CN-121971596-A - Polycarbonate material adjuvant and preparation method and application thereof

CN121971596ACN 121971596 ACN121971596 ACN 121971596ACN-121971596-A

Abstract

The invention discloses a polycarbonate material adjuvant and a preparation method and application thereof, and belongs to the technical field of biological medicine and immunotherapy, wherein the polycarbonate material adjuvant comprises a biodegradable polycarbonate polymer chain segment, and a STING agonist covalently connected to a side chain of the polycarbonate polymer chain segment through an amide bond, and based on the design thought of degradable polymer-drug coupling, the polycarbonate material adjuvant slowly hydrolyzes and releases the STING agonist under the action of in-vivo enzyme, so that the continuous activation of an immune channel is realized. According to the invention, continuous activation of the STING channel is realized by combining the STING agonist with the polycarbonate polymer chain segment, so that the cellular immune response is remarkably enhanced. The polycarbonate material adjuvant can be gradually hydrolyzed and released in vivo, so that the utilization rate of the medicine in local and drainage lymph nodes is improved, meanwhile, the polycarbonate material adjuvant has good biocompatibility and safety, and a new solution is provided for the immunity enhancement of rabies vaccines.

Inventors

LI YUANYUAN
LI HAILUN
HE SIXUAN
Miao Kunrong
LIU XINGQI
WANG DI
GONG ZHIYUAN
Qian Meichen
WANG YANRU

Assignees

吉林大学

Dates

Publication Date: 20260505
Application Date: 20260325

Claims (10)

1. A polycarbonate material adjuvant, wherein the polycarbonate material adjuvant comprises: biodegradable polycarbonate polymer segments, and STING agonists covalently linked to the side chains of the polycarbonate polymer segments through amide linkages; The polycarbonate material adjuvant slowly hydrolyzes and releases STING agonist under the action of in vivo enzyme, so as to realize the continuous activation of immune channel.
2. The polycarbonate material adjuvant of claim 1, wherein the polycarbonate polymer segment is a copolymer of allyl glycidyl ether and 2- ((2- (2- (2-methoxyethoxy) ethoxy) methyl) ethylene oxide.
3. The polycarbonate material adjuvant of claim 1 wherein the STING agonist is acridone acetic acid.
4. A method of preparing a polycarbonate material adjuvant according to any one of claims 1 to 3, comprising the steps of: Synthesizing a polycarbonate polymer chain segment containing active side chains; introducing amino functional groups on side chains of the polycarbonate polymer segments; Coupling a STING agonist molecule to the amino functionality via an amidation reaction to form the polycarbonate material adjuvant.
5. The method for preparing a polycarbonate material adjuvant according to claim 4, wherein the step of synthesizing the polycarbonate polymer segment containing the active side chain comprises the following steps: Adding a catalyst Salen-Co-TFA and a cocatalyst PPN-TFA into a reaction vessel, sequentially adding monomer allyl glycidyl ether and 2- ((2- (2- (2-methoxyethoxy) ethoxy) methyl) ethylene oxide, then filling CO 2 , carrying out reaction, removing byproducts and the catalyst, and carrying out vacuum drying to obtain the polycarbonate polymer chain segment.
6. The method for preparing a polycarbonate material adjuvant according to claim 4 or 5, wherein the step of introducing an amino functional group into a side chain of the polycarbonate polymer segment comprises: Sequentially adding 2-tert-butoxycarbonyl amino ethanethiol and a polycarbonate polymer chain segment into a reaction vessel, then adding benzoin dimethyl ether, and reacting under ultraviolet light; The BOC protected amino-containing polymer is dissolved by an organic solvent, HCl gas is introduced into the polymer, and then byproducts are removed and the polymer is dried in vacuum to obtain the BOC-removed polymer.
7. The method of claim 6, wherein the step of coupling STING agonist molecules to the amino functional groups via an amidation reaction to form the polycarbonate material adjuvant, specifically comprises: Adding acridone acetic acid, 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride, 1-hydroxybenzotriazole and N, N-diisopropylethylamine into a container, adding an organic solvent to dissolve the components, reacting under the protection atmosphere condition to obtain a reaction solution, then dissolving a BOC-free polymer into the organic solvent, adding the reaction solution, reacting under the protection atmosphere condition, removing the organic solvent and impurities, and freeze-drying to obtain the polycarbonate material adjuvant.
8. Use of a polycarbonate material adjuvant according to any one of claims 1-3 in the manufacture of a medicament for the prevention or treatment of a viral infection.
9. The use according to claim 8, wherein the virus is rabies virus.
10. A vaccine composition comprising an antigen, further comprising the polycarbonate material adjuvant of any one of claims 1-3, wherein the antigen is an inactivated rabies virus antigen.

Description

Polycarbonate material adjuvant and preparation method and application thereof Technical Field The invention relates to the technical field of biological medicine and immunotherapy, in particular to a polycarbonate material adjuvant and a preparation method and application thereof. Background Rabies is caused by rabies virus (RABV), which is still a serious threat to public health worldwide. Vaccination has so far remained the primary measure for preventing and controlling rabies. Although the existing rabies inactivated vaccine can provide effective protection, whether the rabies inactivated vaccine is used for pre-exposure prevention or post-exposure prevention, the rabies inactivated vaccine is usually subjected to multiple-dose inoculation according to a preset immunization program, so that higher time and economic burden are brought to a recipient, and the whole-course inoculation compliance is affected to a certain extent. In order to further improve the immunogenicity of the inactivated vaccine, an adjuvant is often introduced. Traditional aluminum salt adjuvants are effective in enhancing humoral immunity, but have certain limitations in inducing cellular immunity, particularly CD8 + T cell responses, and are difficult to meet the need for more comprehensive immune protection. Therefore, the development of novel adjuvants capable of targeting innate immune pathways, while simultaneously compromising humoral and cellular immunity, has become an important direction for vaccine optimization. The type I interferon (IFN-alpha/beta) is an important medium for antiviral natural immunity, can directly inhibit virus replication, promote dendritic cell maturation, enhance antigen presentation, drive Tfh to react with germinal centers, and finally promote the generation of neutralizing antibodies and CD8 + T cells, and is a key for connecting innate and adaptive immunity. The cGAS-STING pathway is a type I interferon-induced core hub, and when it passes through the perception of cytoplasmic DNA or cyclic dinucleotides (cGAMP), it activates TBK1 and IRF3, triggering a broad IFN-I signaling cascade, which in turn induces type I interferon production. In recent years, research shows that STING agonists or manganese salt adjuvants can enhance the neutralizing antibody level and memory immune response induced by rabies vaccine in animal models, but the method still has limitations in slow release property and safety, which leaves room for further improvement in the design and application of novel adjuvants. Small molecule STING agonists (e.g., non-nucleoside compounds) have been shown to enhance both humoral and cellular immunity of vaccines, and in addition, polymeric materials (e.g., PC 7A) themselves can induce sustained IFN- β production by interaction with STING and co-delivery with antigens to enhance CTL responses. However, these strategies either suffer from insufficient duration of activation or remain limited in delivery efficiency and safety. Cridanimod (also known as CMA, 10-carboymethyl-9-acridone) was originally developed as a low molecular weight interferon inducer belonging to class acridone. Recent mechanism studies have shown that CMA drives IFN-I synthesis primarily by binding to and activating the STING (stimulatorofinterferongenes) pathway, thereby recruiting TBK1 and activating IRF 3. This route of action provides the theoretical advantage of having antiviral and immunoadjuvant properties in that STING-mediated IFN-I not only directly inhibits viral replication, but also promotes dendritic cell maturation, enhances antigen presentation and T cell immunity. However, the small molecule nature of the vaccine brings the problems of short half-life, rapid systemic distribution, easy initiation of nonspecific inflammation and the like, and limits the application of the vaccine. Polycarbonate (polycarbonate, PC) is a degradable polymer synthesized by Ring Opening Polymerization (ROP) of cyclic carbonate monomer, and has good biocompatibility and safety due to controllable molecular weight and structure and no acidic side effect of degradation products. Aliphatic polycarbonates offer a milder degradation environment in sustained release drug delivery systems compared to polylactic acid (PLA) or polylactic-co-glycolic acid (PLGA), and thus are widely used in drug delivery, tissue engineering and vaccine adjuvant development. The active site of chain segment or side chain can be modified by click chemistry or amide bond, and the acid sensitivity, reduction sensitivity or ROS sensitivity and other stimulus response structures can be introduced to enhance the targeting and stability of delivery. In recent years, part of PC derivatives are used as inert carriers, can be proved to directly regulate and control immunity, and meanwhile, click chemistry functionalization is a general strategy for coupling small molecules or proteins, and polycarbonate-drug covalent coupling research also shows that environment