Pathology Group, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, 4 Newark Street, London E1 2AT, UK.
Biomaterials. 2011 Nov;32(33):8538-47. doi: 10.1016/j.biomaterials.2011.07.060. Epub 2011 Aug 6.
The CD95/CD95L receptor-ligand system is mainly recognised in the induction of apoptosis. However, it has also been shown that CD95L is over-expressed in many cancer types where it modulates immune-evasion and together with its receptor CD95 promotes tumour growth. Here, we show that CD95 surface modification of relatively large microparticles >0.5 μm in diameter, including those made from biodegradable polylactic-co-glycolic acid (PLGA), enhances intracellular uptake by a range of CD95L expressing cells in a process akin to phagocytosis. Using this approach we describe the intracellular uptake of microparticles and agent delivery in neurons, medulloblastoma, breast and ovarian cancer cells in vitro. CD95 modified paclitaxel-loaded PLGA microparticles are shown to be significantly more effective compared to conventional paclitaxel therapy (Taxol) at the same dose in subcutaneous medulloblastoma (∗∗∗P < 0.0001) and orthotopic ovarian cancer xenograft models where a >65-fold reduction in tumour bioluminescence was measured after treatment (∗P = 0.012). This drug delivery platform represents a new way of manipulating the normally advantageous tumour CD95L over-expression towards a therapeutic strategy. CD95 functionalised drug carriers could contribute to the improved function of cytotoxics in cancer, potentially increasing drug targeting and efficacy whilst reducing toxicity.
CD95/CD95L 受体-配体系统主要在诱导细胞凋亡中被识别。然而，已经表明 CD95L 在许多癌症类型中过度表达，它调节免疫逃逸，与受体 CD95 一起促进肿瘤生长。在这里，我们表明相对较大的微粒（直径> 0.5μm）的 CD95 表面修饰，包括由可生物降解的聚乳酸-共-羟基乙酸（PLGA）制成的微粒，通过类似于吞噬作用的过程增强了一系列表达 CD95L 的细胞的细胞内摄取。使用这种方法，我们描述了微粒和药物在体外神经元、髓母细胞瘤、乳腺癌和卵巢癌细胞中的细胞内摄取和递药。与相同剂量的传统紫杉醇疗法（Taxol）相比，载紫杉醇的 CD95 修饰的 PLGA 微粒明显更有效（∗∗∗P < 0.0001），并且在荷瘤模型中，肿瘤生物发光减少了 65 倍以上（∗P = 0.012）。这种药物递送平台代表了一种操纵通常有利于肿瘤 CD95L 过表达的新方法，朝着治疗策略发展。CD95 功能化药物载体可以提高细胞毒性药物在癌症中的功能，潜在地增加药物靶向性和疗效，同时降低毒性。
