Kanazawa Takanori, Morisaki Kazuki, Suzuki Shohei, Takashima Yuuki
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences , 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Mol Pharm. 2014 May 5;11(5):1471-8. doi: 10.1021/mp400644e. Epub 2014 Apr 16.
New therapeutic strategies are required to develop candidate drugs and ensure efficient delivery of these drugs to the brain and the central nervous system (CNS). Small interfering RNA (siRNA)-based therapies have been investigated as potential novel approaches for the treatment of brain disorders. Previously, we showed that Tat, a cell-penetrating peptide derived from HIV-Tat, and the modified block copolymers (MPEG-PCL-Tat) can form stable complexes with siRNA or can be loaded with an anticancer drug and efficiently deliver the drugs to the brain tissue via intranasal delivery. In this study, to develop a novel, efficient, and safe therapeutic strategy for managing brain disorders, we used MPEG-PCL-Tat micelles with a nose-to-brain delivery system to investigate its therapeutic effects on a rat model of malignant glioma using siRNA with a Raf-1 (siRaf-1)/camptothecin (CPT) codelivery system. MPEG-PCL-Tat and CPT-loaded MPEG-PCL-Tat can form a stable complex with siRNA with a particle size from 60 to 200 nm and a positive charge at N/P ratios up to 5. Additionally, MPEG-PCL-Tat/siRaf-1 and CPT-loaded MPEG-PCL-Tat/siRaf-1 have fostered cell death in rat glioma cells after the high cellular uptake of siRaf-1/drug by the MPEG-PCL-Tat carrier. Furthermore, compared to the unloaded MPEG-PCL-Tat/siRaf-1 complex, a CPT-loaded MPEG-PCL-Tat/siRaf-1 complex achieved the high therapeutic effect because of the additive effects of CPT and siRaf-1. These results indicate that drug/siRNA codelivery using MPEG-PCL-Tat nanomicelles with nose-to-brain delivery is an excellent therapeutic approach for brain and CNS diseases.
需要新的治疗策略来开发候选药物，并确保这些药物能够有效地输送到大脑和中枢神经系统（CNS）。基于小干扰RNA（siRNA）的疗法已被研究作为治疗脑部疾病的潜在新方法。此前，我们发现源自HIV-Tat的细胞穿透肽Tat与改性嵌段共聚物（MPEG-PCL-Tat）可与siRNA形成稳定复合物，或可负载抗癌药物，并通过鼻腔给药将药物有效输送到脑组织。在本研究中，为了开发一种用于治疗脑部疾病的新型、高效且安全的治疗策略，我们使用具有鼻至脑递送系统的MPEG-PCL-Tat胶束，采用Raf-1（siRaf-1）/喜树碱（CPT）共递送系统，研究其对恶性胶质瘤大鼠模型的治疗效果。负载CPT的MPEG-PCL-Tat和MPEG-PCL-Tat可与siRNA形成稳定复合物，粒径为60至200nm，在N/P比高达5时带正电荷。此外，MPEG-PCL-Tat载体对siRaf-1/药物的高细胞摄取后，MPEG-PCL-Tat/siRaf-1和负载CPT的MPEG-PCL-Tat/siRaf-1促进了大鼠胶质瘤细胞的死亡。此外，与未负载的MPEG-PCL-Tat/siRaf-1复合物相比，负载CPT的MPEG-PCL-Tat/siRaf-1复合物由于CPT和siRaf-1的相加作用而实现了高治疗效果。这些结果表明，使用具有鼻至脑递送的MPEG-PCL-Tat纳米胶束进行药物/siRNA共递送是治疗脑部和中枢神经系统疾病的一种优秀治疗方法。
