State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, 100071, China.
J Nanobiotechnology. 2020 May 13;18(1):71. doi: 10.1186/s12951-020-00626-1.
Although many therapeutic strategies for Alzheimer's disease (AD) have been explored, these strategies are seldom used in the clinic. Therefore, AD therapeutic research is still urgently needed. One major challenge in the field of nanotherapeutics is to increase the selective delivery of drugs to a targeted location. Herein, we devised and tested a strategy for delivery of nanoparticles to neurons to inhibit tau aggregation by directly targeting p-tau.
Curcumin (CUR) is loaded onto red blood cell (RBC) membrane-coated PLGA particles bearing T807 molecules attached to the RBC membrane surface (T807/RPCNP). With the advantage of the suitable physicochemical properties of the PLGA nanoparticles and the unique biological functions of the RBC membrane, the RPCNP are stabilized and promote sustained CUR release, which provided improved biocompatibility and resulted in long-term presence in the circulation. Under the synergistic effects of T807, T807/RPCNP can not only effectively penetrate the blood-brain barrier (BBB), but they also possess high binding affinity to hyperphosphorylated tau in nerve cells where they inhibit multiple key pathways in tau-associated AD pathogenesis. When CUR was encapsulated, our data also demonstrated that CUR-loaded T807/RPCNP NPs can relieve AD symptoms by reducing p-tau levels and suppressing neuronal-like cells death both in vitro and in vivo. The memory impairment observed in an AD mouse model is significantly improved following systemic administration of CUR-loaded T807/RPCNP NPs.
Intravenous neuronal tau-targeted T807-modified novel biomimetic nanosystems are a promising clinical candidate for the treatment of AD.
尽管已经探索了许多阿尔茨海默病（AD）的治疗策略，但这些策略很少在临床上使用。因此，仍然迫切需要 AD 治疗研究。纳米治疗学领域的一个主要挑战是增加药物对靶向位置的选择性递送。在这里，我们设计并测试了一种通过直接针对 p-tau 将纳米颗粒递送到神经元以抑制 tau 聚集的策略。
姜黄素（CUR）被加载到载有附着在 RBC 膜表面的 T807 分子的 PLGA 颗粒上的 RBC 膜包被的 PLGA 颗粒（T807/RPCNP）上。利用 PLGA 纳米颗粒的合适理化性质和 RBC 膜的独特生物学功能，RPCNP 得到稳定并促进 CUR 的持续释放，从而提高了生物相容性并导致其在循环系统中长时间存在。在 T807 的协同作用下，T807/RPCNP 不仅可以有效地穿透血脑屏障（BBB），而且对神经细胞中高度磷酸化的 tau 具有高结合亲和力，从而抑制 tau 相关 AD 发病机制中的多个关键途径。当 CUR 被包封时，我们的数据还表明，负载 CUR 的 T807/RPCNP NPs 通过降低 p-tau 水平并抑制神经元样细胞死亡，无论是在体外还是体内，都可以缓解 AD 症状。在 AD 小鼠模型中观察到的记忆障碍在全身给予负载 CUR 的 T807/RPCNP NPs 后得到显著改善。
静脉内神经元 tau 靶向 T807 修饰的新型仿生纳米系统是治疗 AD 的有前途的临床候选物。
