Dual Targeting Nanoparticles For Epilepsy Therapy

Epilepsy is one of the most common neurological diseases.There are more than70 million people worldwide suffer from epilepsy.Antiepileptic drugs（AEDs）are the main means of epilepsy treatment.AEDs cure epilepsy via a variety of mechanisms,including blockading voltage-gated Na⁺channels and voltage-gated Ca²⁺channels,inhibiting GLU transmission,and enhancing GABA transmission.Although there are more than 25 AEDs,about one-third of epilepsy patients are resistant to existing drugs and cannot completely control seizures.The main cause of drug resistance is that most of the AEDs cannot pass through the blood-brain barrier（BBB）.Moreover,even if the drugs enter the brain,it is difficult to specifically target the neurons.In recent years,the use of nanocarriers to deliver drugs to improve the BBB-penetration efficiency of the drugs to treat brain diseases has been extensively studied and reported.LTG is a first line AEDs in clinics.However,it has low solubility in water and is easily metabolized in the liver.Thus,high doses or repeated administration are required to achieve therapeutic concentrations,which can cause side effects.Here,we design a kind of double targeting nanoparticles carrying lamotrigine（LTG）to cross the BBB and further concentrate at the epilepsy lesions.We prepare the nanoparticles on a microfluidic chip by encapsulating LTG in poly（lactic-co-glycolic acid）（PLGA）to form a core（PL）and further capping the core with a shell of lipids conjugated with D-T7 peptide（targets BBB）and Tet1peptide（targets neurons）to form D-T7/Tet1-lipids@PL nanoparticles.D-T7/Tet1-lipids@PL can effectively deliver LTG to the brain and enrich it around neurons,delay the onset of epilepsy and reduce the degree of epileptic seizures.In addition,D-T7/Tet1-lipids@PL shows low toxicity both in vivo and in vitro.Therefore,D-T7/Tet1-lipids@PL is an effective drug delivery system for treating drug-resistant epilepsy.In vitro and in vivo experiments show that the nanoparticles can significantly enhance the accumulation of LTG in the epilepsy lesions and effectively suppress the seizure.Our approach paves a way for optimizing the therapeutic effects of existing antiepileptic drugs.