Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China; Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China.
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China.
J Control Release. 2023 Mar;355:604-621. doi: 10.1016/j.jconrel.2023.01.074. Epub 2023 Feb 16.
Since the complex interactions of multiple mechanisms involved in Alzheimer's disease (AD) preclude the monotherapeutic approaches from clinical application, combination therapy has become an attractive strategy for AD treatment. However, to be emphasized, the realization of the edges of combination therapy greatly depends on the reasonable choice of targets and the rational design of combination scheme. Acknowledgedly, amyloid plaques and hyperphosphorylated tau (p-tau) are two main hallmarks in AD with close pathological correlations, implying the hopeful prospect of combined intervention in them for AD treatment. Herein, we developed the nano-combination system, neuron-targeting PEG-PLA nanoparticles (CT-NP) loading two peptide drugs H102, a β-sheet breaker acting on Aβ, and NAP, a microtubule stabilizer acting on p-tau. Compared with free peptide combination, nano-combination system partly aligned the in vivo behaviors of combined peptides and enhanced peptide accumulation in lesion neurons by the guidance of targeting peptide CGN and Tet1, facilitating the therapeutic performance of peptide combination. Further, to maximize the therapeutic potential of nano-combination system, the combination ratio and mode were screened by the quantitative evaluation with combination index and U test, respectively, in vitro and in vivo. The results showed that the separated-loading CT-NP at the combination molar ratio of 2:1 (H102:NAP), CT-NP/H102 + CT-NP/NAP(2:1), generated the strongest synergistic therapeutic effects on Aβ, p-tau and their linkage, and effectually prevented neuroinflammation, reversed the neuronal damage and restored cognitive performance in 3 × Tg-AD transgenic mice. Our studies provide critical data on the effectiveness of nano-combination therapy simultaneously intervening in Aβ and p-tau, confirming the promising application of nano-combination strategy in AD treatment.
由于阿尔茨海默病（AD）涉及的多种机制的复杂相互作用排除了单一疗法的临床应用，联合治疗已成为 AD 治疗的一种有吸引力的策略。然而，需要强调的是，联合治疗的实现很大程度上取决于目标的合理选择和联合方案的合理设计。诚然，淀粉样斑块和过度磷酸化的 tau（p-tau）是 AD 的两个主要标志物，它们具有密切的病理相关性，这意味着对它们进行联合干预治疗 AD 具有有希望的前景。在此，我们开发了纳米联合系统，即负载两种肽药物 H102（一种作用于 Aβ的β-折叠破坏肽）和 NAP（一种作用于 p-tau 的微管稳定剂）的神经元靶向 PEG-PLA 纳米颗粒（CT-NP）。与游离肽联合相比，纳米联合系统通过靶向肽 CGN 和 Tet1 的引导，部分调整了联合肽的体内行为并增强了病变神经元中肽的积累，从而提高了肽联合的治疗效果。此外，为了最大限度地发挥纳米联合系统的治疗潜力，我们通过体外和体内的组合指数和 U 检验分别对联合比和联合方式进行了定量评价和筛选。结果表明，在联合摩尔比为 2:1（H102:NAP）时，负载分离的 CT-NP、CT-NP/H102+CT-NP/NAP（2:1）产生了最强的协同治疗作用，对 Aβ、p-tau 及其连接以及有效预防神经炎症、逆转 3×Tg-AD 转基因小鼠神经元损伤和恢复认知功能有最强的协同治疗作用。我们的研究提供了同时干预 Aβ和 p-tau 的纳米联合治疗有效性的关键数据，证实了纳米联合策略在 AD 治疗中的应用前景。
