Selective ischemic-hemisphere targeting Ginkgolide B liposomes with improved solubility and therapeutic efficacy for cerebral ischemia-reperfusion injury  

作　　者：Yang Li Miaomiao Zhang Shiyi Li Longlong Zhang Jisu Kim Qiujun Qiu Weigen Lu Jianxin Wang 

机构地区：[1]Department of Pharmaceutics,School of Pharmacy,Fudan University&Key Laboratory of Smart Drug Delivery,Ministry of Education,Shanghai,201203,China [2]National Pharmaceutical Engineering and Research Center,China State Institute of Pharmaceutical Industry,Shanghai 201203,China

出　　处：《Asian Journal of Pharmaceutical Sciences》2023年第2期76-93,共18页亚洲药物制剂科学（英文）

基　　金：This research was funded by the National Natural Science Foundation of China(No.81773911,81690263 and 81573616);the Development Project of Shanghai Peak Disciplines-Integrated Medicine(No.20180101).

摘　　要：Cerebral ischemia-reperfusion injury(CI/RI)remains the main cause of disability and death in stroke patients due to lack of effective therapeutic strategies.One of the main issues related to CI/RI treatment is the presence of the blood-brain barrier(BBB),which affects the intracerebral delivery of drugs.Ginkgolide B(GB),a major bioactive component in commercially available products of Ginkgo biloba,has been shown significance in CI/RI treatment by regulating inflammatory pathways,oxidative damage,and metabolic disturbance,and seems to be a candidate for stroke recovery.However,limited by its poor hydrophilicity and lipophilicity,the development of GB preparations with good solubility,stability,and the ability to cross the BBB remains a challenge.Herein,we propose a combinatorial strategy by conjugating GB with highly lipophilic docosahexaenoic acid(DHA)to obtain a covalent complex GB-DHA,which can not only enhance the pharmacological effect of GB,but can also be encapsulated in liposomes stably.The amount of finally constructed Lipo@GB-DHA targeting to ischemic hemisphere was validated 2.2 times that of free solution in middle cerebral artery occlusion(MCAO)rats.Compared to the marketed ginkgolide injection,Lipo@GB-DHA significantly reduced infarct volume with better neurobehavioral recovery in MCAO rats after being intravenously administered both at 2 h and 6 h post-reperfusion.Low levels of reactive oxygen species(ROS)and high neuron survival in vitro was maintained via Lipo@GB-DHA treatment,while microglia in the ischemic brain were polarized from the pro-inflammatory M1 phenotype to the tissue-repairing M2 phenotype,which modulate neuroinflammatory and angiogenesis.In addition,Lipo@GB-DHA inhibited neuronal apoptosis via regulating the apoptotic pathway and maintained homeostasis by activating the autophagy pathway.Thus,transforming GB into a lipophilic complex and loading it into liposomes provides a promising nanomedicine strategy with excellent CI/RI therapeutic efficacy and industrialization prospects.

关 键 词：Ginkgolide B Cerebral ischemia reperfusion injury(CI/RI) Docosahexaenoic acid Liposomes Brain targeting MICROGLIA 

分 类 号：R743.3[医药卫生—神经病学与精神病学]