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A polyamino acid carrier with an acid-sensitive linking arm in the middle and its preparation method and application

A polyamino acid and linking arm technology, applied in the field of polyamino acid carriers, can solve the problems of easy destruction of the delivery protein, and achieve the effect of stable delivery effect and precise regulation.

Active Publication Date: 2022-03-25
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, non-covalent forces are prone to damage the delivery of proteins in complex in vivo environments

Method used

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  • A polyamino acid carrier with an acid-sensitive linking arm in the middle and its preparation method and application
  • A polyamino acid carrier with an acid-sensitive linking arm in the middle and its preparation method and application
  • A polyamino acid carrier with an acid-sensitive linking arm in the middle and its preparation method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] The preparation of polyamino acid carrier 1:

[0052] Step 1: 4-(4-Hydroxybenzyl)oxazolidine-2,5-dione (III-1)

[0053] L-tyrosine (II-1, 1 g, 5.52 mmol), triphosgene (3.28 g, 11.04 mmol) and 10 mL of anhydrous tetrahydrofuran were successively added to the 100 mL three-necked flask, and the reaction was heated under reflux for 12 h under nitrogen protection, TLC (petroleum ether) : ethyl acetate=1:1) monitoring the completion of the reaction of the raw materials. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain a colorless oily substance. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=4:1-1:1 gradient elution) to obtain 600 mg of white solid, yield: 52.5%. ESI-MS(m / z): 206.1[M-H] - . m.p.138-140°C. 1 H-NMR(300MHz,DMSO),δ(ppm):9.31(s,1H, OH ),9.02(s,1H, NH ),6.98-7.00(d,2H,J=4.5Hz, ArH ),6.70-6.72(d,2H,J=4.5Hz, ArH ),2.93(m,3H,Ar CH 2 CH ). 13...

Embodiment 2

[0069] Preparation of polyamino acid carrier chemically bonded protein preparation:

[0070] Step 1: Add 4 mg of RNase-A to 5 mL of PBS buffer, stir at room temperature for 10 min, and then add 0.1 mg of an inorganic weak base salt (the weak base salt can be: sodium bicarbonate (NaHCO) 3 )) continue to stir for 20min.

[0071] Step 2: 10mg of polyamino acid polymer carrier I was added to 10mL of organic solvent (the organic solvent can be methanol, ethanol, acetonitrile, tetrahydrofuran, acetone or any mixed solvent of the two), ultrasonicated for 10min to be completely dissolved and then stirred at room temperature.

[0072] Step 3: Put 0.1 mg I 2 Dissolve in 1mL organic solvent (organic solvent can be methanol, ethanol, acetonitrile, tetrahydrofuran, acetone or any mixed solvent of the two), and store in the dark

[0073] Step 4: Slowly drop the mixed solution obtained in step 1 into the mixed solvent of step 2, and control the dropping rate to be 2 drops per second. Afte...

Embodiment 3

[0077] Agarose gel electrophoresis of RNase-A

[0078] RNA agarose electrophoresis was used to assess GSH-triggered protein release and recovery of protein viability. 20 μg / mL of RNA and I@RNase-A (40 μg / mL of RNase-A) were incubated with different concentrations of GSH (0, 5 μM, 50 μM, 500 μM and 5 mM) at 37 °C. Then, the mixture was analyzed by 8% agarose gel electrophoresis at a constant voltage of 120 V for 20 minutes. Electropherogram such as Figure 20 As shown, GSH-triggered protein release and recovery can be seen well.

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Abstract

The invention discloses a polyamino acid carrier with an acid-sensitive linking arm in the middle, its preparation method and application. The polyamino acid carrier contains a hydrophilic part, a hydrophobic part and a responsive linking arm. The carrier design introduces a unique disulfide bond. The disulfide bond can be broken into sulfhydryl in vitro in a controlled manner and small molecules with sulfhydryl fragments or genes and protein drugs with inherent sulfhydryl groups on the surface rebond to form covalent disulfide bonds. Complete chemical bond delivery of drugs. Since the polyamino acid carrier is covalently bonded to the drug, it can be stably transported in the systemic circulation. When it reaches the site of high metabolism and high reduction such as tumor or inflammation, it will break the disulfide bond again under the condition of high glutathione (GSH), release and restore the activity of the drug. In this way, the purpose of masking the drug activity first, then stably delivering it in vivo, and restoring the drug activity after reaching the target position is precisely regulated.

Description

technical field [0001] The present invention relates to a macromolecular carrier and its preparation method and application, in particular to a polyamino acid carrier with an acid-sensitive linking arm in the middle, and its preparation method and application. Background technique [0002] Chemotherapy and radiotherapy play an increasingly important role in current cancer treatment. However, chemotherapy and radiotherapy are often accompanied by many obvious side effects, such as physical weakness, digestive disorders, decreased immune function, etc., and the quality of life of patients is poor. Because nano-drug carriers can improve the absorption and stability of drugs, and have certain tissue targeting properties, they can reduce the side effects of chemotherapy and radiotherapy. Therefore, the use of nanomaterials to deliver drugs has received extensive attention from scholars. Common antitumor drugs are mainly divided into small molecule chemotherapy drugs, macromolec...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/62A61K47/60A61K45/00A61K48/00A61P29/00A61P35/00C08G69/40
CPCA61K47/60A61K45/00A61K47/62A61K48/0041A61P35/00A61P29/00C08G69/40
Inventor 孙敏捷朱良瀚刘宁
Owner CHINA PHARM UNIV
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