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Antigen and TLR agonist targeting co-loaded cationic phospholipid-polymer hybrid nanoparticle vaccine adjuvant, and preparation method and application thereof

A vaccine adjuvant and agonist technology, applied in the direction of cancer antigen components, vertebrate antigen components, and resistance to vector-borne diseases, etc., can solve problems such as hindering the clinical manifestations of vaccine adjuvants, weak immune response, and difficult application of adjuvants. Achieve the effects of enhancing cellular and humoral immune responses, strong lymphocyte activation, and enhancing antigen uptake

Active Publication Date: 2018-12-14
INST OF BIOMEDICAL ENG CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, the immunogenicity of vaccines such as nucleic acid vaccines, protein vaccines, and subunit vaccines is weak, which limits the application of vaccines and also leads to the generation and development of adjuvants.
However, currently approved adjuvants such as aluminum adjuvants can only effectively activate humoral immunity but cannot activate cellular immune responses, making it difficult for adjuvants to be used in diseases such as cancer, hepatitis B, and HIV
At the same time, the safety of adjuvants, tolerance to antigens, large-scale production and preparation, and commercial value also make vaccine adjuvants seldom used commercially.
However, free TLR agonists are prone to rapid degradation and clearance in vivo, thus hampering their clinical performance as vaccine adjuvants
Meanwhile, protein or peptide antigens in the free state are often rapidly cleared and are less immunogenic, thus producing only a transient and weak immune response

Method used

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  • Antigen and TLR agonist targeting co-loaded cationic phospholipid-polymer hybrid nanoparticle vaccine adjuvant, and preparation method and application thereof
  • Antigen and TLR agonist targeting co-loaded cationic phospholipid-polymer hybrid nanoparticle vaccine adjuvant, and preparation method and application thereof
  • Antigen and TLR agonist targeting co-loaded cationic phospholipid-polymer hybrid nanoparticle vaccine adjuvant, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] This example provides a cationic phospholipid-polymer hybrid nanoparticle vaccine adjuvant co-loaded with an antigen and a TLR agonist. The preparation method includes the steps:

[0048] S1: Dissolve 20 mg amphiphilic triblock copolymer PCL-b-PEG-b-PCL with 1 mg cationic phospholipid DOTAP, 100 μg TLR7 agonist IMQ, 10 μg TLR4 agonist MPLA in dichloromethane, then remove the organic solvent by rotary evaporation , form a uniform film on the bottle wall, dry the residual solvent with nitrogen, put it in a vacuum drying oven, and dry it in vacuum for 12 hours; among them, the amphiphilic triblock copolymer PCL-b-PEG-b-PCL The molecular weight is 16000, and the mass percentage of the PEG hydrophilic segment is greater than 45%.

[0049]S2: Add 10 mL of double-distilled water to the dried product, hydrate at 65°C for 5 hours, oscillate and mix evenly, and then sonicate for 10 minutes in an ice bath to form a stable emulsion, filter the stable emulsion with a 0.45 μm filter ...

Embodiment 2

[0057] This example provides a cationic phospholipid-polymer hybrid nanoparticle vaccine adjuvant that targets mannose and co-loads antigens and TLR agonists (TLR4 agonist MPLA, TLR7 agonist IMQ and antigen OVA). The preparation method includes steps:

[0058] S1: Mix 20 mg amphiphilic triblock copolymer PCL-b-PEG-b-PCL with 1 mg cationic phospholipid DOTAP, 100 μg TLR7 agonist IMQ, 10 μg TLR4 agonist MPLA, 0.4 mg DSPE-PEG-NH 2 Dissolve in dichloromethane, then remove the organic solvent by rotary evaporation, and form a uniform film on the wall of the bottle, dry the residual solvent with nitrogen, then put it in a vacuum drying oven, and dry it in vacuum for 12 hours; among them, the amphiphilic triembed The molecular weight of segment copolymer PCL-b-PEG-b-PCL is 16000, and the mass percentage of PEG hydrophilic segment is greater than 45%.

[0059] S2: Add 10 mL of double-distilled water to the dried product, hydrate at 65°C for 5 hours, oscillate and mix evenly, and then ...

Embodiment 3

[0063] The mannose-targeted cationic phospholipid-polymer hybrid nanoparticle vaccine adjuvant (MAN-OVA-IMNPs) prepared in Example 2 of the present invention, which co-loads antigen and TLR agonist, was tested for promoting BMDCs maturation and cytotoxicity. The OVA-IMNPs in the following experiments were prepared in Example 1.

[0064] Immature BMDCs were stimulated with free OVA-agonists, OVA-IMNPs or MAN-OVA-IMNPs vaccine adjuvant for 24 hours. Subsequently, BMDCs were collected and co-incubated with 100 μL diluted cy5.5-anti-mouse CD11c, PE-anti-mouse CD40, FITC-anti-mouse CD86, and APC-anti-mouse CD80 for 30 min at 4°C. CD11c was detected by flow cytometry (FACS, BD FACSCalibur, US) + Expression of CD40, CD86 and CD80 on BMDCs.

[0065] MTS reagent (MTS, Promega, Madison, WI) was used to detect the viability of BMDCs after co-incubation with free OVA-agonists or OVA-containing cationic phospholipid-polymer hybrid nanoparticle vaccine adjuvants. The immature BMDCs cells...

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Abstract

The invention relates to an antigen and TLR agonist targeting co-loaded cationic phospholipid-polymer hybrid nanoparticle vaccine adjuvant, and a preparation method and an application thereof. A hydrophobic inner core is encapsulated with a TLR7 agonist, a phospholipid layer is encapsulated with a TLR4 agonist, an antigen is adsorbed by cationic phospholipids in the phospholipid layer, and ligation of a mannose ligand makes the vaccine adjuvant like a specific targeting antigen to have the dendritic cell presenting ability, so the DC cell intake and the maturation promoting effect are enhanced; and the antigen is protected by hybridized nanoparticles, the antigen uptake by DC cells is improved, immune response after antigen stimulation is significantly enhanced by the TLR agonist, and thecross-presentation of the antigen is significantly improved, so vaccine adjuvant has a strong potent T cell killing effect, can induce cytokine secretion, has a long-acting memory T cell response, andhas an excellent prevention effect on tumors.

Description

technical field [0001] The invention relates to the technical field of vaccine adjuvants, in particular to a cationic phospholipid-polymer hybrid nanoparticle vaccine adjuvant targeting co-loaded antigens and TLR agonists, as well as its preparation method and application. Background technique [0002] Immunotherapy is another new type of therapy after surgery, therapy and radiation therapy. Immunotherapy works in three ways: 1) designing monoclonal antibodies to enhance the immune response to kill cancer cells; 2) using immune checkpoint inhibitors to help the immune system recognize and attack tumor cells, such as PDL-1, CTAL-4, etc. ; 3) Synthetic vaccines trigger immune responses to treat and prevent tumors. Unlike chemotherapy, which directly uses drugs to kill tumor cells, immunotherapy is a treatment method that activates or rebuilds the patient's immune system and changes the tumor microenvironment to regenerate the body's ability to recognize and kill tumor cells. ...

Claims

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Application Information

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IPC IPC(8): A61K39/39A61K39/00A61K9/16A61K47/34A61K47/26A61K47/24A61P37/04A61P35/00
CPCA61K9/1617A61K9/1623A61K9/1641A61K39/0008A61K39/0011A61K39/39A61K2039/55511A61K2039/55572A61K2039/57A61K2039/575A61P35/00A61P37/04Y02A50/30
Inventor 朱敦皖张琳华务圣洁秦玉黄晨露
Owner INST OF BIOMEDICAL ENG CHINESE ACAD OF MEDICAL SCI
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