Sci Adv｜Chen Zhong's team treats epilepsy with an electrically responsive co-targeted nano-drug delivery system

Editor-in-Chief | Epilepsy is a common neurological disease with a global incidence of about 0.
7%, of which there are more than 10 million epilepsy patients in China
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Epilepsy seizures originate from the abnormally hypersynchronized electrical activity of paroxysmal neurons in the brain.
When the hyperexcitability of epileptic foci cannot be completely suppressed, epileptiform discharges may spread to adjacent brain regions through dominant conduction neural circuits.
finally enter the attack period
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Therefore, how to limit the abnormal discharge of epileptic foci to local and timely inhibition is the key to prevent epileptic seizures
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Due to the uncertainty of the timing of seizures, most patients need to take antiepileptic drugs on a long-term and regular basis to achieve the purpose of preventive seizure control
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This will not only increase the long-term side effects of drugs, but also about 30% of epilepsy patients will develop resistance to anti-epileptic drugs and become refractory epilepsy (also known as drug-resistant epilepsy)
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Therefore, increasing the effective concentration of drugs in the epilepsy lesion area with the lowest drug dose and suppressing abnormal discharge in time are the two key factors to be overcome to improve the curative effect, which has also become one of the key scientific issues in drug treatment research in the field of epilepsy
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On January 13, 2022, the team of Professor Zhong Chen, President of Zhejiang University of Traditional Chinese Medicine, published a research paper titled Nanoengineered on-demand drug delivery system improves efficacy of pharmacotherapy for epilepsy online in the journal Science Advances
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This study uses multidisciplinary technology to design an electric field-sensitive nano-drug delivery system with combined brain targeting capability for the precise delivery of anti-epileptic drugs, aiming at the disease characteristics of abnormal brain discharge during epilepsy.
Provides a new strategy and idea
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In order to improve the above problems, the research group constructed a brain-targeting peptide-mediated electric field-sensitive nanohydrogel drug delivery system in the early stage, which not only greatly improved the ability of antiepileptic drugs to pass through the blood-brain barrier, but also used electric field-sensitive nanohydrogels to coagulate The principle that the glue can convert electrical energy into mechanical energy when stimulated by an electric field enables the drug to be rapidly released locally at the epilepsy focus (abnormal discharge area) to a therapeutic concentration, thereby inhibiting the abnormal discharge of neurons (Ying et al.
Angew Chem Int Edit, 2014; Wang et al.
, Neurotherapeutics, 2016)
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However, the sensitivity of the hydrogel drug delivery system to the drug release induced by electrical response needs to be further improved, and the hydrogel material itself has certain toxic effects
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Therefore, on the basis of the previous research, the research group continued to explore the efficient and low-toxic drug delivery system for the treatment of epilepsy
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In this study, pyrrole and dopamine were used as polymer monomer molecules, and phenytoin sodium was selected as an anti-epileptic model drug to prepare drug-loaded composite nanoparticles.
Signal-responsive combined brain-targeted antiepileptic drug delivery system to improve antiepileptic efficacy
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Through the optimization of a series of synthetic formulations and material characterization, it was found that the introduction of polydopamine is crucial for the performance improvement of the nano-drug delivery system
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When the content of polydopamine was 5%, the electrical conductivity and drug response sensitivity of the composite nanomaterials were significantly improved, and the electrical conductivity was increased to more than two orders of magnitude compared to the single polypyrrole material
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The results of drug release experiments show that the nano-drug delivery system can rapidly release antiepileptic drugs under current stimulation as low as 50 μA, and its response speed is as fast as 30 seconds, which meets the clinical discharge characteristics of epileptic seizures
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Importantly, under the condition of continuous "on-off-on" intermittent electrical stimulation, the drug delivery system achieves precise and synchronous drug response release, which also provides feasibility for controlling persistent epileptic seizures or recurrent epileptic seizures.
foundation
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At the same time, the obtained nano-drug delivery system has obvious absorption in the near-infrared light region, and realizes the reversible regulation of the permeability of the blood-brain barrier through the photothermal conversion of near-infrared light in the deep tissue; The combined brain-targeted delivery of drugs was achieved under the action
of
Subsequently, the study constructed three overall epilepsy models of acute, persistent and spontaneous.
Through a series of behavioral observations, pathological analysis, and EEG analysis studies, it was verified that the nano-drug delivery system can indeed reduce the level of epilepsy and prolong epilepsy.
The grand mal potential time and the intensity of epileptic seizures were reduced.
The experimental group could control epileptic seizures more effectively than the positive drug at the same dose (clinical routine subthreshold dose)
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Further, the study analyzed the changes of drug concentration in the brain through real-time microdialysis, and clarified the reason for the improvement of drug efficacy: the nano-drug delivery system can realize the targeted delivery of drugs to the brain, and automatically and quickly release anti-epileptic drugs in response to the electrical signal of epileptic seizures.

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It is worth noting that, after acute and chronic long-term administration tests, this study proposes that the nano-drug delivery system has no obvious toxic and side effects and has high biological safety
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To sum up, this study is based on the actual needs of existing antiepileptic drug treatment, based on the electrophysiological mechanism of epileptic seizures, combined with the multifunctional strategy of nano-drug delivery system, and used the advantages of combined targeting technology and material electrical response characteristics.
, developed an electrical-responsive combined targeted nano-drug delivery system for epilepsy, which provides a new solution and idea for epilepsy drug treatment
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Professor Chen Zhong's team has long been committed to the pathogenesis of epilepsy and other chronic encephalopathy and the discovery of drug targets.
The previous series of research results were published in Neuron, Nature Neuroscience, Nature Nanotechnology, Nature Communications, Biological Psychology, Annals of Neurology, Progress in Neurobiology, Chemical Internationally renowned journals such as Society Reviews, Signal Transduction and Targeted Therapy
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The first author of this paper is Dr.
Wu Di, associate researcher of Zhejiang University of Traditional Chinese Medicine, Fei Fan, a doctoral student of Zhejiang University, is the co-first author, and Professor Chen Zhong and researcher Wang Yi of Zhejiang University of Traditional Chinese Medicine are the co-corresponding authors of this paper
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The research was also supported and helped by experts such as Professor Fang Wenjun of Zhejiang University and Professor Xie Hujun of Zhejiang Technology and Business University
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A recent photo of Professor Chen Zhong's team Link to the original text: http://doi.
org/10.
1126/sciadv.
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.