Sex-Dependent Macromolecule and Nanoparticle Delivery in Experimental Brain Injury
Sex-Dependent Macromolecule and Nanoparticle Delivery in Experimental Brain Injury
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DOI：
10.1089/ten.tea.2020.0040
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发表时间：
2020-07-01
影响因子：
4.1
通讯作者：
Stabenfeldt, Sarah E.
中科院分区：
文献类型：
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作者：
Bharadwaj, Vimala N.;Copeland, Connor;Stabenfeldt, Sarah E.
开发有效的脑疾病治疗剂具有挑战性，特别是血脑屏障（BBB）严重限制了治疗剂进入脑实质。创伤性脑损伤（TBI）可能导致短暂的BBB渗透性，这为通过静脉内施用从大分子到纳米颗粒（NP）的治疗递送提供了独特的机会，用于开发精确的治疗剂。在这方面，我们解决了在理解治疗剂的范围/大小、递送窗口以及生物因素对最佳递送参数的潜在影响方面的关键差距。在这里，我们表明，第一次，尽我们所知，24小时后局灶性TBI雌性小鼠表现出较高的大分子示踪剂和NP积累与雄性小鼠相比，表明性别依赖性的差异，血脑屏障通透性。此外，我们首次报告了在雌性和雄性小鼠中局灶性损伤后3天内提供基于NP的治疗剂的潜力。损伤诱导的BBB渗透性与性别和时间曲线的关系对于更准确地定制时间依赖性精度和个性化纳米治疗至关重要。在这项研究中，我们在创伤性脑损伤（TBI）的临床前小鼠模型中确定了血/脑屏障破坏的性别依赖性时间特征，这导致了TBI后完全不同的大分子和纳米颗粒递送特征。这项工作的意义和潜在影响是深远的，因为它表明，需要真正的个性化医疗TBI是必要的，以提供正确的治疗在正确的时间为正确的病人。
The development of effective therapeutics for brain disorders is challenging, in particular, the blood-brain barrier (BBB) severely limits access of the therapeutics into the brain parenchyma. Traumatic brain injury (TBI) may lead to transient BBB permeability that affords a unique opportunity for therapeutic delivery via intravenous administration ranging from macromolecules to nanoparticles (NPs) for developing precision therapeutics. In this regard, we address critical gaps in understanding the range/size of therapeutics, delivery window(s), and moreover, the potential impact of biological factors for optimal delivery parameters. Here we show, for the first time, to the best of our knowledge, that 24-h postfocal TBI female mice exhibit a heightened macromolecular tracer and NP accumulation compared with male mice, indicating sex-dependent differences in BBB permeability. Furthermore, we report for the first time the potential to deliver NP-based therapeutics within 3 days after focal injury in both female and male mice. The delineation of injury-induced BBB permeability with respect to sex and temporal profile is essential to more accurately tailor time-dependent precision and personalized nanotherapeutics. Impact statement In this study, we identified a sex-dependent temporal profile of blood/brain barrier disruption in a preclinical mouse model of traumatic brain injury (TBI) that contributes to starkly different macromolecule and nanoparticle delivery profiles post-TBI. The implications and potential impact of this work are profound and far reaching as it indicates that a demand of true personalized medicine for TBI is necessary to deliver the right therapeutic at the right time for the right patient.