CN-121975121-A - Nanocomposite with function of scavenging active oxygen to restore HMGB1 stimulation activity, and preparation method and application thereof

Abstract

The invention provides a nano-composite with the function of removing active oxygen to recover the stimulation activity of HMGB1, a preparation method and application thereof, which can recover the stimulation activity of high mobility protein 1 (HMGB 1) by removing excessive active oxygen after cold-hot composite ablation operation, maintain the function of T cells and promote the smooth progression of immune death of tumor cells, and is prepared by a nano coprecipitation method by coating immune adjuvant with drug-carrying molecules R 1 P or R 1 PR 2 , wherein the drug-carrying molecules R 1 PR 2 have fluorescence imaging function. The invention provides a method for preparing the drug-carrying molecule and the nano drug-carrying platform and application thereof in tumor treatment. The thioether-containing group in the drug-carrying molecule can relieve the micro-environment oxidative stress environment, and can change the configuration at fixed points in the presence of active oxygen, so that the drug-carrying molecule has the active oxygen response capability.

Inventors

• FANG ZHUTING
• YANG ZHEN
• ZHANG SHAN
• HUANG YUHAN

Assignees

• 福建省肿瘤医院（福建省肿瘤研究所、福建省癌症防治中心）

Dates

Publication Date

20260505

Application Date

20260122

Claims (9)

1. 1. A drug-carrying molecule compound characterized by the structure R 1 P: ; wherein n is a natural number less than or equal to 5-60, R 1 is a hydrophilic group, and specifically any one of the following structures: 。
2. 2. A compound of a drug-carrying molecule with imaging function, which is prepared by capping R 1 P with a fluorescent group R 2 -Cl in the presence of a catalyst, and has the following structure R 1 PR 2 : ; Wherein R 2 is a group with a fluorescence imaging function, specifically any one of the following structures: 。
3. 3. A nanocomposite having the function of scavenging active oxygen to restore the stimulatory activity of HMGB1, characterized in that it is prepared by a nano co-precipitation method using the drug-carrying molecule of claim 1 or 2 and a fat-soluble immunoadjuvant.
4. 4. A method for the preparation of a compound carrying a drug molecule according to claim 1 or 2, comprising the steps of: Propylene sulfide is polymerized in the presence of hydrophilic initiator molecules R 1 -SH and a catalyst to generate drug-carrying molecules R 1 P: Drug-loaded molecule R 1 PR 2 is prepared by capping R 1 P with a fluorophore R 2 -Cl in the presence of a catalyst.
5. 5. The preparation method according to claim 4, comprising the following steps: 1) Stirring hydrophilic initiator molecules R 1 -SH and 1, 8-diazabicyclo [5.4.0] undec-7-ene DBU for reaction for 1 hour in a nitrogen atmosphere, dissolving propylene sulfide in tetrahydrofuran, dripping in the tetrahydrofuran, stirring for three times, and settling with diethyl ether to obtain a product R 1 P; 2) Stirring R 1 P and DBU for reaction for 1 hour under nitrogen atmosphere, dissolving the fluorescent group R 2 -Cl in N, N-dimethylformamide, then dripping in, stirring overnight, and settling with diethyl ether for three times to obtain the product R 1 PR 2 .
6. 6. The method of claim 5, wherein the molar ratio of the hydrophilic initiator molecules R 1 -SH to DBU used in step 1) is 1:2-1:4, and the molar ratio of the hydrophilic initiator molecules R 1 -SH to the propylene sulfide is 1:50-1:150.
7. 7. The method of claim 5, wherein the molar ratio of R 1 P to DBU used in step 2) is 1:2 to 1:4, and the molar ratio of R 1 P to the fluorophore R 2 -Cl is 1:0.5 to 1:1.5.
8. 8. The method for preparing the nanocomposite according to claim 3, wherein the method comprises dissolving the drug-carrying molecule according to claim 1 or 2 and the fat-soluble immunoadjuvant in an organic solvent, performing ultrasonic dissolution, and then dripping the obtained solution into a mixed solution of the organic solvent and deionized water in a volume ratio of 1:8-10, stirring for 0.5-2 h, and then performing dialysis for 3 days.
9. 9. Use of a drug-carrying molecule according to claim 1 or 2 or a nanocomposite according to claim 3 for the preparation of an anti-tumor drug.

Description

Nanocomposite with function of scavenging active oxygen to restore HMGB1 stimulation activity, and preparation method and application thereof Technical Field The invention belongs to the technical field of organic materials, and particularly relates to a self-assembled nano-composite which is based on poly (propylene sulfide) (PPS) and has the functions of scavenging active oxygen (Reactive Oxygen Species, ROS) and recovering the stimulation activity of high mobility protein 1 (HMGB 1) and near infrared two-region fluorescence monitoring, a preparation method thereof and application of the self-assembled nano-composite as an auxiliary cold-hot composite ablation diagnosis and treatment platform and a multifunctional nano-drug carrying platform. Background The cold-hot combined ablation technology (Cryo-thermal ablation or Cryo-radio frequency/Cryo-microwave combination therapy) is an emerging cross direction in the field of local treatment of tumors, combines the advantages of cryoablation and thermal ablation, and is used for realizing more thorough and immune-friendly tumor removal. In recent years, the technology has the core of realizing triple clinical goals of thorough ablation, immune activation and minimally invasive treatment by utilizing the superposition effect of cold and heat stress, and is increasingly paid attention to the clinical treatment of solid tumors. 1) the technology firstly dehydrates tumor cells through freezing (the lowest temperature can reach-196 ℃) and simultaneously forms ice crystals which can cause cell membrane rupture to lead the cells to generate irreversible physical damage, 2) the technology further coagulates necrotic residual cells through heating (the highest temperature can reach 80 ℃), 3) causes multiple damages of cell mechanical property, permeability and metabolism through cold-heat multiple circulation, and 4) simultaneously promotes Immunogenic Cell Death (ICD) and immune activation through cold-heat stress. Whereas ICDs are a specific cell death pattern in which cells can elicit an immune response in the body during death, they are of interest in tumor therapy. The large data indicate that modest ROS production (e.g., due to photodynamic therapy, chemotherapy, or radiation therapy) can induce ICD production, promote tumor cell release loss-associated molecular patterns (DAMPs), such as high mobility protein 1HMGB1, calreticulin (CRT), adenosine Triphosphate (ATP), and thereby activate Dendritic Cells (DCs) and T cell immune responses. However, the rapid temperature fluctuation in the cold-hot composite ablation technology can destroy the steady state of mitochondria and endoplasmic reticulum, so that electron leakage, calcium overload and oxidase activation are caused, when the temperature is restored to a sublevel, the electron leakage is carried out to oxygen to form O 2- (superoxide anion), and then various ROS such as H 2O2, OH and the like are generated. These excessive ROS present in the Tumor Microenvironment (TME) are involved in both tumor cell death and promotion of immune activation by inducing ICD, one of the core biochemical mechanisms of anti-tumor effects of cold-heat complex therapies. However, a large amount of data suggests that under certain conditions, excessive ROS in the microenvironment may also trigger DNA mutations that may disrupt the correct release of these DAMPs signaling molecules, resulting in loss of immunogenicity or induction of non-immune necrotic cell death, promoting tumorigenesis. Thus, strategies to maintain the activity of DAMPs molecules, prolong the survival of T cells, and restore immune function by alleviating the oxidative stress environment in TMEs are urgently needed. The nanomaterial has the advantages of high reactivity, high targeting, multifunction, controllability and the like by virtue of unique size effect, surface effect and designability, and has great clinical transformation potential in the fields of drug delivery, imaging diagnosis and treatment, immune regulation, comprehensive treatment and the like. By designing the visual nano delivery material for relieving the oxidative stress environment, the cold-heat composite ablation technology can be well assisted to perform high-efficiency tumor treatment. A great deal of work has reported that "polythioethers" or "sulfides (thioether, R-S-R')" polymers PPS, such polymers having thioether linkages (-S-) in the main or side chains, can eliminate ROS. PPS may be oxidized to a sulfur oxidation state (e.g., R-S (=o) -R '(sulfoxide) →r-S (=o) 2 -R' (sulfone)) by an oxidizing agent (e.g., ROS such as H 2O2、·OH、·O2-). The polymer chain configuration is changed from a hydrophobic state to a hydrophilic state, so that drug delivery release or material degradation is triggered, and the crosslinking density is changed. This allows the material to "scavenge" and "respond" to ROS to release therapeutic agents. The ideal nanocarrier also needs to track its specific dis