Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai 201203, China.
Biomaterials. 2012 Jul;33(20):5115-23. doi: 10.1016/j.biomaterials.2012.03.058. Epub 2012 Apr 6.
The treatment of a brain glioma is still one of the most difficult challenges in oncology. To effectively treat brain glioma and reduce the side effects, drugs must be transported across the blood brain barrier (BBB) and then targeted to the brain cancer cells because most anti-tumor drugs are highly toxic to the normal brain tissue. A cascade delivery strategy was developed to perform these two aims and to achieve enhanced and precisely targeted delivery. Herein, we utilize a phage-displayed TGN peptide and an AS1411 aptamer, which are specific targeting ligands of the BBB and cancer cells, respectively and we conjugate them with nanoparticles to establish the brain glioma cascade delivery system (AsTNP). In vitro cell uptake and three-dimensional tumor spheroid penetration studies demonstrated that the system could not only target endothelial and tumor cells but also penetrate the endothelial monolayers and tumor cells to reach the core of the tumor spheroids, which was extremely important but mostly ignored in glioma therapy. In vivo imaging further demonstrated that the AsTNP provided the highest tumor distribution and tumor/normal brain ratio. The distribution was also reconfirmed by fluorescent images of the brain slides. As a result, the docetaxel-loaded AsTNP presents the best anti-glioma effect with improved glioma bearing survival. In conclusion, the AsTNP could precisely target to the brain glioma, which was a valuable target for glioma imaging and therapy.
脑胶质瘤的治疗仍然是肿瘤学中最具挑战性的难题之一。为了有效治疗脑胶质瘤并减少副作用，药物必须穿过血脑屏障（BBB），然后靶向脑癌细胞，因为大多数抗肿瘤药物对正常脑组织具有高度毒性。本文设计了级联递药策略来实现这两个目标，并实现增强和精确的靶向递药。在这里，我们利用噬菌体展示的 TGN 肽和 AS1411 适体，它们分别是 BBB 和癌细胞的特异性靶向配体，并将它们与纳米颗粒偶联，建立脑胶质瘤级联递药系统（AsTNP）。体外细胞摄取和三维肿瘤球穿透研究表明，该系统不仅可以靶向内皮细胞和肿瘤细胞，还可以穿透内皮单层和肿瘤细胞，到达肿瘤球的核心，这在胶质瘤治疗中极其重要，但大多被忽略。体内成像进一步证实，AsTNP 提供了最高的肿瘤分布和肿瘤/正常脑比值。脑切片的荧光图像也重新证实了这种分布。结果，载多西紫杉醇的 AsTNP 呈现出最好的抗胶质瘤效果，提高了荷瘤生存。总之，AsTNP 可以精确靶向脑胶质瘤，这是脑胶质瘤成像和治疗的一个有价值的靶点。
