Multiple Protective Roles of Nanoliposome-Incorporated Baicalein against Alpha-Synuclein Aggregates
Multiple Protective Roles of Nanoliposome-Incorporated Baicalein against Alpha-Synuclein Aggregates
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DOI：
10.1002/adfm.202007765
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发表时间：
2020-11-18
影响因子：
19
通讯作者：
Otzen, Daniel E.
中科院分区：
文献类型：
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作者：
Aliakbari, Farhang;Mohammad-Beigi, Hossein;Otzen, Daniel E.
纳米颗粒可用于增加药物稳定性、溶解度和可用性。小分子黄芩素抑制原纤维化，并解毒与帕金森病（PD）相关的α-突触核蛋白（α SN）的聚集体，但它具有不稳定性、低溶解度和随之而来的低可用性。在这里，它表明，黄芩素纳入两性离子纳米脂质体（NLP-Ba）解决了这些问题。NLP-Ba抑制α SN原纤维起始、伸长、次级成核，并且还比游离黄芩素更有效地解聚成熟原纤维，并防止可溶性α SN聚集体接种新原纤维。重要的是，NLP-Ba干扰寡聚体透化膜的能力。NLP-Ba和α SN之间的相互作用通过不同的生物物理技术证实。这种纳米系统在体外穿过血脑屏障，并在体内有效对抗鱼藤酮神经毒性。NLP-Ba对α SN纤维化/细胞毒性的影响归因于游离黄芩素和空NLP的组合。结果表明NLP-Ba在降低PD中的α SN致病性方面具有神经保护作用，并突出了纳米脂质体动员难溶性疏水性药物的用途。
Nanoparticles are useful for increasing drug stability, solubility, and availability. The small molecule baicalein inhibits fibrillation, and detoxifies aggregates of alpha-synuclein (alpha SN) associated with Parkinson's disease (PD), but it suffers from instability, low solubility and consequent low availability. Here it is demonstrated that incorporation of baicalein into zwitterionic nanoliposomes (NLP-Ba) addresses these problems. NLP-Ba inhibits alpha SN fibril initiation, elongation, secondary nucleation, and also depolymerizes mature fibrils more effectively than free baicalein and prevents soluble alpha SN aggregates from seeding new fibrils. Importantly, NLP-Ba perturbs oligomers' capacity to permeabilize the membrane. The interaction between NLP-Ba and alpha SN is confirmed by different biophysical techniques. This nanosystem crosses the blood-brain barrier in vitro and is effective against rotenone neurotoxicity in vivo. The effect of NLP-Ba on alpha SN fibrillation/cytotoxicity is attributed to a combination of free baicalein and empty NLPs. The results indicate a neuroprotective role for NLP-Ba in decreasing alpha SN pathogenicity in PD and highlight the use of nanoliposomes to mobilize poorly soluble hydrophobic drugs.