A stepwise-targeting strategy for the treatment of cerebral ischemic stroke

• Published in: Journal of nanobiotechnology 2021-11, Vol.19 (1), p.371-371
• Main Authors: Hu, Jingbo, Tan, Xueying, Wang, Dongwei, Li, Yixuan, Liang, Hongze, Peng, Jiejun, Li, Fengyan, Zhou, Quan, Geng, Peiwu, Wang, Shuanghu, Yu, Yue, Liu, Jin
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Antioxidants; Antioxidants - chemistry; Antioxidants - pharmacology; Blood-brain barrier; Brain - drug effects; Brain damage; Brain Ischemia - metabolism; Care and treatment; Cell Line; Cerebral ischemic stroke; Diagnosis; Drug delivery systems; Drug Delivery Systems - methods; Drugs; Ethanol; Glutamic acid receptors; Hemodialysis; Identification and classification; Ischemia; Melatonin; Melatonin - chemistry; Melatonin - pharmacology; Membrane potential; Mice; Micelles; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - pharmacology; Oxidative stress; Oxidative Stress - drug effects; Peptides; Recovery of function; Risk factors; Stepwise-targeting delivery; Stroke; Stroke (Disease); Testing
• ISSN: 1477-3155; 1477-3155
• DOI: 10.1186/s12951-021-01118-6

Effective amelioration of neuronal damages in the case of cerebral ischemic stroke (CIS) is essential for the protection of brain tissues and their functional recovery. However, most drugs can not penetrate the blood-brain barrier (BBB), resulting in the poor therapeutic outcomes. In this study, the derivatization and dual targeted delivery technologies were used to actively transport antioxidant melatonin (MLT) into the mitochondria of oxidative stress-damaged cells in brain tissues. A mitochondrial targeting molecule triphenylphosphine (TPP) was conjugated to melatonin (TPP-MLT) to increase the distribution of melatonin in intracellular mitochondria with the push of mitochondrial transmembrane potential. Then, TPP-MLT was encapsulated in dual targeted micelles mediated by TGN peptide (TGNYKALHPHNG) with high affinity for BBB and SHp peptide (CLEVSRKNG) for the glutamate receptor of oxidative stress-damaged neural cells.TGN/SHp/TPP-MLT micelles could effectively scavenge the overproduced ROS to protect neuronal cells from oxidative stress injury during CIS occurrence, as reflected by the improved infarct volume and neurological deficit in CIS model animals. These promising results showed this stepwise-targeting drug-loaded micelles potentially represent a significant advancement in the precise treatment of CIS.