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Gene therapy with RALA/iNOS composite nanoparticles significantly enhances survival in a model of metastatic prostate cancer.
Cancer Nanotechnology ( IF 4.5 ) Pub Date : 2018-06-01 , DOI: 10.1186/s12645-018-0040-x
Cian M McCrudden 1 , John W McBride 1 , Joanne McCaffrey 1 , Emma M McErlean 1 , Nicholas J Dunne 2 , Vicky L Kett 1 , Jonathan A Coulter 1 , Tracy Robson 3 , Helen O McCarthy 1
Affiliation  

Recent approvals of gene therapies by the FDA and the EMA for treatment of inherited disorders have further opened the door for assessment of nucleic acid pharmaceuticals for clinical usage. Arising from the presence of damaged or inappropriate DNA, cancer is a condition particularly suitable for genetic intervention. The RALA peptide has been shown to be a potent non-viral delivery platform for nucleic acids. This study examines the use of RALA to deliver a plasmid encoding inducible nitric oxide synthase (iNOS) as an anti-cancer treatment. The physiochemical properties of the RALA/DNA nanoparticles were characterized via dynamic light scattering and transmission electron microscopy. The nanoparticles were labelled with fluorophores and tracked over time using confocal microscopy with orthogonal sections to determine cellular location. In vitro studies were employed to determine functionality of the nanoparticles both for pEGFP-N1 and CMV-iNOS. Nanoparticles were injected intravenously into C57/BL6 mice with blood and serum samples analysed for immune response. PC3-luc2M cells were injected into the left ventricle of SCID mice followed by treatment with RALA/CMV-iNOS nanoparticles to evaluate the tumour response in a metastatic model of prostate cancer. Functional cationic nanoparticles were produced with gene expression in PC-3 prostate cancer cells. Furthermore, repeated administrations of RALA/DNA nanoparticles into immunocompetent mice did not produce any immunological response: neutralization of the vector or release of inflammatory mediators. RALA/CMV-iNOS reduced the clonogenicity of PC-3 cells in vitro, and in an in vivo model of prostate cancer metastasis, systemically delivered RALA/CMV-iNOS significantly improved the survival of mice. These studies further validate RALA as a genetic cargo delivery vehicle and iNOS as a potent therapy for the treatment of cancer.

中文翻译:


使用 RALA/iNOS 复合纳米颗粒进行基因治疗可显着提高转移性​​前列腺癌模型的生存率。



FDA 和 EMA 最近批准用于治疗遗传性疾病的基因疗法,进一步为临床使用核酸药物的评估打开了大门。由于 DNA 受损或不适当,癌症是一种特别适合基因干预的疾病。 RALA 肽已被证明是一种有效的非病毒核酸递送平台。本研究探讨了使用 RALA 传递编码诱导型一氧化氮合酶 (iNOS) 的质粒作为抗癌治疗。通过动态光散射和透射电子显微镜表征 RALA/DNA 纳米粒子的理化性质。纳米粒子用荧光团标记,并使用正交切片的共聚焦显微镜随时间进行跟踪以确定细胞位置。采用体外研究来确定纳米颗粒对于 pEGFP-N1 和 CMV-iNOS 的功能。将纳米颗粒静脉注射到 C57/BL6 小鼠体内,并分析其血液和血清样本的免疫反应。将 PC3-luc2M 细胞注射到 SCID 小鼠的左心室,然后用 RALA/CMV-iNOS 纳米颗粒治疗,以评估前列腺癌转移模型中的肿瘤反应。利用 PC-3 前列腺癌细胞中的基因表达生产功能性阳离子纳米颗粒。此外,向免疫活性小鼠重复施用 RALA/DNA 纳米颗粒不会产生任何免疫反应:中和载体或释放炎症介质。 RALA/CMV-iNOS 在体外降低了 PC-3 细胞的克隆形成性,在前列腺癌转移的体内模型中,全身递送 RALA/CMV-iNOS 显着提高了小鼠的存活率。 这些研究进一步验证了 RALA 作为基因货物递送载体和 iNOS 作为治疗癌症的有效疗法。
更新日期:2018-06-01
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