Bacterial-mediated DNA delivery to tumour associated phagocytic cells
Bacterial-mediated DNA delivery to tumour associated phagocytic cells
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DOI：
10.1016/j.jconrel.2014.10.030
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发表时间：
2014-12-28
影响因子：
10.8
通讯作者：
Tangney, M.
中科院分区：
文献类型：
--
作者：
Byrne, W. L.;Murphy, C. T.;Tangney, M.
吞噬细胞，包括巨噬细胞、树突状细胞和中性粒细胞，现在被认为在包括癌症在内的许多疾病中起着负面作用。特别是，巨噬细胞在多种疾病中发挥着病理生理作用，是一种有效的、普遍存在的治疗靶点。为了将新的治疗方式转化为临床现实，需要有选择性和高效地在原位靶向这些吞噬细胞的技术。我们提出了一种新的递送策略，使用非致病细菌来实现针对肿瘤相关吞噬细胞的基因递送。非侵入性细菌缺乏主动进入宿主细胞的能力，吞噬细胞除外。我们利用这一自然特性，在将携带转基因的细菌直接注射到肿瘤区域后，实现肿瘤相关吞噬细胞的“被动转基因”。使用体外分化的人类单核细胞系和两个体内小鼠模型(卵巢癌腹水和实体结肠癌模型)，证明了携带报告结构的细菌的交付证据。结果证实，递送策略是针对吞噬细胞的，并且细菌载体本身向肿瘤招募了更多的吞噬细胞。虽然实体瘤和腹水肿瘤模型在体内证明了向吞噬细胞传递的证据，但这一策略也可以应用于其他环境，包括非癌症相关疾病。(C)2014爱思唯尔B.V.保留所有权利。
Phagocytic cells including macrophages, dendritic cells and neutrophils are now recognised as playing a negative role in many disease settings including cancer. In particular, macrophages are known to play a pathophysiological role in multiple diseases and present a valid and ubiquitous therapeutic target. The technology to target these phagocytic cells in situ, both selectively and efficiently, is required in order to translate novel therapeutic modalities into clinical reality. We present a novel delivery strategy using non-pathogenic bacteria to effect gene delivery specifically to tumour-associated phagocytic cells. Non-invasive bacteria lack the ability to actively enter host cells, except for phagocytic cells. We exploit this natural property to effect 'passive transfection' of tumour-associated phagocytic cells following direct administration of transgene-loaded bacteria to tumour regions. Using an in vitro-differentiated human monocyte cell line and two in vivo mouse models (an ovarian cancer ascites and a solid colon tumour model) proof of delivery is demonstrated with bacteria carrying reporter constructs. The results confirm that the delivery strategy is specific for phagocytic cells and that the bacterial vector itself recruits more phagocytic cells to the tumour. While proof of delivery to phagocytic cells is demonstrated in vivo for solid and ascites tumour models, this strategy may be applied to other settings, including non-cancer related disease. (C) 2014 Elsevier B.V. All rights reserved.