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Protein nanogel remotely controlled by infrared light as well as preparation method and application of protein nanogel

A remote control and nanogel technology, which is applied in the field of protein nanogel remotely controlled by infrared light and its preparation, can solve the problems of immunogenicity, cycle time safety or unsatisfactory targeted drug delivery, and limit wide application , to achieve the effects of improving pH-responsive release kinetics, enhancing cancer therapy, and high-efficiency loading capacity

Active Publication Date: 2021-10-01
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since the physical and chemical properties of natural therapeutic proteins are completely different from those of traditional small molecule drugs, direct administration often has problems such as immunogenicity, circulation time, safety or targeted drug delivery, which limits its wide application.

Method used

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  • Protein nanogel remotely controlled by infrared light as well as preparation method and application of protein nanogel
  • Protein nanogel remotely controlled by infrared light as well as preparation method and application of protein nanogel
  • Protein nanogel remotely controlled by infrared light as well as preparation method and application of protein nanogel

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] The synthesis of embodiment 1 protein nanogel

[0064] (1) Synthesis of PEG-DAM: 100mg of 6-branched-chain amino polyethylene glycol (6arm PEG-NH 2 ; Molecular weight 20k; PEG for short) (1eq,5*10 -6 mol, 6eq; note: 1eq is the amount of PEG; 6eq is the amino group amount of 1eq PEG), 37.8mg 2,3-dimethylmaleic anhydride (DaM; purchased from Sigma) (60eq, 5*10 -5 mol) and 0.02ml triethanolamine (TEA) (30eq, 3*10 -5 mol) into a round bottom bottle, dissolved in 3ml of dichloromethane (DCM) for reaction, the reaction continued for 24 hours, then dried up the DCM with nitrogen to obtain the crude product, and then the crude product was dissolved in water and the solution was transferred to the intercepted In a dialysis bag with a molecular weight of 14kDa, dialyze in a large beaker filled with deionized water for 24 hours, then transfer to a 50ml centrifuge tube, freeze at -20°C, and freeze-dry in a lyophilizer to obtain the product, which is named as PEG-DAM, its NMR spe...

Embodiment 2

[0077] Embodiment 2 in vitro experiments

[0078] Cell culture experiment: mouse breast cancer cells (4T1) were obtained from ATCC (American Type Culture Collection, ATCC), and kept at 37°C, 5% CO 2 , culture medium containing 10% (v / v) fetal bovine serum (FBS) and 1% (w / v) penicillin / streptomycin (cultivate in a 10mL dish, the total number of cells is about 12×10 6 cell), and then undergo MTT experiment (incubate with 96-well plate for 24 hours first, inoculum amount is 30000-40000 / well, cultivate to 70000-80000 / well, then add drugs for related operations and incubate for 24 hours, and measure cells by MTT method Survival rate), to study the killing effect of PEG-IR825 / PEG-DAM-βCD / IFNα (referred to as PI825@PDC / IFNα) on 4T1 tumor cells (based on IR825, the concentrations were 0.25, 0.125, 0.0625, 0.0313, 0.0156mM) , with IR825 dye, PEG-IR825, IR825+L, PEG-IR825+L, PI825@PDC / IFNα+L as controls (+L means infrared light irradiation, 808nm, about 10min).

[0079] The result is ...

Embodiment 3

[0080] Embodiment 3 in vivo experiments

[0081] The animal model was balb / c mice. When inoculating mouse tumors, 4T1 cells (about 2×10 6 ) suspended in an appropriate amount of PBS buffer (pH 7.4), and injected subcutaneously into the back of the mouse (after inoculating the tumor, wait until the tumor volume is about 60-90mm 3 (about 1-2 weeks), and then carry out the following experiments:

[0082] (1) In order to study the in vivo behavior of mice, PEG-IR825 / PEG-DAM-βCD / IFNα (PI825@PDC / IFNα) and PEG-IR825 were intravenously injected into mice at 200 μL / mouse (IR825 10mg / kg, IFNα: 1mg / kg). At different time points (2, 4, 8, 12, 24 h), the in vivo distribution of PEG-IR825 / PEG-DAM-βCD / IFNα and PEG-IR825 was observed using a small animal imaging system. Finally, the mice were sacrificed after 24 hours, and the liver (liver; abbreviated as Li), spleen (spleen; abbreviated as sp), kidney (kidney; abbreviated as ki), heart (heart; abbreviated as he), and lungs (lungs; Lu for...

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Abstract

The invention discloses protein nanogel remotely controlled by infrared light as well as a preparation method and application of the protein nanogel. The method comprises the following steps: (1) adding 6-branched chain amino polyethylene glycol, 2, 3-dimethyl maleic anhydride and triethanolamine into dichloromethane, and synthesizing PEG-DAM; (2) adding the PEG-DAM, EDC and NHS into dimethyl sulfoxide, and adding beta-cyclodextrin to synthesize PEG-DAM-beta CD; (3) adding an IR825 dye, EDC and NHS into dimethyl sulfoxide, and adding 6-branched chain amino polyethylene glycol to synthesize PEG-IR825; and (4) dissolving the PEG-DAM-betaCD into water, adding the PEG-IR825 and the protein, and synthesizing to obtain the protein nanogel. The protein nanogel can slightly release protein in an acid environment, and meanwhile, programmable in-vitro release can be triggered through remote near-infrared rays, so that targeted therapy on tumors is achieved.

Description

technical field [0001] The invention belongs to the technical field of protein drugs, and in particular relates to a protein nanogel remotely controlled by infrared light and its preparation method and application. Background technique [0002] Since the first introduction of recombinant human insulin in 1982, therapeutic proteins are becoming leading new drugs for a variety of clinical treatments. However, since the physical and chemical properties of natural therapeutic proteins are completely different from those of traditional small molecule drugs, direct drug delivery often suffers from unsatisfactory immunogenicity, circulation time, safety or targeted drug delivery, which limits its wide application. [0003] In cancer therapy, considering the different physicochemical properties of the surrounding environment and pathological tissues, the application of many pH-, enzyme-, and light-sensitive carriers in the protein delivery process has attracted widespread attention....

Claims

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Application Information

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IPC IPC(8): A61K47/69A61K47/60A61K38/21A61K38/38A61K41/00A61P35/00C08G81/00
CPCA61K47/6951A61K47/6903A61K47/60A61K41/0052A61K41/0042A61K38/212A61K38/38A61P35/00C08G81/00A61K2300/00
Inventor 刘小文卓诗洁陈健张希灿张鹏张烽余俊宇
Owner JINAN UNIVERSITY