BioChem - DOS

Alleviating Recombinant Tissue Plasminogen Activator-induced Hemorrhagic Transformation in Ischemic Stroke via Targeted Delivery of a Ferroptosis Inhibitor

Advanced science

Geng, Yan‐ Qin; Qiu, Li‐ Na; Cheng, Yuan‐ Qiu; Li, Juan‐ Juan; Ma, Yi‐ Lin; Zhao, Cheng‐ Cheng; Cai, Ying; Zhang, Xue‐ Bin; Chen, Jieli; Pan, Yu‐ Chen; Wang, Ke‐ Rang; Yao, Xiu‐ Hua; Guo, Dong‐ Sheng; Wu, Jia‐ Ling

<P><B>Abstract</B><P>Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) is the primary treatment for ischemic stroke. However, rtPA treatment can substantially increase blood&#x2010;brain barrier (BBB) permeability and susceptibility to hemorrhagic transformation. Herein, the mechanism underlying the side effects of rtPA treatment is investigated and demonstrated that ferroptosis plays an important role. The ferroptosis inhibitor, liproxstatin&#x2010;1 (Lip) is proposed to alleviate the side effects. A well&#x2010;designed macrocyclic carrier, glucose&#x2010;modified azocalix[4]arene (GluAC4A), is prepared to deliver Lip to the ischemic site. GluAC4A bound tightly to Lip and markedly improved its solubility. Glucose, modified at the upper rim of GluAC4A, imparts BBB targeting to the drug delivery system owing to the presence of glucose transporter 1 on the BBB surface. The responsiveness of GluAC4A to hypoxia due to the presence of azo groups enabled the targeted release of Lip at the ischemic site. GluAC4A successfully improved drug accumulation in the brain, and Lip@GluAC4A significantly reduced ferroptosis, BBB leakage, and neurological deficits induced by rtPA in vivo. These findings deepen the understanding of the side effects of rtPA treatment and provide a novel strategy for their effective mitigation, which is of great significance for the treatment and prognosis of patients with ischemic stroke.</P></P>

2024

Wiley (John WileySons)

2198-3844

11

24

pp.2309517

10.1002/advs.202309517

http://click.ndsl.kr/servlet/OpenAPIDetailView?keyValue=05787966&target=NART&cn=NART130427291