Lo Yu-Chen, Lin Wen-Jen
School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan.
Drug Research Center, College of Medicine, National Taiwan University, Taipei 10050, Taiwan.
Pharmaceutics. 2023 Oct 6;15(10):2429. doi: 10.3390/pharmaceutics15102429.
Palbociclib (PBC) is an FDA-approved CDK4/6 inhibitor used for breast cancer treatment. PBC has been demonstrated its ability to suppress the proliferation of glioma cells by inducing cell cycle arrest. However, the efflux transporters on the blood-brain barrier (BBB) restricts the delivery of PBC to the brain. The nano-delivery strategy with BBB-penetrating and glioma-targeting abilities was designed. Poly(lactide-co-glycolide)-poly(ethylene glycol) (PLGA-PEG) was functionalized with the potential peptide, T7 targeting peptide and/or R9 penetrating peptide, to prepare PBC-loaded nanoparticles (PBC@NPs). The size of PBC@NPs was in the range of 168.4 ± 4.3-185.8 ± 4.4 nm (PDI < 0.2), and the zeta potential ranged from -17.8 ± 1.4 mV to -14.3 ± 1.0 mV dependent of conjugated peptide. The transport of PBC@NPs across the bEnd.3 cell model was in the order of dual-peptide modified NPs > T7-peptide modified NPs > peptide-free NPs > free PBC, indicating facilitated delivery of PBC by NPs, particularly the T7/R9 dual-peptide modified NPs. Moreover, PBC@NPs significantly enhanced U87-MG glioma cell apoptosis by 2.3-6.5 folds relative to PBC, where the dual-peptide modified NPs was the most effective one. In conclusion, the PBC loaded dual-peptide functionalized NPs improved cellular uptake in bEnd.3 cells followed by targeting to U87-MG glioma cells, leading to effective cytotoxicity and promoting cell death.
哌柏西利（PBC）是一种经美国食品药品监督管理局（FDA）批准的用于治疗乳腺癌的细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂。PBC已被证明能够通过诱导细胞周期停滞来抑制胶质瘤细胞的增殖。然而，血脑屏障（BBB）上的外排转运体限制了PBC向脑内的递送。因此设计了具有血脑屏障穿透和胶质瘤靶向能力的纳米递送策略。聚（丙交酯-共-乙交酯）-聚（乙二醇）（PLGA-PEG）用潜在的肽、T7靶向肽和/或R9穿透肽进行功能化，以制备负载PBC的纳米颗粒（PBC@NPs）。PBC@NPs的尺寸在168.4±4.3-185.8±4.4nm范围内（多分散指数<0.2），ζ电位范围为-17.8±1.4mV至-14.3±1.0mV，取决于共轭肽。PBC@NPs跨bEnd.3细胞模型的转运顺序为双肽修饰的纳米颗粒>T7肽修饰的纳米颗粒>无肽纳米颗粒>游离PBC，表明纳米颗粒促进了PBC的递送，特别是T7/R9双肽修饰的纳米颗粒。此外，相对于PBC，PBC@NPs显著增强了U87-MG胶质瘤细胞凋亡2.3-6.5倍，其中双肽修饰的纳米颗粒最为有效。总之，负载PBC的双肽功能化纳米颗粒提高了在bEnd.3细胞中的细胞摄取，随后靶向U87-MG胶质瘤细胞，导致有效的细胞毒性并促进细胞死亡。
