Selective brain entry of lipid nanoparticles in haemorrhagic stroke is linked to biphasic blood-brain barrier disruption.
Selective brain entry of lipid nanoparticles in haemorrhagic stroke is linked to biphasic blood-brain barrier disruption.
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在出血性中风中，脂质纳米颗粒对大脑的选择性进入与血脑屏障的双相破坏有关。
DOI：
10.7150/thno.72167
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Allan, Stuart M.
中科院分区：
文献类型：
--
作者：
Al-Ahmady, Zahraa S.;Dickie, Ben R.;Aldred, Isabelle;Jasim, Dhifaf A.;Barrington, Jack;Haley, Michael;Lemarchand, Eloise;Coutts, Graham;Kaur, Satinderdeep;Bates, Jessica;Curran, Sarah;Goddard, Ruth;Walker, Megan;Parry-jones, Adrian;Kostarelos, Kostas;Allan, Stuart M.
出血性中风是一个重大的公共卫生负担，但我们的知识和能力，以治疗这种类型的中风是缺乏的。以前我们表明，我们可以通过选择性移位脂质纳米颗粒通过血脑屏障（BBB）破坏的网站，以靶向缺血性中风病变。我们在本研究中提供的数据提供了令人信服的证据，即小鼠出血性中风诱导BBB损伤，其模拟人类病理学的关键特征，更重要的是，为基于脂质纳米颗粒的治疗剂选择性地进入出血部位提供了一个大门。方法：采用胶原酶诱导小鼠出血性脑卒中模型。在出血性中风后3小时、24小时和48小时静脉内注射脂质纳米颗粒，并使用体内光学成像和组织学研究其在脑中的积累。BBB完整性，脑含水量和铁积累的特点是使用动态对比增强MRI，定量T1映射，和梯度回波MRI。结果如下：使用体内SPECT/CT成像和光学成像显示双相脂质纳米颗粒进入出血部位，在出血性卒中后3-24 h出现早期摄取增加，随后在48-72 h出现第二阶段。脂质纳米颗粒在出血后进入脑显示出与Gd-DOTA的跨BBB渗漏率（Ktranss [min-1]）相同的进入模式，Gd-DOTA是BBB破坏的生物标志物，使用动态对比增强MRI测量。讨论内容：我们的研究结果表明，脂质体选择性地积聚到病变部位与BBB高渗透性的双相模式有关。这种方法提供了一种独特的机会来选择性地和有效地递送治疗性分子穿过BBB，这种方法尚未用于出血性中风治疗，并且使用游离的小药物分子无法实现。
Haemorrhagic stroke represents a significant public health burden, yet our knowledge and ability to treat this type of stroke are lacking. Previously we showed that we can target ischaemic-stroke lesions by selective translocation of lipid nanoparticles through the site of blood-brain barrier (BBB) disruption. The data we presented in this study provide compelling evidence that haemorrhagic stroke in mice induces BBB injury that mimics key features of the human pathology and, more importantly, provides a gate for entry of lipid nanoparticles-based therapeutics selectively to the bleeding site. Methods: Haemorrhagic stroke was induced in mice by intra-striatal collagenase injection. lipid nanoparticles were injected intravenously at 3 h, 24 h & 48 h post-haemorrhagic stroke and accumulation in the brain studied using in-vivo optical imaging and histology. BBB integrity, brain water content and iron accumulation were characterised using dynamic contrast-enhanced MRI, quantitative T1 mapping, and gradient echo MRI. Results: Using in-vivo SPECT/CT imaging and optical imaging revealed biphasic lipid nanoparticles entry into the bleeding site, with an early phase of increased uptake at 3-24 h post-haemorrhagic stroke, followed by a second phase at 48-72 h. Lipid nanoparticles entry into the brain post-haemorrhage showed an identical entry pattern to the trans-BBB leakage rate (Ktrans [min-1]) of Gd-DOTA, a biomarker for BBB disruption, measured using dynamic contrast-enhanced MRI. Discussion: Our findings suggest that selective accumulation of liposomes into the lesion site is linked to a biphasic pattern of BBB hyper-permeability. This approach provides a unique opportunity to selectively and efficiently deliver therapeutic molecules across the BBB, an approach that has not been utilised for haemorrhagic stroke therapy and is not achievable using free small drug molecules.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
DOI：
10.1159/000346599
发表时间：
2013
期刊：
Cerebrovascular diseases (Basel, Switzerland)
影响因子：
--
作者：
Brouwers HB;Greenberg SM
通讯作者：
Greenberg SM
影响因子：
5.4
作者：
Bulbake U;Doppalapudi S;Kommineni N;Khan W
通讯作者：
Khan W
影响因子：
3.4
作者：
GREENBLATT, DJ;SETHY, VH
通讯作者：
SETHY, VH
影响因子：
5.7
作者：
Dickie, Ben R.;Vandesquille, Matthias;Parker, Geoff J. M.
通讯作者：
Parker, Geoff J. M.