Biomaterials. 2015 Jan;36:98-109. doi: 10.1016/j.biomaterials.2014.09.008.
Now it is well evidenced that tumor growth is a comprehensive result of multiple pathways, and glioma parenchyma cells and stroma cells are closely associated and mutually compensatory. Therefore, drug delivery strategies targeting both of them simultaneously might obtain more promising therapeutic benefits. In the present study, we developed a multi-targeting drug delivery system modified with uPA-activated cell-penetrating peptide (ACPP) for the treatment of brain glioma (ANP). In vitro experiments demonstrated nanoparticles (NP) decorated with cell-penetrating peptide (CPP) or ACPP could significantly improve nanoparticles uptake by C6 glioma cells and nanoparticles penetration into glioma spheroids as compared with traditional NP and thus enhanced the therapeutic effects of its payload when paclitaxel (PTX) was loaded. In vivo imaging experiment revealed that ANP accumulated more specifically in brain glioma site than NP decorated with or without CPP. Brain slides further showed that ACPP contributed to more nanoparticles accumulation in glioma site, and ANP could co-localize not only with glioma parenchyma cells, but also with stroma cells including neo-vascular cells and tumor associated macrophages. The pharmacodynamics results demonstrated ACPP could significantly improve the therapeutic benefits of nanoparticles by significantly prolonging the survival time of glioma bearing mice. In conclusion, the results suggested that nanoparticles modified with uPA-sensitive ACPP could reach multiple types of cells in glioma tissues and provide a novel strategy for glioma targeted therapy.
现在有充分的证据表明，肿瘤的生长是多种途径的综合结果，神经胶质瘤实质细胞和基质细胞密切相关且相互补偿。因此，同时针对这两者的药物输送策略可能会获得更有前途的治疗效果。在本研究中，我们开发了一种多靶向药物输送系统，该系统经过尿激酶激活的细胞穿透肽（ACPP）修饰，用于治疗脑胶质瘤（ANP）。体外实验表明，与传统的纳米颗粒（NP）相比，修饰有细胞穿透肽（CPP）或 ACPP 的纳米颗粒能够显著提高 C6 神经胶质瘤细胞对纳米颗粒的摄取能力，并且能够提高纳米颗粒穿过神经胶质瘤球体的能力，从而增强载药紫杉醇（PTX）的治疗效果。体内成像实验表明，与未修饰 CPP 的 NP 相比，ANP 更特异性地在脑胶质瘤部位积聚。脑组织切片进一步表明，ACPP 有助于更多的纳米颗粒积聚在神经胶质瘤部位，并且 ANP 不仅可以与神经胶质瘤实质细胞共定位，还可以与包括新生血管细胞和肿瘤相关巨噬细胞在内的基质细胞共定位。药效学结果表明，ACPP 可以通过显著延长荷瘤小鼠的生存时间，显著提高纳米颗粒的治疗效果。总之，结果表明，经过尿激酶敏感的 ACPP 修饰的纳米颗粒可以到达神经胶质瘤组织中的多种类型的细胞，为神经胶质瘤的靶向治疗提供了一种新策略。
