Brain-Targeted Liposomes Loaded with Monoclonal Antibodies Reduce Alpha-Synuclein Aggregation and Improve Behavioral Symptoms in Parkinson's Disease.
Brain-Targeted Liposomes Loaded with Monoclonal Antibodies Reduce Alpha-Synuclein Aggregation and Improve Behavioral Symptoms in Parkinson's Disease.
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DOI：
10.1002/adma.202304654
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发表时间：
2023-12
期刊：
影响因子：
--
通讯作者：
Schroeder A
中科院分区：
文献类型：
--
作者：
Sela M;Poley M;Mora-Raimundo P;Kagan S;Avital A;Kaduri M;Chen G;Adir O;Rozencweig A;Weiss Y;Sade O;Leichtmann-Bardoogo Y;Simchi L;Aga-Mizrachi S;Bell B;Yeretz-Peretz Y;Or AZ;Choudhary A;Rosh I;Cordeiro D;Cohen-Adiv S;Berdichevsky Y;Odeh A;Shklover J;Shainsky-Roitman J;Schroeder JE;Hershkovitz D;Hasson P;Ashkenazi A;Stern S;Laviv T;Ben-Zvi A;Avital A;Ashery U;Maoz BM;Schroeder A
单克隆抗体（mAb）有望治疗帕金森病（PD），尽管向大脑的递送不良阻碍了其治疗应用。在目前的研究中，我们证明了脑靶向脂质体（BTL）增强了mAb穿过血脑屏障（BBB）并进入神经元的递送，从而允许PD脑的细胞内和细胞外治疗。用转铁蛋白修饰BTL，以通过PD期间BBB上过表达的转铁蛋白受体来改善脑靶向。BTL负载有SynO 4，一种抑制α-突触核蛋白（AS）聚集（PD的病理学标志）的mAb。我们表明，100 nm的BTL穿越人血脑屏障模型完整，并采取了原代神经元。在神经元内，SynO 4从纳米颗粒中释放出来并与其靶点结合，从而减少AS聚集，增强神经元活力。体内，静脉内BTL给药导致脑细胞中mAb增加7倍，减少AS聚集和神经炎症。BTL治疗还改善了小鼠的行为运动功能和学习能力，具有良好的安全性。因此，靶向纳米技术提供了一个有价值的平台，药物输送治疗脑神经变性。
Monoclonal antibodies (mAbs) hold promise in treating Parkinson’s disease (PD), although poor delivery to the brain hinders their therapeutic application. In the current study, we demonstrate that brain-targeted liposomes (BTL) enhance the delivery of mAbs across the blood-brain-barrier (BBB) and into neurons, thereby allowing the intracellular and extracellular treatment of the PD brain. BTL were decorated with transferrin to improve brain targeting through overexpressed transferrin-receptors on the BBB during PD. BTL were loaded with SynO4, a mAb that inhibits alpha-synuclein (AS) aggregation, a pathological hallmark of PD. We show that 100-nm BTL cross human BBB models intact and were taken up by primary neurons. Within neurons, SynO4 was released from the nanoparticles and bound to its target, thereby reducing AS aggregation, and enhancing neuronal viability. In-vivo, intravenous BTL administration resulted in a 7-fold increase in mAbs in brain cells, decreasing AS aggregation and neuroinflammation. Treatment with BTL also improved behavioral motor function and learning ability in mice, with a favorable safety profile. Accordingly, targeted nanotechnologies offer a valuable platform for drug delivery to treat brain neurodegeneration.
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影响因子：
2.9
作者：
Faucheux, BA;Hauw, JJ;Hirsch, EC
通讯作者：
Hirsch, EC
影响因子：
48
作者：
Dempsey, Graham T.;Vaughan, Joshua C.;Chen, Kok Hao;Bates, Mark;Zhuang, Xiaowei
通讯作者：
Zhuang, Xiaowei
影响因子：
11
作者：
Brant B;Stern T;Shekhidem HA;Mizrahi L;Rosh I;Stern Y;Ofer P;Asleh A;Umanah GKE;Jada R;Levy NS;Levy AP;Stern S
通讯作者：
Stern S
DOI：
10.1073/pnas.2109256118
发表时间：
2021-12-28
影响因子：
11.1
作者：
Dilliard, Sean A.;Cheng, Qiang;Siegwart, Daniel J.
通讯作者：
Siegwart, Daniel J.
影响因子：
11
作者：
Hopperton KE;Mohammad D;Trépanier MO;Giuliano V;Bazinet RP
通讯作者：
Bazinet RP