Abstract

Conventional cancer combination therapy usually involves systemic delivery of anticancer drugs which may lead to the destruction of normal cells and physiological toxicity due to the lack of targeting ability and toxicity of drug carriers. In the present study, a triple combination nanosystem of gene therapy, chemotherapy and phototherapy delivered by multifunctional RNA nanohydrogels (RNA NHs) was established. By taking the advantages of DNA nanotechnology and rolling circle transcription (RCT), three lung cancer inhibitor microRNA (let-7a, microRNA 34a, microRNA 145) hairpins were integrated in one RNA NH nanoparticle, leading to the simultaneous silencing of three targeted mRNAs. Meanwhile, RNA NH carried doxorubicin (DOX, a chemotherapy drug) as well as 5,10,15,20-tetrakis (1-methylpyridinium-4-yl) porphyrin (TMPyP4, a photosensitizer) and delivered these drugs to cancer cells. It was demonstrated that lung cancer inhibitor microRNAs integrated in RNA NHs, DOX and TMPyP4 could play a synergistic anti-cancer role in multi-drug resistance cancer cells. Under the action of aptamer sequence S6 that was modified with cholesterol, the resulting RNA NHs were condensed to feasible size without the assistance of polyelectrolyte condensation reagents and showed cancer-specific cellular targeting. Subsequently, thousands of copies of miRNA together with chemotherapy drug as well as photosensitizer were delivered to cancer cells specifically, and an ideal synergistic treatment effect was achieved in vivo, thus playing a combined role of gene therapy, chemotherapy and phototherapy. Through this study, it can be concluded that the triple combination therapy nanosystem can overcome the multidrug resistance caused by the malfunction of genes in chemotherapy and shows a great potential in the field of multifunctional synergistic cancer treatment.

中文翻译：

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基于多功能RNA水凝胶的三结合纳米技术平台用于肺癌治疗

摘要

常规的癌症联合疗法通常涉及全身递送抗癌药物，由于缺乏靶向能力和药物载体的毒性，其可能导致正常细胞的破坏和生理毒性。在本研究中，建立了由多功能RNA纳米水凝胶（RNA NHs）提供的基因治疗，化学疗法和光疗三重组合纳米系统。利用DNA纳米技术和滚环转录（RCT）的优势，将三个肺癌抑制剂microRNA（let-7a，microRNA 34a，microRNA 145）发夹整合到一个RNA NH纳米颗粒中，从而导致三个目标mRNA的同时沉默。同时，RNA NH携带阿霉素（DOX，一种化疗药物）以及5,10,15,20-四（1-甲基吡啶-4-基）卟啉（TMPyP4，光敏剂）并将这些药物投放到癌细胞中。结果表明，整合在RNA NHs，DOX和TMPyP4中的肺癌抑制微RNA在多药耐药癌细胞中可发挥协同抗癌作用。在用胆固醇修饰的适体序列S6的作用下，无需聚电解质缩合试剂的帮助，将得到的RNA NHs缩合至可行的大小，并显示出针对癌症的细胞靶向。随后，将数千拷贝的miRNA连同化疗药物以及光敏剂一起特异性地递送至癌细胞，并获得了理想的协同治疗效果。DOX和TMPyP4可以在多药耐药癌细胞中发挥协同抗癌作用。在用胆固醇修饰的适体序列S6的作用下，无需聚电解质缩合试剂的帮助，即可将得到的RNA NHs浓缩至可行的大小，并显示出针对癌症的细胞靶向作用。随后，将数千拷贝的miRNA连同化疗药物以及光敏剂一起特异性地递送至癌细胞，并获得了理想的协同治疗效果。DOX和TMPyP4可以在多药耐药癌细胞中发挥协同抗癌作用。在用胆固醇修饰的适体序列S6的作用下，无需聚电解质缩合试剂的帮助，将得到的RNA NHs缩合至可行的大小，并显示出针对癌症的细胞靶向。随后，将数千拷贝的miRNA连同化疗药物以及光敏剂一起特异性地递送至癌细胞，并获得了理想的协同治疗效果。在体内，因此起着基因治疗，化学疗法和光疗相结合的作用。通过这项研究，可以得出结论，三联疗法纳米系统可以克服化学疗法中基因失灵引起的多药耐药性，并在多功能协同癌症治疗领域显示出巨大的潜力。