CN-121987827-A - Brain targeting and electrical stimulation responsive nano system and preparation method and application thereof

Abstract

The invention is suitable for the technical field of biological medicine, and provides a brain targeting and electrical stimulation responsive nano system and a preparation method and application thereof. Aiming at the defects of low delivery efficiency and lack of space-time controllability of the existing therapeutic drugs, the invention constructs a brain targeting and electrical stimulation responsive nano system which can target and penetrate through BBB, enrich epileptic lesions, remarkably improve the bioavailability of the drugs in the brain, reduce the nonspecific distribution of peripheral organs and the systemic toxic and side effects, simultaneously release nano materials in an electrical response way, realize the controllable treatment of epileptic lesions, effectively relieve the oxidative stress and the neuroinflammation at the lesions, play a neuroprotective role and have good clinical transformation prospect.

Inventors

• MENG HONGMEI
• JIANG TING

Assignees

• 吉林大学第一医院

Dates

Publication Date

20260508

Application Date

20260409

Claims (6)

1. 1. The preparation method of the brain targeting and electrical stimulation responsive nano system is characterized by comprising the following steps of: (1) Dissolving polyvinyl alcohol in deionized water, adding hydrochloric acid to adjust the pH value of a system, slowly dripping pyrrole monomers and dopamine under magnetic stirring, adding CeO 2 aqueous dispersion liquid after uniform mixing to obtain mixed liquid, then dissolving ammonium persulfate in the deionized water, quickly dripping the ammonium persulfate into the mixed liquid under stirring, quickly converting a reaction system into black, severely stirring at room temperature for reaction under dark condition, centrifuging and washing the product at high speed after the reaction is finished, and collecting precipitate to obtain black product PPY/PDA-CeO 2 composite nanoparticles; (2) Surface PEGylation modification, namely re-suspending the PPY/PDA-CeO 2 composite nanoparticles in deionized water, adding Mal-PEG 2000 -NH 2 under continuous stirring, stirring at room temperature in a dark place for reaction, centrifuging and washing the product to obtain a PEGylated PPY/PDA-CeO 2 nanoparticle intermediate; (3) And (3) coupling a brain targeting ligand ANG, namely dispersing PEGylated PPY/PDA-CeO 2 nano particles in deionized water, adding the brain targeting peptide ANG, stirring at room temperature for reaction, centrifuging, washing and freeze-drying a product after the reaction is finished, and collecting the final product PPY/PDA-CeO 2 -ANG nano particles, wherein the sequence of the brain targeting peptide ANG is shown as SEQ ID NO. 1.
2. 2. The method for preparing a brain-targeted and electrically-stimulated-responsive nanosystem according to claim 1, wherein in the step (1), the concentration of the CeO 2 aqueous dispersion is 100 μg/μl; the volume-mass ratio of the pyrrole monomer, dopamine and CeO 2 aqueous dispersion is 67 mu L, 4mg and 50 mu L.
3. 3. The method of claim 1, wherein in step (2), the Mal-PEG 2000 -NH 2 is at a concentration of 4: 4 mg/mL.
4. 4. The method for preparing a brain targeting and electrostimulation responsive nanosystem as claimed in claim 1, wherein in step (3), the concentration of the brain targeting peptide ANG is 4mg/mL.
5. 5. A brain-targeting and electrostimulation-responsive nanosystem, characterized in that it is prepared by the preparation method according to any one of claims 1 to 4.
6. 6. Use of the brain-targeted and electrostimulation-responsive nanosystem of claim 5 in the preparation of a medicament for the treatment of epilepsy.

Description

Brain targeting and electrical stimulation responsive nano system and preparation method and application thereof Technical Field The invention belongs to the technical field of biological medicine, and particularly relates to a brain targeting and electrical stimulation responsive nano system and a preparation method and application thereof. Background Epilepsy is a chronic nervous system disease characterized by large-scale abnormal synchronous discharge of brain neurons, and the pathogenesis is complex and changeable. However, the existing treatment methods have significant technical bottlenecks that firstly, about 30% of patients show drug-refractory epilepsy and are insensitive to conventional drugs, secondly, the existing drugs lack targeting and need to be taken with high doses for a long time, so that systemic adverse reactions such as dizziness, cognitive function decline and liver and kidney injury are often caused, and furthermore, although surgical excision or neuromodulation can be used as supplementary therapy, the existing treatment methods are limited by high invasiveness, complication risks and strict indication ranges. Therefore, developing a new therapeutic strategy that can effectively cross the Blood Brain Barrier (BBB) and achieve precise delivery of lesions is a challenge in the art. On the pathological mechanism level, oxidative Stress (OS) has been shown to be a central factor driving epileptogenesis and chronicity, during which glutamate excitotoxicity and intracellular calcium overload lead to mitochondrial dysfunction, inducing explosive production of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS), and excessive ROS not only destroy neuronal membrane structures through lipid peroxidation, but also activate glial cell-mediated neuroinflammatory cascades leading to abnormal remodeling of neural networks, forming a malignant cycle of "epileptic seizure-oxidative stress-re-onset". Given the relative weakness of the endogenous antioxidant system of brain tissue and the difficulty in maintaining effective concentrations of conventional small molecule antioxidants at focal sites, it is highly desirable to construct an intervention system that targets the brain microenvironment and efficiently eliminates ROS to block the pathological processes described above. The existing antiepileptic drugs (such as carbamazepine, lamotrigine and other neurotransmitter modulators such as sodium valproate) can relieve symptoms to a certain extent, but the therapeutic efficacy is significantly limited by the pharmacokinetic properties. Most small molecular drugs are difficult to effectively penetrate the BBB, are easily identified by an external pump such as P-glycoprotein and the like which are highly expressed by cerebrovascular endothelial cells and actively discharged, so that the bioavailability of the drug in brain parenchyma is extremely low, in addition, in order to maintain the intracranial effective treatment concentration, the clinic is forced to adopt large-dose systemic administration, which leads to nonspecific accumulation of the drug in liver, kidney and blood systems and causes serious systemic toxic and side effects, and about 30 percent of patients are insensitive to the existing antiepileptic drugs and finally evolve into drug-refractory epilepsy. The conventional micromolecular antioxidant has the defects of poor water solubility, short half-life, low BBB permeability and the like, is difficult to maintain effective concentration at a focus part, the natural enzyme preparation is easy to inactivate or degrade in an in-vivo physiological environment, the biological stability is poor, and more importantly, the conventional antioxidant therapy depends on the passive diffusion or sustained release of medicines, cannot realize accurate clearance against the pathological microenvironment during epileptic seizure, and the intervention mode lacking space-time controllability possibly interferes with redox balance in normal neurophysiologic metabolism and has potential risks. Disclosure of Invention The embodiment of the invention aims to provide a preparation method of a brain targeting and electrical stimulation responsive nano system, which aims to solve the problems in the background technology. The embodiment of the invention is realized in such a way that the preparation method of the brain targeting and electrical stimulation responsive nano system comprises the following steps: (1) Dissolving polyvinyl alcohol in deionized water, adding hydrochloric acid to adjust the pH value of a system, slowly dripping pyrrole monomers and dopamine under magnetic stirring, adding CeO 2 aqueous dispersion liquid after uniform mixing to obtain mixed liquid, then dissolving ammonium persulfate in the deionized water, quickly dripping the ammonium persulfate into the mixed liquid under stirring, quickly converting a reaction system into black, severely stirring at room temperature for