Targeted cytolysins synergistically potentiate cytoplasmic delivery of gelonin immunotoxin.
Targeted cytolysins synergistically potentiate cytoplasmic delivery of gelonin immunotoxin.
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DOI：
10.1158/1535-7163.mct-12-1023
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发表时间：
2013-09
影响因子：
5.7
通讯作者：
Wittrup KD
中科院分区：
文献类型：
--
作者：
Pirie CM;Liu DV;Wittrup KD
靶向内吞摄取是朝向组织特异性细胞质大分子递送的第一步;然而，从内溶酶体隔室的低效逃逸使得目前这通常不切实际。我们在这里报告了一个有针对性的溶细胞素的方法，显着增强内体释放的独立靶向有效的白树毒素免疫毒素。纤维连接蛋白结构域工程的亲和力，表皮生长因子受体或癌胚抗原融合到植物毒素白树毒素或细菌孔形成溶细胞素。这些融合蛋白在体外抗原特异性细胞毒性（将效力提高几个数量级）和体内肿瘤生长抑制中显示协同活性。此外，诱导细胞凋亡所需的内化白树素分子的数量从0.5 ×106减少到< 103。靶向增强显示出增强其他大分子有效载荷（如DNA、siRNA和miRNA）的细胞质递送的前景。
Targeted endocytic uptake is a first step towards tissue-specific cytoplasmic macromolecular delivery; however inefficient escape from the endolysosomal compartment makes this generally impractical at present. We report here a targeted cytolysin approach that dramatically potentiates endosomal release of an independently-targeted potent gelonin immunotoxin. Fibronectin domains engineered for affinity to epidermal growth factor receptor or carcinoembryonic antigen were fused to the plant toxin gelonin or bacterial pore-forming cytolysins. These fusion proteins display synergistic activity in both antigen-specific cytotoxicity in vitro, enhancing potency by several orders of magnitude, and in tumor growth inhibition in vivo. In addition, the number of internalized gelonin molecules required to induce apoptosis is reduced from ∼5×106 to < 103. Targeted potentiation shows promise for enhancing cytoplasmic delivery of other macromolecular payloads, such as DNA, siRNA, and miRNA.