Delivery of miR-212 by chimeric peptide-condensed supramolecular nanoparticles enhances the sensitivity of pancreatic ductal adenocarcinoma to doxorubicin
Delivery of miR-212 by chimeric peptide-condensed supramolecular nanoparticles enhances the sensitivity of pancreatic ductal adenocarcinoma to doxorubicin
复制标题
嵌合肽缩合超分子纳米颗粒递送 miR-212 增强胰腺导管腺癌对阿霉素的敏感性
DOI：
10.1016/j.biomaterials.2018.11.035
复制
发表时间：
2019-02-01
期刊：
影响因子：
14
通讯作者：
Liang, Tingbo
中科院分区：
文献类型：
--
作者：
Chen, Wei;Zhou, Yue;Liang, Tingbo
胰腺导管腺癌是一种破坏性的恶性肿瘤，预后差。需要新的治疗靶点和方法来改善PDAC患者的总体生存率。MicroRNA-212（miR-212）在多种癌症中被报道为肿瘤抑制因子，但其在胰腺癌进展中的确切作用和确切机制尚不清楚。在这项研究中，我们开发了一种新的嵌合肽（PL-1），它由plectin-l靶向的PDAC特异性和富含精氨酸的RNA结合基序组成，可以浓缩miRNA以自组装超分子纳米颗粒。这些纳米颗粒可以特异性地、高效地将miR-212递送到PDAC细胞中，并且在RNase和血清中也显示出良好的稳定性。此外，我们证明PL-1/miR-212纳米颗粒可以显着增强阿霉素对PDAC的体外和体内化疗效果。在机制上，PL-1/miR-212纳米颗粒联合miR-212干预导致USP 9 X（ubiquitin specific peptidase 9，X-linked，USP 9 X）表达明显降低，并最终增强阿霉素诱导的PDAC细胞凋亡和自噬。这些发现提供了一种新的有希望的通过PL-1/miR-212纳米颗粒的抗癌策略，并将miR-212/USP 9 X确定为未来针对人类PDAC的系统性治疗的新的潜在靶点。
Pancreatic ductal adenocarcinoma (PDAC) is a destructive cancer with poor prognosis. Both novel therapeutic targets and approaches are needed to improve the overall survival of PDAC patients. MicroRNA-212 (miR-212) has been reported as a tumor suppressor in multiple cancers, but its definitive role and exact mechanism in the progression of pancreatic cancer is unclear. In this study, we developed a new chimeric peptide (PL-1) composed of plectin-l-targeted PDAC-specific and arginine-rich RNA-binding motifs which could condense miRNA to self assemble supramolecular nanoparticles. These nanoparticles could deliver miR-212 into PDAC cells specifically and efficiently which also showed good stability in RNase and serum. Moreover, we demonstrated that PL-1/miR-212 nanoparticles could dramatically enhance the chemotherapeutic effect of doxorubicin for PDAC both in vitro and in vivo. In terms of mechanism, combined miR-212 intervention by PL-1/miR-212 nanoparticles resulted in obvious decrease of USP9X expression (ubiquitin specific peptidase 9, X-linked, USP9X) and eventually enhanced the doxorubicin induced apoptosis and autophagy of PDAC cells. These findings provide a new promising anti-cancer strategy via PL-1/miR-212 nanoparticles and identify miR-212/USP9X as a new potential target for future systemic therapy against human PDAC.