CN-118846117-B - Metformin and CeO2Assembled ROS responsive hydrogel microneedle and application thereof in diabetes wound treatment

Abstract

The invention discloses a ROS response hydrogel microneedle assembled by metformin and CeO 2 and application thereof in diabetes wound treatment, and belongs to the technical field of biological medicines. According to the invention, the mesoporous silica nanoparticle is internally loaded with the metformin (Met) and simultaneously externally forms the cerium oxide (CeO 2 ) coating, so that the MSN@Met-CeO 2 composite nanoparticle is prepared, and is carried on the ROS responsive hydrogel microneedle patch, so that the medicine is delivered efficiently, the purpose of synchronously removing ROS in wound tissues endogenously and exogenously is achieved, and good healing of diabetic wounds is promoted.

Inventors

• LI MENGYANG
• HU DAHAI
• DONG YUHANG
• LIU XIAOXIA
• Shang Yage
• Yuan Yixuan

Assignees

• 中国人民解放军空军军医大学

Dates

Publication Date

20260508

Application Date

20240628

Claims (5)

1. 1. The ROS response type hydrogel microneedle containing MSN@Met-CeO 2 composite nano particles is characterized in that the MSN@Met-CeO 2 composite nano particles are of a core-shell structure, mesoporous silica loaded with metformin in a pore canal is used as an inner core, and cerium oxide loaded on the surface of the inner core is used as an outer shell; The mass ratio of the metformin to the cerium oxide is 1 (0.1-0.2); the mass ratio of the metformin to the mesoporous silica is 1 (3-5); the MSN@Met-CeO 2 composite nano-particle has a spherical shape and a size of 60-80 nm.
2. 2. The method of preparing ROS-responsive hydrogel microneedles of claim 1, comprising the steps of: (1) Dispersing mesoporous silica nano particles in water, adding a metformin solution under stirring, stirring for reacting for 12-36 hours at 200-600 r/min, and then carrying out ultrafiltration washing on the product by using a 100kd ultrafiltration tube to remove unsupported metformin to obtain MSN@Met; (2) Dispersing the MSN@Met prepared in the step (1) in ethanol, adding Ce (NO 3 ) 3 •6H 2 O and hexamethyldinaphthylamine, stirring for 2-4 h, refluxing for 3-5 h at 70-80 ℃, centrifuging, and washing the product to obtain MSN@Met-CeO 2 ; (3) Adding the MSN@Met-CeO 2 prepared in the step (2) into a mixed solution of PVA and PVP, uniformly mixing, adding a TSPBA cross-linking agent, uniformly mixing, pouring the mixed solution into a microneedle mould, carrying out vacuum treatment to fill the cavity of the microneedle small hole with the mixed solution, finally standing for 8-12h at room temperature, fully drying at 35-38 ℃, and demoulding.
3. 3. The method for preparing the ROS-responsive hydrogel microneedle according to claim 2, wherein the mesoporous silica nanoparticle in step (1) is dispersed in water according to a concentration of 0.5-2mg/ml, and the concentration of the metformin solution is 0.5-1.5 mg/ml.
4. 4. The method for preparing ROS-responsive hydrogel microneedles according to claim 2, wherein the msn@met in step (2) is dispersed in ethanol at a concentration of 60-150 mg/ml.
5. 5. The method for preparing ROS responsive hydrogel microneedles according to claim 2, wherein the concentration of PVA in the mixed solution of PVA and PVP in step (2) is 10-15 wt%, and the concentration of PVP is 7-10 wt%.

Description

ROS-responsive hydrogel microneedle assembled by metformin and CeO 2 and application of ROS-responsive hydrogel microneedle in diabetes wound surface treatment Technical Field The invention belongs to the technical field of biological medicine, and particularly relates to a ROS response type hydrogel microneedle assembled by metformin and CeO 2 and application thereof in diabetes wound surface treatment. Background Diabetes is a chronic metabolic disease of complex etiology, and absolute or relative insulin deficiency causes an increase in blood glucose in a patient. Diabetes affects millions of people worldwide, and prevalence rises rapidly over the past three decades. It is estimated that this trend will also continue and it is expected that the prevalence will increase from the current 5.1% to 7.7% at 2030. For individuals with diabetes, particularly those with unhealed ulcer wounds, is a common complication that can lead to hospitalization or even amputation of the patient. The wound surface of diabetics generally appears in lower limbs, is difficult to heal and has poor prognosis. The mechanism of difficult healing is related to hyperglycemia, neuropathy, microvascular complications, chronic inflammation, low immunity and the like. The method for treating the diabetic wound surface is numerous, the external treatment is mainly used in traditional Chinese medicine treatment, the fumigation and washing of the medicine, the external application, the silver ion introduction and the like are mainly used in Western medicine treatment, and besides the conventional treatment, HIF-PHD inhibitor, dressing, platelet-RICH PLASMA (PRP), negative pressure wound surface treatment, hyperbaric oxygen and the like are also used in Western medicine treatment. Current methods of treatment, including wound cleansing, dressing application, revascularization and adjuvant therapies (such as negative pressure wound therapy and oxygen therapy), often have difficulty meeting the multi-dimensional requirements required for effective healing of diabetic ulcers. Studies have shown that overproduction of ROS severely impedes wound healing, as it can trigger apoptosis and exacerbate oxidative stress damage. Therefore, efficient removal of ROS within a wound is an essential key step in restoring wound microenvironment homeostasis and achieving successful healing. Recently, hydrogels based on metal Nanoparticles (NPs) have been developed as potential wound dressings. However, most metal NP-based hydrogels are primarily focused on extracellular antioxidant activity, while endogenous ROS balance restoration is neglected, and thus such hydrogels have limited application in the treatment of diabetic wounds. To overcome these limitations, researchers have attempted to modify NPs with various biological macromolecules or compounds, but such modified metal NPs still have not been shown to have desirable effects in the treatment of diabetic wounds due to the lack of good biocompatibility or exposure to low oxygen microenvironments. In addition, diabetic wounds often affect drug delivery and absorption by forming a physical-chemical barrier from infected and necrotic tissue, and thus common treatment modalities are not effective. Disclosure of Invention In view of the defects of the prior art, the inventor designs a novel wound dressing, can solve the problem of synergetically removing the internal and external active oxygen by the wound tissue, realizes high-efficiency drug delivery, and promotes good healing of the diabetic wound. In order to achieve the technical purpose, the inventor considers that a large amount of ROS generated by the microenvironment of the wound surface is one of important factors affecting the healing of the wound surface. ROS, including hydrogen peroxide (H 2O2), superoxide anions (O 2·-), and hydroxyl radicals (-OH), are byproducts of intracellular oxidation reactions. Under physiological conditions, ROS play an important role in maintaining the conduction of multiple signal paths in cells, under infection conditions, ROS can play an antibacterial role by directly destroying the biological macromolecular structure, and excessive ROS can cause the increase of the permeability of mitochondrial double-layer membranes so as to trigger apoptosis. In the wound repair process, there is a great deal of evidence that excessive ROS in wound tissue is a critical factor that causes delayed or incomplete healing of the wound. Mitochondria are the main source of intracellular ROS production, and previous researches show that under the condition of high-sugar hypoxia, the metformin can relieve the intracellular mitochondrial stress, reduce mitochondrial division and further reduce mitochondrial ROS production. However, metformin alone does not reduce the production of ROS by tissue cells, which may be caused by the adverse effect of metformin on the acidic environment in wound tissue. Because of the unique out-of-core electron arra