{"title":"超声波联合血脑屏障靶向脑部递送四合一分子聚合体,通过异丙酚-哌替啶协同抑制GABA受体提高麻醉效果并降低毒性","authors":"Shuo Zhang, Yishu Wang, Mingting Zhu, Bingyang Liu, Wenpu Zhao, Shuai Zhang, Ji Xia, Lei Shi, Peng Tang, Feiqian Wang, Siyuan Zhang, Mingxi Wan, Daocheng Wu, Wei Gao","doi":"10.1002/agt2.573","DOIUrl":null,"url":null,"abstract":"<p>To enhance the anesthetic efficacy and reduce toxic side effects, a strategy is proposed involving the utilization of general anesthetics of Propofol (Pro) and Etomidate (Eto) to synergistic inhibition GABA receptors simultaneously. Four-in-one molecular aggregates were prepared to implement this strategy, which comprised of Pro and Eto with the bridging molecule monoglyceride monooleate (GMO) and surfactant F127 through intermolecular forces. The blood-brain barrier (BBB) targeted lactoferrin (LF) is affixed to their surface, obtaining the final molecular aggregates. By employing lactoferrin enrich aggregates to the BBB, followed by ultrasound combine microbubbles to open the BBB, a remarkable 4.5-fold enhancement in brain drug delivery was achieved. The molecular aggregates group maintained stable parameters of heart rate, diastolic blood pressure, and systolic blood pressure. A notable increase of more than twice therapeutic index (TI) value was observed, implying their higher anesthesia efficiency and reduced toxicity. Electroencephalogram (EEG) experiments demonstrate a significant elevation in the proportion of δ waves from 28% to 80% for aggregates, accompanied by a nearly fivefold reduction in the proportion of <i>θ</i> waves, meaning a significant improvement in synergistic anesthesia effectiveness (interaction index 0.289) with lower drug dosage. Furthermore, mouse immunofluorescence brain slice experiments suggest Pro and Eto enter the GABA receptor simultaneously, resulting in synergistic inhibition of GABA receptors.</p>","PeriodicalId":72127,"journal":{"name":"Aggregate (Hoboken, N.J.)","volume":null,"pages":null},"PeriodicalIF":13.9000,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/agt2.573","citationCount":"0","resultStr":"{\"title\":\"Ultrasound combined blood-brain barrier targeting brain delivery of four-in-one molecular aggregates for the enhancement of anesthetic efficacy and toxicity reduction via propofol-etomidate synergistically inhibition GABA receptor\",\"authors\":\"Shuo Zhang, Yishu Wang, Mingting Zhu, Bingyang Liu, Wenpu Zhao, Shuai Zhang, Ji Xia, Lei Shi, Peng Tang, Feiqian Wang, Siyuan Zhang, Mingxi Wan, Daocheng Wu, Wei Gao\",\"doi\":\"10.1002/agt2.573\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>To enhance the anesthetic efficacy and reduce toxic side effects, a strategy is proposed involving the utilization of general anesthetics of Propofol (Pro) and Etomidate (Eto) to synergistic inhibition GABA receptors simultaneously. Four-in-one molecular aggregates were prepared to implement this strategy, which comprised of Pro and Eto with the bridging molecule monoglyceride monooleate (GMO) and surfactant F127 through intermolecular forces. The blood-brain barrier (BBB) targeted lactoferrin (LF) is affixed to their surface, obtaining the final molecular aggregates. By employing lactoferrin enrich aggregates to the BBB, followed by ultrasound combine microbubbles to open the BBB, a remarkable 4.5-fold enhancement in brain drug delivery was achieved. The molecular aggregates group maintained stable parameters of heart rate, diastolic blood pressure, and systolic blood pressure. A notable increase of more than twice therapeutic index (TI) value was observed, implying their higher anesthesia efficiency and reduced toxicity. Electroencephalogram (EEG) experiments demonstrate a significant elevation in the proportion of δ waves from 28% to 80% for aggregates, accompanied by a nearly fivefold reduction in the proportion of <i>θ</i> waves, meaning a significant improvement in synergistic anesthesia effectiveness (interaction index 0.289) with lower drug dosage. Furthermore, mouse immunofluorescence brain slice experiments suggest Pro and Eto enter the GABA receptor simultaneously, resulting in synergistic inhibition of GABA receptors.</p>\",\"PeriodicalId\":72127,\"journal\":{\"name\":\"Aggregate (Hoboken, N.J.)\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":13.9000,\"publicationDate\":\"2024-04-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/agt2.573\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Aggregate (Hoboken, N.J.)\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/agt2.573\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Aggregate (Hoboken, N.J.)","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/agt2.573","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
摘要
为了提高麻醉效果并减少毒副作用,我们提出了一种策略,即利用丙泊酚(Pro)和依托咪酯(Eto)这两种全身麻醉剂同时协同抑制 GABA 受体。为实施这一策略,制备了四合一分子聚合体,由 Pro 和 Eto 与桥接分子单油酸甘油酯(GMO)和表面活性剂 F127 通过分子间作用力组成。血脑屏障(BBB)靶向乳铁蛋白(LF)被粘附在它们的表面,从而得到最终的分子聚合体。将乳铁蛋白富集到 BBB 上,然后用超声波结合微气泡打开 BBB,脑部药物输送显著提高了 4.5 倍。分子聚合体组保持了稳定的心率、舒张压和收缩压参数。治疗指数(TI)值显著增加了两倍多,这意味着它们的麻醉效率更高,毒性更低。脑电图(EEG)实验表明,聚合体的δ波比例从 28% 显著升高到 80%,同时θ波比例降低了近五倍,这意味着随着药物剂量的降低,协同麻醉效果显著提高(交互作用指数为 0.289)。此外,小鼠免疫荧光脑片实验表明,Pro 和 Eto 同时进入 GABA 受体,从而对 GABA 受体产生协同抑制作用。
Ultrasound combined blood-brain barrier targeting brain delivery of four-in-one molecular aggregates for the enhancement of anesthetic efficacy and toxicity reduction via propofol-etomidate synergistically inhibition GABA receptor
To enhance the anesthetic efficacy and reduce toxic side effects, a strategy is proposed involving the utilization of general anesthetics of Propofol (Pro) and Etomidate (Eto) to synergistic inhibition GABA receptors simultaneously. Four-in-one molecular aggregates were prepared to implement this strategy, which comprised of Pro and Eto with the bridging molecule monoglyceride monooleate (GMO) and surfactant F127 through intermolecular forces. The blood-brain barrier (BBB) targeted lactoferrin (LF) is affixed to their surface, obtaining the final molecular aggregates. By employing lactoferrin enrich aggregates to the BBB, followed by ultrasound combine microbubbles to open the BBB, a remarkable 4.5-fold enhancement in brain drug delivery was achieved. The molecular aggregates group maintained stable parameters of heart rate, diastolic blood pressure, and systolic blood pressure. A notable increase of more than twice therapeutic index (TI) value was observed, implying their higher anesthesia efficiency and reduced toxicity. Electroencephalogram (EEG) experiments demonstrate a significant elevation in the proportion of δ waves from 28% to 80% for aggregates, accompanied by a nearly fivefold reduction in the proportion of θ waves, meaning a significant improvement in synergistic anesthesia effectiveness (interaction index 0.289) with lower drug dosage. Furthermore, mouse immunofluorescence brain slice experiments suggest Pro and Eto enter the GABA receptor simultaneously, resulting in synergistic inhibition of GABA receptors.