PDF(Pubmed)
Abstract：
Chondrosarcoma (CS) is a malignant cartilage-forming bone tumor that is inherently resistant to chemotherapy and radiotherapy, leaving surgery as the only treatment option. We have designed a tumor-targeted bacteriophage (phage)-derived particle (PDP), for targeted systemic delivery of cytokine-encoding transgenes to solid tumors. Phage has no intrinsic tropism for mammalian cells; therefore, it was engineered to display a double cyclic RGD4C ligand on the capsid to target tumors. To induce cancer cell death, we constructed a transgene cassette expressing a secreted form of the cytokine tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL). We detected high expression of αvβ3 and αvβ5 integrin receptors of the RGD4C ligand, and of the TRAIL receptor-2 in human CS cells (SW1353), but not in primary normal chondrocytes. The RGD4C.PDP-Luc particle carrying a luciferase reporter gene, Luc, effectively and selectively mediated gene delivery to SW1353 cells, but not primary chondrocytes. Transduction of SW1353 cells with RGD4C.PDP-sTRAIL encoding a human sTRAIL, resulted in the expression of TRAIL and subsequent cell death without harming the normal chondrocytes. Intravenous administration of RGD4C.PDP-sTRAIL to mice with established human CS resulted in a decrease in tumor size and tumor viability. Altogether, RGD4C.PDP-sTRAIL can be used to target systemic treatment of CS with the sTRAIL.
摘要：
软骨肉瘤（CS）是一种恶性软骨形成性骨肿瘤，对化疗和放疗具有固有的抵抗力，将手术作为唯一的治疗选择。我们设计了一种肿瘤靶向噬菌体（噬菌体）衍生颗粒（PDP），用于将编码细胞因子的转基因靶向全身递送至实体瘤。噬菌体对哺乳动物细胞没有内在的向性；因此，它被设计为在衣壳上显示双环RGD4C配体以靶向肿瘤。诱导癌细胞死亡，我们构建了一个表达分泌型细胞因子肿瘤坏死因子相关凋亡诱导配体(sTRAIL)的转基因盒.我们检测到RGD4C配体的αvβ3和αvβ5整合素受体的高表达，和人CS细胞中的TRAIL受体2（SW1353），但不存在于原代正常软骨细胞中.RGD4C。携带荧光素酶报告基因的PDP-Luc颗粒，吕克,有效和选择性地介导基因传递到SW1353细胞，但不是原代软骨细胞.用RGD4C转导SW1353细胞。PDP-sTRAIL编码人sTRAIL，导致TRAIL的表达和随后的细胞死亡，而不损害正常软骨细胞。静脉内施用RGD4C。PDP-sTRAIL对具有建立的人CS的小鼠导致肿瘤大小和肿瘤活力的降低。总之,RGD4C。PDP-sTRAIL可用于靶向用sTRAIL全身治疗CS。
