Rauch Daniel A, Harding John C, Ratner Lee, Wickline Samuel A, Pan Hua
Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
USF Health Heart Institute, University of South Florida, Tampa, FL 33602, USA.
Nanomaterials (Basel). 2021 Jun 16;11(6):1582. doi: 10.3390/nano11061582.
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive, clonal malignancy of mature T cells caused by human T-cell leukemia virus type 1. Although it is a rare tumor type, it serves as an excellent model of a virus driven process that transforms cells and engenders a highly malignant tumor that is extraordinarily difficult to treat. The viral transcriptional transactivator (Tax) in the HTLV-1 genome directly promotes tumorigenesis, and Tax-induced oncogenesis depends on its ability to constitutively activate NF-κB signaling. Accordingly, we developed and evaluated a nano-delivery system that simultaneously inhibits both canonical (p65) and noncanonical (p100) NF-κB signaling pathways locally in tumors after systemic administration. Our results demonstrate that siRNA is delivered rapidly to ATLL tumors after either i.p. or i.v. injection. The siRNA treatment significantly reduced both p65 and p100 mRNA and protein expression. Anti-NF-κB nanotherapy significantly inhibited tumor growth in two distinct tumor models in mice: a spontaneous Tax-driven tumor model, and a Tax tumor cell transplant model. Moreover, siRNA nanotherapy sensitized late-stage ATLL tumors to the conventional chemotherapeutic agent etoposide, indicating a pleiotropic benefit for localized siRNA nanotherapeutics.
成人T细胞白血病/淋巴瘤（ATLL）是由1型人类T细胞白血病病毒引起的成熟T细胞侵袭性克隆恶性肿瘤。尽管它是一种罕见的肿瘤类型，但它是病毒驱动过程的一个极佳模型，该过程可使细胞发生转化并产生极难治疗的高度恶性肿瘤。HTLV-1基因组中的病毒转录反式激活因子（Tax）直接促进肿瘤发生，且Tax诱导的肿瘤发生取决于其组成性激活NF-κB信号通路的能力。因此，我们开发并评估了一种纳米递送系统，该系统在全身给药后能在肿瘤局部同时抑制经典（p65）和非经典（p100）NF-κB信号通路。我们的结果表明，腹腔注射或静脉注射后，siRNA能迅速递送至ATLL肿瘤。siRNA治疗显著降低了p65和p100的mRNA及蛋白表达。抗NF-κB纳米疗法在两种不同的小鼠肿瘤模型中显著抑制了肿瘤生长：一种是自发的Tax驱动肿瘤模型，另一种是Tax肿瘤细胞移植模型。此外，siRNA纳米疗法使晚期ATLL肿瘤对传统化疗药物依托泊苷敏感，表明局部siRNA纳米疗法具有多效性益处。
