Antagonistic peptide, copolymer thereof, nano-assembly as well as preparation methods and applications of antagonistic peptide, copolymer and nano-assembly

A nano-assembly and antagonistic peptide technology, applied in the field of medicine, can solve the problems of IR780 such as poor water solubility, limited action distance, and short action time of singlet oxygen, so as to improve the anti-tumor effect, inhibit the escape process, and improve the utilization rate.

Active Publication Date: 2020-07-17
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

It has been reported that PD-L1 is highly upregulated on many types of tumor cells, such as melanoma, ovarian cancer and non-small cell lung cancer, but the inventors found that the immune system alone cannot completely kill malignant and invasive tumors, and the immune system If there is not enough antigen in the treatment process, the desired therapeutic effect cannot be exerted
[0004] IR780 iodide (IR780) is a typical near-infrared dye. The excellent characteristics of both photothermal and photodynamic properties make it have good clinical application prospects. However, the inventors found that IR780 has poor water solubility and difficult delivery in vivo, which limits its wide application. The factors used, and the singlet oxygen produced by IR780 as a photosensitizer has a short action time and a limited action distance, so it is difficult to achieve the ideal therapeutic effect

Method used

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  • Antagonistic peptide, copolymer thereof, nano-assembly as well as preparation methods and applications of antagonistic peptide, copolymer and nano-assembly
  • Antagonistic peptide, copolymer thereof, nano-assembly as well as preparation methods and applications of antagonistic peptide, copolymer and nano-assembly
  • Antagonistic peptide, copolymer thereof, nano-assembly as well as preparation methods and applications of antagonistic peptide, copolymer and nano-assembly

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1 Synthesis of M-APP

[0055] (The structure of the M-APP polypeptide is: Mercaptopropionic acid-L-Met-PLGLVG-DPPA-1)

[0056] The preparation process of M-APP is as follows:

[0057] First carry out resin swelling, soak 10 grams of Rink amide AM Resin (resin substitution degree is 0.35mmol / g) with 200mL methylene chloride for 15 minutes, wait for the resin to swell, and remove the methylene chloride. Next, remove the amino protection, add 200mL hexahydropyridine / DMF solution, use nitrogen agitation, and react twice at room temperature for 5 minutes and 15 minutes, and wash the resin with DMF after the reaction. Add a small amount of resin to the color detector and heat at 100°C for 3 minutes. The color of the solution and resin should be blue or red, which means the reaction is complete. It can be judged that the amino Fmoc protection has been removed. Then, carry out the condensation reaction, add 2 times the number of moles of Fmoc-D-Phe-OH and HBTU, di...

Embodiment 2

[0060] Example 2 Molecular synthesis of IR780-M-APP

[0061] IR780 was precisely weighed with an analytical balance, dissolved in anhydrous N,N-dimethylformamide (DMF) solvent, and placed in a round bottom flask. Weigh M-APP (prepared according to the method described in Example 1), dissolve it in anhydrous DMF, add it to the DMF solution of IR780 being stirred, and add triethylamine (TEA), and react under argon protection and room temperature For 48 hours, the ratio of the amount of IR780, M-APP and TEA was 5:1:20. After the reaction, dimethyl sulfoxide was dialyzed to remove anhydrous DMF and unreacted IR780, dialyzed overnight, followed by methanol dialyzed to remove dimethyl sulfoxide, evaporated under reduced pressure to remove methanol in the solution, and vacuum dried overnight to obtain IR780- M-APP product. The structure identification of IR780-M-APP is as follows: figure 1 B and figure 1 C shows:

[0062] 1. In-flight mass spectrometry (ESI-TOF-MS):

[0063]...

Embodiment 3

[0066] Example 3 Preparation of IR780-M-APP NPs

[0067] Accurately weigh 2 mg of IR780-M-APP, dissolve it in 500 μL of methanol, and place it in a round-bottom flask; sonicate, add 2 mL of membrane-passed water into the methanol solution of IR780-M-APP, and continue to sonicate (ultrasonic conditions: 100W, 30min) Form nano-aggregates and evaporate under reduced pressure to obtain a nanoparticle solution of IR780-M-APP, that is, nano-preparation IR780-M-APP NPs. The TEM results are as follows figure 2 As shown, the morphology of the prepared IR780-M-APP NPs was shown to be nanoparticle morphology, confirming the successful preparation of the formulation.

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Abstract

The invention provides an antagonistic peptide, a copolymer thereof, a nano-assembly as well as preparation methods and applications of the antagonistic peptide, the copolymer and the nano-assembly. The antagonistic peptide is a PD-L1 antagonistic peptide, is named M-APP, and has a structure shown in the specification. The M-APP is used as a raw material to prepare the copolymer IR780-M-APP with aclear structure, the copolymer IR780-M-APP can be self-assembled to form the nano-assembly, so that the problem of poor immunogenicity in immunotherapy is solved, and the utilization rate of the immune antagonistic peptide is improved; and through photodynamic therapy, the problem of poor water solubility of IR780 can be solved, the effect of phototherapy is improved, and the efficacy of immunotherapy is enhanced.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to antagonistic peptides, their copolymers and nano assemblies, and their preparation methods and applications. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily taken as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to those skilled in the art. [0003] In recent years, studies have shown that the incidence of melanoma continues to rise worldwide. In recent years, the incidence rate in my country has increased by 5 times. Melanoma is an aggressive malignant tumor that arises from melanocytes in the skin and rarely occurs outside the skin. Melanoma metastases are increasingly diverse in treatment. However, the treatment of metastatic melanoma has become increasingly co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/00C07K1/107C07K1/06C07K1/04A61K38/16A61K47/64A61K41/00A61K9/51A61K9/00A61P35/00A61P37/02
CPCC07K14/00A61K47/6425A61K41/0057A61K41/0052A61P35/00A61P37/02A61K9/5169A61K9/0019A61K38/00
Inventor 栾玉霞姜悦王宁宁
Owner SHANDONG UNIV
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