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Immunologically active peptide-biliverdin conjugate as well as preparation method and application thereof

A technology of immunoactive peptides and conjugates, which is applied in the field of immunoactive peptide-biliverdin conjugates, which can solve the problems of unresolved biological safety performance, unclear metabolic mechanism, and short half-life of small molecules, so as to prevent tumors Effects of metastasis and recurrence, enhancement of immune function, and remodeling of tumor inflammatory microenvironment

Active Publication Date: 2020-08-18
INST OF PROCESS ENG CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These published photothermal preparations all show high photothermal conversion efficiency and effectively inhibit the growth of tumors, but there are still general problems: 1) the long-term biological safety performance needs to be studied; 2) the metabolic mechanism is not yet clear; 3) Tumor metastasis and recurrence after photothermal therapy
At the same time, immunomodulatory peptide-related drugs have been commercially available, such as thymopentin for injection, recombinant human interferon α-2b injection, Yunzhi glycopeptide capsules, etc., but these published or commercially available immunomodulatory drugs have the following problems : 1) Small molecules have short half-life and are easy to degrade; 2) Weak immune effect; 3) Complex ingredients and serious immune-related adverse events
[0006] There are no published reports on the formation of conjugates of biliverdin molecules and immunoactive peptide molecules through chemical synthesis, their preparation methods and their application in "photothermal immune" tumor therapy

Method used

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  • Immunologically active peptide-biliverdin conjugate as well as preparation method and application thereof
  • Immunologically active peptide-biliverdin conjugate as well as preparation method and application thereof
  • Immunologically active peptide-biliverdin conjugate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0135] According to the following steps, the biliverdin-SIINFEKL conjugate was obtained by chemical synthesis: Weigh a certain amount of biliverdin, EDC·HCl, NHS, and DMF, add them to the reactor in turn and mix them uniformly; put the obtained mixture at room temperature Stir in the dark for 24 hours; then add water to stir and collect the precipitate; add anhydrous DMF to the obtained precipitate and mix evenly, then add SIINFEKL peptide and anhydrous triethylamine, and stir at room temperature for 24 hours in the dark; collect the above reaction The precipitate was purified by size exclusion chromatography; the resulting material was recrystallized to obtain the pure molecular conjugate. Among them, the concentration of biliverdin was 100 mM, the concentration of EDC·HCl was 100 mM, the concentration of NHS was 50 mM, and the concentration of peptide was 200 mM. The 1HNMR information of the prepared conjugate is as follows:

[0136]1HNMR (600MHz) δ=11.95~13.00(3H),10.68(s,...

Embodiment 2

[0139] The biliverdin molecule and SIINFEKL were synthesized according to the chemical synthesis method in Example 1 to prepare a biliverdin-SIINFEKL conjugate. A certain mass of conjugate was weighed, pre-dissolved in a small amount of DMSO solution, and then directly dissolved in PBS solution, stirred and dissolved, then filtered and sterilized, and the pH value was adjusted to neutral. The prepared conjugates with different concentration gradients were co-incubated with human umbilical vein endothelial cells HUVEC in the dark, and the biological safety of the conjugates was evaluated by MTT colorimetry. figure 2 The results of the cell activity experiment of the conjugate prepared in Example 2 show that the prepared conjugate has high biological safety and has no obvious cytotoxicity to human umbilical vein endothelial cells HUVEC.

Embodiment 3

[0141] First, biliverdin and excess zinc acetate were chemically synthesized to obtain biliverdin-Zn metal complexes. The experimental method was as follows: biliverdin and excess zinc acetate were dissolved in methanol solution, stirred at 60°C for 4 hours, and the obtained The solution was rotary evaporated to remove the solvent to obtain a solid, and the obtained solid was purified by a reverse-phase chromatographic column to obtain the biliverdin-Zn complex, wherein the mass concentration ratio of biliverdin to zinc acetate was 1:5. The biliverdin-Zn metal complex and NYSKPTDRQYHF were prepared according to the aforementioned chemical synthesis method to obtain the biliverdin-Zn-NYSKPTDRQYHF conjugate. A certain mass of conjugate was weighed, pre-dissolved in a small amount of DMSO solution, and then directly dissolved in PBS solution, stirred and dissolved, then filtered and sterilized, and the pH value was adjusted to neutral. The prepared conjugates with different conce...

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Abstract

The invention relates to an immunologically active peptide-biliverdin conjugate, a preparation method thereof and application thereof in cancer diagnosis, and / or tumor immunotherapy, and / or tumor 'photothermal immunotherapy' (tumor photothermal therapy combined immunotherapy). The conjugate disclosed by the invention not only can stimulate an organism to generate a tumor immune effect, but also can relieve and / or eliminate tumor inflammation, remodel a tumor inflammatory microenvironment and realize photo-thermal immune cancer diagnosis and treatment. The conjugate disclosed by the invention is high in biocompatibility, good in stability and long in half-life period. The conjugate is prepared from immunologically active peptide and biliverdin through chemical synthesis, the peptide end ofthe conjugate plays a role in immunoregulation, and the pigment end of the conjugate plays a role in tumor imaging diagnosis, tumor photo-thermal ablation, immune inflammatory microenvironment regulation and the like. The conjugate can significantly enhance the anti-tumor effect and effectively inhibit tumor metastasis and recurrence.

Description

technical field [0001] The present invention belongs to the field of "photothermal immunity" anti-tumor medicine, especially relates to a kind of conjugate of immunoactive peptide-biliverdin, its preparation method and its application in cancer diagnosis, and / or tumor immunotherapy, and / or tumor " Application in "photothermal immunity" therapy (tumor photothermal therapy combined with immunotherapy). Background technique [0002] Traditional tumor treatment methods such as surgery, chemotherapy, and radiotherapy all face side effects to varying degrees. "Photothermal immunotherapy" is the product of the combination of photothermal tumor therapy and tumor immunotherapy. It is a safe, accurate, and broad-spectrum new type of tumor therapy. Therapeutic method shows good curative effect on advanced tumors with metastatic and multiple lesions. The basic principle is that photothermal immune drugs are actively or passively targeted and gathered at the tumor site. Under the excita...

Claims

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Application Information

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IPC IPC(8): A61K41/00A61P35/00A61K49/14A61K49/22A61K51/08A61K38/07A61K38/08A61K38/10A61K38/16A61K103/00A61K103/10A61K103/34A61K103/20
CPCA61K38/07A61K38/08A61K38/10A61K38/16A61K41/0052A61K49/14A61K49/221A61K51/08A61P35/00A61K2300/00
Inventor 闫学海邢蕊蕊常蕊邹千里
Owner INST OF PROCESS ENG CHINESE ACAD OF SCI
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