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A kind of polypeptide, lipid carrier modified by polypeptide and application

A lipid carrier and fatty acid technology, which is applied in the field of polypeptide and polypeptide modified lipid carrier, can solve the problems of reducing macrophage phagocytosis, difficult production, and low clinical value, so as to promote in vivo delivery, prolong in vivo half-life, and reduce recognition Effects with phagocytosis

Active Publication Date: 2021-07-20
SOUTHWEST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, nanomedicine preparations with CD47 can significantly reduce the phagocytosis of macrophages, but as a complete protein, CD47 is not easy to produce and has little clinical value, so the applicant refers to the research of Rodriguez et al [Rodriguez P L, Harada T, Christian D A , et al.Minimal "Self" Peptides That Inhibit Phagocytic Clearance and Enhance Delivery of Nanoparticles[J].Science,2013,339(6122):971-975.], they screened out the active site of CD47 and named it "Self" Peptide, and then demonstrated that polystyrene nanoparticles labeled "Self" peptide exhibited the same anti-phagocytosis effect as CD47

Method used

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  • A kind of polypeptide, lipid carrier modified by polypeptide and application
  • A kind of polypeptide, lipid carrier modified by polypeptide and application
  • A kind of polypeptide, lipid carrier modified by polypeptide and application

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Experimental program
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Effect test

Embodiment 1

[0039] The implementation mode of linking cholesterol to polypeptide is according to literature [Ingallinella P, Bianchi E, Ladwa NA, et al. Addition of a cholesterol group to an HIV-1 peptide fusion inhibits dramatically increases its antiviral potency. Proceedings of the National Academy of Sciences, 2009, 106( 14): 5801-5806.] Carry out, specifically, obtain polypeptide C by solid-phase synthesis D GK D L D E. D I D V D T D K D GE D R D S D L D E. D T D V D E. D C D T D Y D N D G. Dissolve 100 mg of cholesterol (injection grade, purchased from Everett Company) and 40 mg of bromoacetic acid (purity greater than 99%, purchased from Adamas) in 1500 μL of anhydrous dichloromethane (purchased from Sigma Company), and add 44 μL of N, N'-diisopropylcarbodiimide (98%+, purchased from Adamas) and 1.5mg 4-dimethylaminopyridine (99%, purchased from Adamas) were used as catalysts, stirred at 400rpm at room temperature for 48h, then reduced Dry under pressure to obtai...

Embodiment 2

[0041] Both L-type "Self" peptide (LMS) and D-type "Self" peptide (DMS) are synthesized by solid-phase synthesis, wherein the specific sequence of LMS is as follows: GNYTCEVTELSREGKTVIELK (as shown in SEQ ID NO.1), and in the amino The segment is synthesized by solid phase [Cao L, Fischer A, Bornscheuer U T, et al. Lipase-Catalyzed Solid Phase Synthesis of Sugar Fatty Acid Esters. Biocatalysis, 1996, 14(4): 15.] Adding palmitic acid, the specific sequence of DMS is as follows : GK D L D E. D I D V D T D K D GE D R D S D L D E. D T D V D E. D C D T D Y D N D G, and add palmitic acid at the amino segment by solid-phase synthesis.

[0042] The two configurations of polypeptides were prepared as 5 mg / ml solutions in PBS, and mouse serum (Abbkine) was added to RPMI 1640 to obtain solution A containing 25% (volume ratio) of mouse serum. Add the peptide solution to solution A to a final peptide concentration of 100 μg / ml. Incubate at 37°C for 0.5, 1, 2, 4, 8, and ...

Embodiment 3

[0044]Polypeptide solution (1 mg / ml) was prepared in methanol, egg yolk lecithin (PL-100m, Ivet) solution (28 mg / ml) was prepared in ethanol, cholesterol (injection grade, purchased from Ivet) was prepared in chloroform Special) solution (12mg / ml). The phospholipid, cholesterol and polypeptide solutions were mixed at 500:250:40 (volume ratio) to obtain about 2ml of mixed solution. Evaporate to dryness under reduced pressure to obtain a phospholipid film, and remove a small amount of organic solvent with nitrogen gas. PBS solution (pH = 7.2) was added to the film and shaken in a constant temperature water bath at 37° C. to obtain multilamellar liposomes. The liposomes were respectively passed through liposome extruders containing 400nm, 200nm and 100nm polycarbonate membranes for 20 times each to obtain the desired polypeptide liposomes, which were stored for future use.

[0045] RAW264.7 cells in the logarithmic growth phase (purchased from the Shanghai Cell Bank of the Chin...

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Abstract

The present invention relates to a polypeptide, a lipid carrier modified by the polypeptide and its application as a drug for inhibiting the phagocytosis of macrophages. The present invention provides a nano-preparation that can be absorbed for a long time on the basis that it is easily phagocytized by macrophages during delivery in vivo A method to facilitate intrananoparticle delivery on the surface of macrophage cell membranes. After the "Self" D-type polypeptide and phospholipids or other materials are used to form a lipid carrier, when it interacts with macrophages, it can reside on the surface of macrophages for a long time, inhibiting the phagocytosis of macrophages, thereby significantly improving nanocarriers. in vivo delivery. The lipid carrier of the invention can be adsorbed on the surface of macrophages and promote the phosphorylation of SIRPα protein in macrophages to inhibit the phagocytosis of macrophages. After entering the body, it can inhibit the phagocytosis of macrophages and prolong the in vivo half-life of the subsequently injected drug. The research of the present invention shows that by administering the lipid carrier, the half-life of the nano-preparation in the body can be significantly prolonged, and the distribution of the drug in the liver and spleen can be reduced.

Description

technical field [0001] The invention belongs to the field of biotechnology, and relates to a polypeptide, a lipid carrier modified by the polypeptide and applications thereof. Background technique [0002] The concept of macrophage blockade or reticuloendothelial blockade (RES blockade) was proposed in 1969 [Saba T M, Di L N. Reticuloendothelial blockade and recovery as a function of opsonic activity. American Journal of Physiology, 1969, 216 (216): 197-205.], because this strategy realizes the long circulation process is simple, does not change the existing preparation form, and was widely studied in the 1980s, Proffitt et al [Proffitt R T, Williams L E, Presant C A, et al .Liposomal blockade of the reticuloendothelial system:improved tumor imaging with small unilamellar vesicles.Science.1983,220(4596):502-505.] The reticuloendothelial system was closed, and then the liposomes labeled with radioactive elements were used for localization in vivo. It was found that compared ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/705A61K9/127A61K47/42A61K47/24A61K47/28A61K47/44A61K47/10
CPCA61K9/127A61K47/10A61K47/24A61K47/28A61K47/42A61K47/44C07K14/70503
Inventor 李翀唐宜轩于洋
Owner SOUTHWEST UNIV
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