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通过靶向递送达泊酚抑制剂缓解缺血性脑卒中重组组织型纤溶酶原激活剂诱导的出血性转化。

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

机构信息

School of Medicine, Nankai University, Tianjin, 300071, China.

Tianjin Huanhu Hospital, Tianjin, 300350, China.

出版信息

Adv Sci (Weinh). 2024 Jun;11(24):e2309517. doi: 10.1002/advs.202309517. Epub 2024 Apr 22.

DOI:10.1002/advs.202309517
PMID:38647405
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11199968/
Abstract

Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) is the primary treatment for ischemic stroke. However, rtPA treatment can substantially increase blood-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-1 (Lip) is proposed to alleviate the side effects. A well-designed macrocyclic carrier, glucose-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.

摘要

静脉注射重组组织纤溶酶原激活剂（rtPA）是治疗缺血性脑卒中的主要方法。然而，rtPA 治疗会显著增加血脑屏障（BBB）的通透性，增加出血性转化的易感性。在此，研究了 rtPA 治疗副作用的机制，并证明铁死亡起着重要作用。铁死亡抑制剂 Liproxstatin-1（Lip）被提出用于减轻副作用。设计了一种大环载体，即葡萄糖修饰的偶氮杯[4]芳烃（GluAC4A），用于将 Lip 递送到缺血部位。GluAC4A 与 Lip 紧密结合，并显著提高了其溶解度。位于 GluAC4A 上边缘的葡萄糖修饰使其具有 BBB 靶向性，这是由于 BBB 表面存在葡萄糖转运蛋白 1。由于偶氮基团的存在，GluAC4A 对缺氧具有响应性，从而能够在缺血部位靶向释放 Lip。GluAC4A 成功地增加了药物在大脑中的积累，并且 Lip@GluAC4A 显著减少了 rtPA 体内诱导的铁死亡、BBB 渗漏和神经功能缺损。这些发现加深了对 rtPA 治疗副作用的理解，并为其有效缓解提供了一种新策略，这对于缺血性脑卒中患者的治疗和预后具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/3a98db83fb07/ADVS-11-2309517-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/370c57e649c4/ADVS-11-2309517-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/7e77d9dfcd2a/ADVS-11-2309517-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/d102f0d89448/ADVS-11-2309517-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/a3883711fb75/ADVS-11-2309517-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/2fe6ceb0dc21/ADVS-11-2309517-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/50a448d98987/ADVS-11-2309517-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/8494b302d99b/ADVS-11-2309517-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/3a98db83fb07/ADVS-11-2309517-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/370c57e649c4/ADVS-11-2309517-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/7e77d9dfcd2a/ADVS-11-2309517-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/d102f0d89448/ADVS-11-2309517-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/a3883711fb75/ADVS-11-2309517-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/2fe6ceb0dc21/ADVS-11-2309517-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/50a448d98987/ADVS-11-2309517-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/8494b302d99b/ADVS-11-2309517-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f37/11199968/3a98db83fb07/ADVS-11-2309517-g004.jpg

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