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Polyamino acid carrier with acid-sensitive connecting arm in middle as well as preparation method and application of polyamino acid carrier

A polyamino acid and connecting arm technology, applied in the field of polyamino acid carrier, can solve the problem of easily damaged delivery protein, and achieve the effect of stable delivery and precise regulation

Active Publication Date: 2020-09-11
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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  • Polyamino acid carrier with acid-sensitive connecting arm in middle as well as preparation method and application of polyamino acid carrier
  • Polyamino acid carrier with acid-sensitive connecting arm in middle as well as preparation method and application of polyamino acid carrier
  • Polyamino acid carrier with acid-sensitive connecting arm in middle as well as preparation method and application of polyamino acid carrier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] The preparation of polyamino acid carrier I:

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

[0053] Add L-tyrosine (II-1, 1g, 5.52mmol), triphosgene (3.28g, 11.04mmol) and 10mL anhydrous tetrahydrofuran to a 100mL three-necked flask in sequence, and heat under reflux for 12h under nitrogen protection. TLC (petroleum ether : Ethyl acetate=1:1) to monitor the completion of the raw material reaction. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain a colorless oil. 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 C-NMR (75MHz, DMSO) δ 170.76, 156.37, 151.56, 130...

Embodiment 2

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

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

[0071] Step 2: Add 10mg of polyamino acid polymer carrier I into 10mL of organic solvent (the organic solvent can be methanol, ethanol, acetonitrile, tetrahydrofuran, acetone or any mixed solvent of the two), sonicate for 10 minutes and stir at room temperature after it is completely dissolved.

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

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

Embodiment 3

[0077] Agarose gel electrophoresis of RNase-A

[0078] RNA agarose electrophoresis was used to assess GSH-triggered protein release and restoration of protein viability. 20 μg / mL of RNA and I@RNase-A (the concentration of RNase-A was 40 μg / mL) 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 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 connecting arm in the middle as well as a preparation method and application of the polyamino acid carrier. The polyamino acid carrier contains a hydrophilic part, a hydrophobic part and a responsive connecting arm; a specific disulfide bond is introduced into the carrier design, the disulfide bond can be controllably broken into sulfydryl in vitro, the small molecule with the sulfydryl fragment or the gene with sulfydryl inherent on the surface is bonded with the protein drug again, and a covalent disulfide bond is formedto complete chemical bonding delivery of the drug. The polyamino acid carrier and the drug are bonded in a covalent bond manner, so that the drug can be stably transported in systemic circulation. When the carrier reaches high-metabolism and high-reducibility parts such as tumors or inflammations, disulfide bonds are broken again under the condition of high glutathione (GSH), and the activity ofthe drug is released and recovered. Therefore, the purposes of firstly masking the drug activity, then stably delivering the drug in vivo and recovering accurate regulation and control of the drug activity after the drug reaches a target position are achieved.

Description

technical field [0001] The invention relates to a polymer carrier and its preparation method and application, in particular to a polyamino acid carrier with an acid-sensitive linking arm in the middle, 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, immune function decline, etc., and the quality of life of patients is poor. Because nano-drug carriers can improve the absorption and stability of drugs, they have certain tissue targeting and can reduce the side effects of chemotherapy and radiotherapy. Therefore, the use of nanomaterials to deliver drugs has attracted widespread attention from scholars. Common anti-tumor drugs are mainly divided into small molecule chemotherapeutic drugs, macromolecular gene drugs and macrom...

Claims

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Application Information

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Patent Type & Authority Applications(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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