CN-122005450-A - Drug-loaded nano micelle and preparation method and application thereof

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a drug-loaded nano micelle and a preparation method and application thereof. The invention adopts a total synthesis method to introduce bromoalkanes with different chain lengths on leonurine phenolic hydroxyl groups to prepare leonurine derivatives, and prepares drug-loaded nano-micelles by using Triptolide (TP) and leonurine derivatives. The embodiment of the invention verifies that the drug-loaded nano-micelle can reduce in-vivo and in-vitro toxicity caused by triptolide and improve the treatment effect on a type II collagen-induced mouse arthritis model. The novel triptolide compatible medicine prepared by the invention has small toxic and side effects and good curative effect on rheumatoid arthritis.

Inventors

• WANG CAN
• LI MENGFEI
• LIU YALIN
• ZHANG TINGTING
• ZHU XIN
• WU XIANGXIANG
• ZENG HUAHUI

Assignees

• 河南中医药大学

Dates

Publication Date

20260512

Application Date

20260203

Claims (8)

1. 1. The drug-loaded nano micelle is characterized by being prepared by combining leonurine derivatives serving as carriers with triptolide.
2. 2. The drug-loaded nano-micelle according to claim 1, wherein the drug-loaded nano-micelle has a particle size of 153.72.91: 5.91 nm, a polymer dispersibility index of 0.22+ -0.11, an encapsulation efficiency of 50.18 + -0.47% and a drug loading of 20.07+ -0.19%.
3. 3. The drug-loaded nano-micelle according to claim 1, wherein the mass ratio of leonurine derivative to triptolide in the drug-loaded nano-micelle is 3:1.
4. 4. The drug-loaded nano micelle of claim 1, wherein the leonurine derivative has a lipid-water distribution coefficient of CLogP <6, and the leonurine derivative has a molecular structural formula shown in formula 1: Formula 1.
5. 5. The drug-loaded nano-micelle according to claim 4, wherein the synthesis process of the leonurine derivative is as follows: S1, carrying out esterification reaction on syringic acid by using anhydrous methanol and concentrated sulfuric acid to obtain a yellow solid compound; s2, 4-amino-1-butanol, methylene dichloride, N-bis (t-butoxycarbonyl) -1H-pyridine-1-formamidine and triethylamine undergo nucleophilic substitution reaction to obtain a white solid compound; s3, reacting the yellow solid compound in the step S1 with acetonitrile solvent, anhydrous potassium carbonate and bromododecane to obtain yellow oily liquid, and then reacting with anhydrous methanol and sodium hydroxide to obtain a white solid compound through chromatography; S4, mixing the white solid compound obtained in the step S3 with the white solid compound obtained in the step S2, methylene dichloride, N-diisopropylcarbodiimide and p-toluenesulfonic acid for reaction, obtaining a light yellow solid through column chromatography, adding methylene dichloride for complete dissolution, adding trifluoroacetic acid for reaction, detecting the disappearance of raw materials in a thin layer, stopping the reaction, concentrating under reduced pressure, and benefiting the parent grass alkali derivative through column chromatography.
6. 6. The method for preparing the drug-loaded nano-micelle of claim 1, which is characterized by comprising the steps of respectively dissolving leonurine derivatives and triptolide in absolute methanol to prepare 1 mmol/L leonurine derivatives and triptolide mother liquor, uniformly mixing the leonurine derivatives and the triptolide mother liquor, and removing the methanol by ultrasonic and reduced pressure rotary evaporation to obtain the drug-loaded nano-micelle.
7. 7. The preparation method according to claim 6, wherein the leonurine derivative and the triptolide mother solution are mixed according to the mass ratio of the leonurine derivative to the triptolide being 3:1.
8. 8. The use of the drug-loaded nano-micelle according to any one of claims 1 to 4 or the drug-loaded nano-micelle prepared by the preparation method according to claim 6 in the preparation of rheumatoid arthritis drugs.

Description

Drug-loaded nano micelle and preparation method and application thereof Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to a drug-loaded nano micelle and a preparation method and application thereof. Background Rheumatoid arthritis (Rheumatoid arthritis, RA) is a systemic autoimmune disease with a global incidence of about 0.4% to 1.3% and the most obvious clinical manifestations are synovial joint hyperplasia, joint inflammation, cartilage erosion and bone destruction. With increasing time of onset, rheumatoid arthritis can cause irreversible damage to the patient's articular cartilage, bone and other adjacent tissues, which can ultimately lead to serious joint deformities and even disability if no medication is given. At present, the treatment of the rheumatoid arthritis mainly comprises drug treatment, surgical treatment, psychological rehabilitation treatment and the like in clinic. The main purpose of the rheumatoid arthritis treatment is to reduce the joint inflammatory reaction, simultaneously slow down the lesion development and reduce the damage to irreversible bone, protect knee joints and muscles as much as possible, and finally relieve the illness state of patients or reduce the disability rate of patients. The anti-inflammatory drugs commonly used in clinic are mainly divided into four categories, namely non-steroidal drugs, glucocorticoids, biological agents and antirheumatic drugs. However, as an autoimmune disease, rheumatoid arthritis has strong drug resistance, and most of clinically conventional drugs cannot fundamentally cure the rheumatoid arthritis, and only play roles in delaying the symptom manifestation of the rheumatoid arthritis and preventing the further worsening and development of the disease. In China, traditional Chinese medicines have been widely used as substitutes for conventional anti-inflammatory medicines for many years after the continuous accumulation for thousands of years. Clinically, the traditional Chinese medicines of tripterygium wilfordii, total glucosides of paeony and sinomenine have been used for treating rheumatoid arthritis, and most of the medicines have good curative effects in treating the rheumatoid arthritis. However, the traditional Chinese medicine contains a large amount of ineffective components, which may cause serious toxic and side effects. Therefore, when the traditional Chinese medicine is used for treating diseases, the actions of the components must be further clarified so as to improve the curative effect of the traditional Chinese medicine. Tripterygium Wilfordii (TWHF), which is a plant of Tripterygium genus of Celastraceae family, is also named Huang Tengmu, fibrauretine root, gelsemium elegans, etc., and is widely distributed in regions of the Yangtze river in the south and in the southwest. The main medicinal part is xylem, and has the effects of dispelling pathogenic wind, removing dampness, promoting blood circulation, removing obstruction in collaterals, relieving swelling, relieving pain, killing parasites and removing toxic substances. Triptolide (TP) is an epoxy diterpenoid compound extracted from dry roots of Tripterygium wilfordii, also called triptolide, and is one of main active ingredients of Tripterygium wilfordii. It has anti-inflammatory, immunoregulatory, and antitumor activities and pharmacological effects. In recent years, with intensive research, triptolide has been found to be useful in the treatment of autoimmune diseases such as rheumatoid arthritis. Although triptolide has better medicinal effects in the aspect of clinically treating rheumatoid arthritis, the triptolide has higher toxicity, and can cause higher hepatorenal and reproductive toxicity to patients during treatment, which limits a great amount of clinical application of triptolide. More and more researches show that triptolide mainly has serious toxic and side effects on the digestive system, the urinary system, the reproductive system, the circulatory system and the immune system of an organism. The traditional Chinese medicine composition can cause adverse reactions of gastrointestinal tracts after long-term administration, clinically presents inappetence, abdominal pain and diarrhea, clinically presents symptoms such as hepatomegaly, hematuria, proteinuria and the like in terms of liver and kidney functions, simultaneously presents symptoms such as liver cell arrangement disorder, tubular shrinkage and the like in pathology, reduces the number and activity of male sperms in terms of reproductive toxicity, and generally leads to side effects such as fertility decline, immune dysfunction and the like. Therefore, development of a novel triptolide compatible medicine with small toxic and side effects and good curative effect is needed. Disclosure of Invention The invention aims to provide a drug-loaded nano micelle, a preparation method and application thereof, the drug-loaded nano micelle