Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China; Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, 201203, PR China.
Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China; Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, 201203, PR China.
J Control Release. 2014 Oct 28;192:317-24. doi: 10.1016/j.jconrel.2014.07.050. Epub 2014 Aug 4.
Alzheimer's disease (AD) is a complex neurodegenerative disease with few effective treatments. The non-targeted distribution of drugs decreases drug efficiency and cause side effects. The cascade targeting strategy has been suggested for precise drug delivery. We developed a dual-functional nanoparticle drug delivery system loaded with β-sheet breaker peptide H102 (TQNP/H102). Two targeting peptides, TGN and QSH, were conjugated to the surface of the nanoparticles for blood-brain barrier transport and Aβ42 targeting, respectively. The prepared nanoparticles were spherical and uniform. The brain distribution study of H102 was conducted with the HPLC-mass spectrometry method to evaluate whether this nano-carrier could achieve increased AD-lesion delivery. The highest uptake of H102 was observed in the hippocampi of the TQNP/H102 group mice 1h after administration, which was 2.62 and 1.86 times the level of non-modified nanoparticles (NP/H102) and TGN modified nanoparticles (TNP/H102), respectively. The neuroprotective effects of H102 preparations were evaluated using Morris water maze experiment, biochemical indexes assay and tissue histology. The spatial learning and memory of the AD model mice in the TQNP/H102 group were significantly improved compared with the AD control group, and were also better than other preparations at the same dosage, even the TNP/H102 group. These results were consistent with the values of biochemical indexes in mouse hippocampi as well as the histological observations. The results demonstrate that TQNP is a promising carrier for peptide or protein drugs, such as H102, for entry into the central nervous system (CNS) and subsequent location of brain AD lesions, thus offering a highly-specific method for AD therapy.
阿尔茨海默病（AD）是一种复杂的神经退行性疾病，目前治疗方法有限。药物的非靶向分布降低了药物效率并导致副作用。级联靶向策略已被提出用于精确药物递送。我们开发了一种载有β-折叠破坏肽 H102（TQNP/H102）的双功能纳米颗粒药物递送系统。两种靶向肽 TGN 和 QSH 分别连接到纳米颗粒表面，用于血脑屏障转运和 Aβ42 靶向。所制备的纳米颗粒呈球形且均匀。使用 HPLC-质谱法进行 H102 的脑分布研究，以评估这种纳米载体是否可以实现增加 AD 病变部位的递送。给药后 1h，TQNP/H102 组小鼠的 H102 摄取量最高，分别是非修饰纳米颗粒（NP/H102）和 TGN 修饰纳米颗粒（TNP/H102）的 2.62 倍和 1.86 倍。使用 Morris 水迷宫实验、生化指标测定和组织学评估 H102 制剂的神经保护作用。与 AD 对照组相比，TQNP/H102 组 AD 模型小鼠的空间学习和记忆能力显著提高，并且在相同剂量下也优于其他制剂，甚至优于 TNP/H102 组。这些结果与小鼠海马生化指标值以及组织学观察结果一致。结果表明，TQNP 是一种有前途的载体，可将肽或蛋白质药物（如 H102）递送至中枢神经系统（CNS），并随后定位大脑 AD 病变，从而为 AD 治疗提供了一种高度特异的方法。
