH 7.0, 0.2M), dialyzed for 48 hours, and freeze-dried to obtain a white floc of maleimide-polyglutamic acid-...

Embodiment 3

[0118] Example 3 Preparation of IFN maleimide-polyglutamic acid-aspartic acid complex

[0119] Dissolve the maleimide-polyglutamic acid-aspartic acid polymer (Mal-PGA-Asp1, 48 mg) prepared in reaction scheme 1 of Example 2 in deionized water (10 ml), add recombinant human interference IFN α-2b (IFN α-2b, 10mg), react at 4°C for 12 hours. This preparation condition is conducive to retaining the activity of recombinant human interferon α-2b. It is separated by dialysis, ultrafiltration and size exclusion chromatography. Purification, the obtained IFN-maleimide-polyglutamic acid-aspartic acid complex, the general structural formula is:

[0120]

[0121] Among them, n=51 (average value); m=42 (average value); z=21 (average value); Mal is N-(2-aminoethyl)-6-maleimide caproamide; γ- PGA is γ-polyglutamic acid; Asp is aspartic acid; IFN is recombinant human interferon α-2b (IFN α-2b).

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Abstract

The invention discloses a maleimide-polyglutamic acid-aspartic acid polymer. The maleimide-polyglutamic acid-aspartic acid polymer is formed by the covalent bonding of a gamma-polyglutamic acid-aspartic acid polymer and amine compounds containing maleimide groups, wherein the bonding is realized by forming an amido bond between a free carboxyl group of the gamma-polyglutamic acid-aspartic acid polymer and amino groups on the amine compounds containing the maleimide groups under the coaction of a condensing agent and a catalyst. The invention also discloses a maleimide-polyglutamic acid-aspartic acid composite and a preparation method and application thereof. By coupling biological active molecules with a sulfydryl group, the stability and in-vivo activity of the maleimide-polyglutamic acid-aspartic acid polymer can be improved, and the in-vivo half life of the maleimide-polyglutamic acid-aspartic acid polymer can be prolonged; and meanwhile, the polymer which is coupled with targetingmolecules with the sulfydryl group and is combined with an anti-tumor medicine can become a polymer medicine with active targeting.

Description

technical field [0001] The invention relates to a maleimide-polyglutamic acid-aspartic acid polymer and a compound thereof, a preparation method and application thereof, and belongs to the technical field of biomedicine. Background technique [0002] γ-polyglutamic acid is an amino acid polymer produced by microbial fermentation, which is formed by condensation of α-amino and γ-carboxyl groups of glutamic acid. γ-polyglutamic acid has non-immunogenicity, biocompatibility and degradability, and has a wide range of applications in various fields. As a drug carrier, γ-polyglutamic acid can improve the water solubility of the drug, prolong the release time of the drug, reduce the toxic and side effects of the drug, and can be used in the field of biomedical technology. For example, patent 00817029.0 discloses the combination of polyglutamic acid and therapeutic agent Large-scale production of clinical development of drugs; patent 200610024353.0 discloses γ-polyglutamic acid-cis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G69/48A61K47/48
Inventor 耿旭黄静吴自荣劳勋周杰张利
Owner SHANGHAI INST OF BIOLOGICAL PROD CO LTD
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