Department of Medical Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Department of Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China.
Biomater Sci. 2021 Oct 12;9(20):6673-6690. doi: 10.1039/d1bm00748c.
Pancreatic cancer (PC), characterized by its dense desmoplastic stroma and hypovascularity, is one of the most lethal cancers with a poor prognosis in the world. Traditional treatments such as chemotherapy, radiotherapy, and targeted therapy show little benefit in the survival rate in patients with advanced PC due to the poor penetration and resistance of drugs, low radiosensitivity, or severe side effects. Gene therapy can modify the morbific and drug-resistant genes as well as insert the tumor-suppressing genes, which has been shown to have great potential in PC treatment. The development of safe non-viral vectors for the highly efficient delivery of nucleic acids is essential for effective gene therapy, and has been attracting much attention. In this review, we first summarized the PC-promoting genes and gene therapies using plasmid DNA, mRNA, miRNA/siRNA-based RNA interference technology, and genome editing technology. Second, the commonly used non-viral nanovector and theranostic gene delivery nanosystem, especially the tumor microenvironment-sensitive delivery nanosystem and the cell/tumor-penetrating delivery nanosystem, were introduced. Third, a combination of non-viral nanovector-based gene therapy and other therapies, such as immunotherapy, chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT), for PDAC treatment was discussed. Finally, a number of clinical trials have demonstrated the proof-of-principle that gene therapy or the combination of gene therapy and chemotherapy using non-viral vectors can inhibit the progression of PC. Although most of the non-viral vector-based gene therapies and their combination therapy are still under preclinical research, the development of genetics, molecular biology, and novel vectors would promote the clinical transformation of gene therapy.
胰腺癌（PC）以其密集的纤维组织和低血管生成性为特征，是世界上最致命的癌症之一，预后较差。由于药物穿透性差、耐药性、放射敏感性低或副作用严重，传统治疗方法如化疗、放疗和靶向治疗在晚期 PC 患者的生存率方面收效甚微。基因治疗可以修饰致病和耐药基因，并插入肿瘤抑制基因，在 PC 治疗中显示出巨大的潜力。开发用于高效传递核酸的安全非病毒载体对于有效的基因治疗至关重要，已引起广泛关注。在这篇综述中，我们首先总结了促进 PC 的基因和使用质粒 DNA、mRNA、miRNA/siRNA 为基础的 RNA 干扰技术和基因组编辑技术的基因治疗。其次，介绍了常用的非病毒纳米载体和治疗性基因传递纳米系统，特别是肿瘤微环境敏感传递纳米系统和细胞/肿瘤穿透传递纳米系统。第三，讨论了基于非病毒纳米载体的基因治疗与其他治疗方法（如免疫疗法、化学疗法、光热疗法（PTT）和光动力疗法（PDT））联合治疗 PDAC。最后，许多临床试验证明了使用非病毒载体的基因治疗或基因治疗与化疗的联合治疗可以抑制 PC 的进展。尽管大多数基于非病毒载体的基因治疗及其联合治疗仍处于临床前研究阶段，但遗传学、分子生物学和新型载体的发展将促进基因治疗的临床转化。
