A new painkiller nanomedicine to bypass the blood-brain barrier and the use of morphine
A new painkiller nanomedicine to bypass the blood-brain barrier and the use of morphine
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DOI：
10.1126/sciadv.aau5148
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发表时间：
2019-02-01
期刊：
影响因子：
13.6
通讯作者：
Couvreur, Patrick
中科院分区：
文献类型：
--
作者：
Feng, Jiao;Lepetre-Mouelhi, Sinda;Couvreur, Patrick
内源性神经肽的临床应用由于药代动力学问题（包括血浆稳定性和血脑屏障通透性）而在历史上受到限制。在这项研究中，我们表明，快速代谢的亮氨酸脑啡肽（LENK）神经肽可能成为高效的，由于一个简单的共轭与脂质角鲨烯（SQ）。使用不同的化学接头合成相应的LENK-SQ生物缀合物，以便在其配制成纳米颗粒后调节LENK释放。这种新的基于SQ的纳米制剂防止了LENK的快速血浆降解，并赋予释放的神经肽显著的抗痛觉过敏作用，其持续时间长于在大鼠炎症模型中用吗啡治疗后（Hargreaves试验）。生物分布研究以及脑渗透性和非渗透性阿片受体拮抗剂的使用表明，LENK-SQ NP通过外周定位的阿片受体起作用。这项研究代表了一种新的纳米医学方法，允许将LENK神经肽特异性递送到炎症组织中以控制疼痛。
The clinical use of endogenous neuropeptides has historically been limited due to pharmacokinetic issues, including plasma stability and blood-brain barrier permeability. In this study, we show that the rapidly metabolized Leu-enkephalin (LENK) neuropeptide may become pharmacologically efficient owing to a simple conjugation with the lipid squalene (SQ). The corresponding LENK-SQ bioconjugates were synthesized using different chemical linkers in order to modulate the LENK release after their formulation into nanoparticles. This new SQ-based nanoformulation prevented rapid plasma degradation of LENK and conferred on the released neuropeptide a notable antihyperalgesic effect that lasted longer than after treatment with morphine in a rat model of inflammation (Hargreaves test). The biodistribution study as well as the use of brain-permeant and -impermeant opioid receptor antagonists indicated that LENK-SQ NPs act through peripherally located opioid receptors. This study represents a novel nanomedicine approach, allowing the specific delivery of LENK neuropeptide into inflamed tissues for pain control.