Department of Microbiology and Immunology, Medical University of South Carolina, Charleston 29425, USA.
Chemical Engineering, School for Engineering of Matter, Transport, and Energy, Arizona State University, Tempe 85287-6106 USA.
J Control Release. 2014 Feb 28;176:35-43. doi: 10.1016/j.jconrel.2013.12.012. Epub 2013 Dec 24.
Gene therapy has garnered significant attention as a therapeutic approach for bladder cancer but efficient delivery and gene expression remain major hurdles. The goal of this study was to determine if cationic polymers can enhance adenoviral gene expression in cells that are difficult to transduce in vitro and to subsequently investigate lead candidates for their capacity to increase adenoviral gene expression in an orthotopic in vivo model of bladder cancer. In vitro screening of linear polyamine-based and aminoglycoside-based polymer libraries identified several candidates that enhanced adenoviral reporter gene expression in vitro. The polyamine-based polymer NPGDE-1,4 Bis significantly enhanced adenoviral gene expression in the orthotopic model of bladder cancer but unfortunately further use of this polymer was limited by toxicity. In contrast, the aminoglycoside-based polymer paromomycin-BGDE, enhanced adenoviral gene expression within the bladder without adverse events. Our study demonstrates for the first time that cationic polymers can enhance adenoviral gene expression in an orthotopic model of bladder cancer, thereby providing the foundation for future studies to determine therapeutic benefits of polymer-adenovirus combination in bladder cancer gene therapy.
基因治疗作为膀胱癌的一种治疗方法引起了广泛关注，但有效的传递和基因表达仍然是主要障碍。本研究的目的是确定阳离子聚合物是否可以增强体外难以转导的细胞中腺病毒基因的表达，并随后研究其在膀胱癌原位模型中增加腺病毒基因表达的能力的候选药物。基于线性聚胺和氨基糖苷的聚合物文库的体外筛选确定了几种可增强体外腺病毒报告基因表达的候选药物。聚胺基聚合物 NPGDE-1,4 Bis 显著增强了膀胱癌的原位模型中的腺病毒基因表达，但不幸的是，该聚合物的进一步使用受到毒性的限制。相比之下，氨基糖苷类聚合物巴龙霉素-BGDE 增强了膀胱中的腺病毒基因表达而没有不良事件。我们的研究首次表明，阳离子聚合物可以增强膀胱癌的原位模型中的腺病毒基因表达，从而为未来的研究提供了基础，以确定聚合物-腺病毒联合在膀胱癌基因治疗中的治疗益处。
