He Guan Zhen, Lin Wen Jen
School of Pharmacy, College of Medicine, National Taiwan University, No. 33, Linsen S. Rd., Taipei 10050, Taiwan.
Int J Mol Sci. 2025 Jun 16;26(12):5768. doi: 10.3390/ijms26125768.
Seliciclib, a cyclin-dependent kinase 5 (CDK5) inhibitor, has demonstrated neuroprotective potential. However, its therapeutic application is limited by poor permeability across the blood-brain barrier (BBB). In this study, polymeric nanoparticles (NPs) modified with a BBB-targeting peptide ligand (His-Ala-Ile-Tyr-Pro-Arg-His) were employed to encapsulate seliciclib. In vitro transport studies showed that the peptide-modified NPs exhibited significantly greater translocation across a bEnd.3 cell monolayer compared to unmodified NPs. Furthermore, in vivo biodistribution analysis revealed that the brain accumulation of peptide-modified NPs was 3.38-fold higher than that of unmodified NPs. Notably, the peptide-conjugated, seliciclib-loaded NPs demonstrated a significant neuroprotective effect against the neurotoxin 1-methyl-4-phenylpyridinium (MPP⁺) in differentiated SH-SY5Y cells.
塞利西利布是一种细胞周期蛋白依赖性激酶5（CDK5）抑制剂，已显示出神经保护潜力。然而，其治疗应用受到血脑屏障（BBB）通透性差的限制。在本研究中，用BBB靶向肽配体（His-Ala-Ile-Tyr-Pro-Arg-His）修饰的聚合物纳米颗粒（NPs）被用于包裹塞利西利布。体外转运研究表明，与未修饰的NPs相比，肽修饰的NPs在bEnd.3细胞单层上的转运明显更高。此外，体内生物分布分析显示，肽修饰的NPs在脑中的蓄积比未修饰的NPs高3.38倍。值得注意的是，肽偶联的、负载塞利西利布的NPs在分化的SH-SY5Y细胞中对神经毒素1-甲基-4-苯基吡啶鎓（MPP⁺）表现出显著的神经保护作用。
