Co-delivery of microRNA-21 antisense oligonucleotides and gemcitabine using nanomedicine for pancreatic cancer therapy.
Co-delivery of microRNA-21 antisense oligonucleotides and gemcitabine using nanomedicine for pancreatic cancer therapy.
复制标题
使用纳米药物共同递送 microRNA-21 反义寡核苷酸和吉西他滨用于胰腺癌治疗。
DOI：
10.1111/cas.13267
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发表时间：
2017-07
期刊：
影响因子：
5.7
通讯作者：
Zeng L
中科院分区：
文献类型：
--
作者：
Li Y;Chen Y;Li J;Zhang Z;Huang C;Lian G;Yang K;Chen S;Lin Y;Wang L;Huang K;Zeng L
胰腺癌的肿瘤转移是自然发生的，化疗的效果往往较差。精准医学将下调靶基因与化疗药物相结合，有望提高治疗效果。因此，我们开发了一种靶向共递送纳米颗粒（NP）载体，将microRNA‐21反义寡核苷酸（ASO‐miR‐21）与吉西他滨（Gem）联合治疗，并研究了其对胰腺癌细胞转移和生长的协同抑制作用。采用聚乙二醇-聚亚胺-磁性氧化铁NPs共递送ASO - miR - 21和Gem。使用抗CD44v6单链可变片段（scFvCD 44v6）包裹颗粒以获得活性和靶向递送。我们的研究结果表明，ASO下调致癌基因miR - 21，导致肿瘤抑制基因PDCD4和PTEN上调，抑制上皮-间质转化，从而抑制胰腺癌细胞的增殖，诱导克隆的形成、迁移和侵袭。在体外实验中，与ASO‐miR‐21或Gem单独处理相比，ASO‐miR‐21和Gem共同递送诱导了更多的细胞凋亡，并在更大程度上抑制了胰腺癌细胞的生长。在动物实验中，scFvCD 44v6 - PEG -聚乙烯亚胺/ASO -磁性氧化铁NP/Gem比非靶向NPs在肿瘤部位积累更多，并诱导了肿瘤增殖和转移的有效抑制。采用磁共振成像技术观察NPs的肿瘤归巢。这些结果表明，miR - 21基因沉默与使用scFv功能化NP载体的Gem治疗相结合，对胰腺癌细胞具有协同抗肿瘤作用，这是一种很有前景的胰腺癌治疗策略。
Tumor metastasis occurs naturally in pancreatic cancer, and the efficacy of chemotherapy is usually poor. Precision medicine, combining downregulation of target genes with chemotherapy drugs, is expected to improve therapeutic effects. Therefore, we developed a combined therapy of microRNA‐21 antisense oligonucleotides (ASO‐miR‐21) and gemcitabine (Gem) using a targeted co‐delivery nanoparticle (NP) carrier and investigated the synergistic inhibitory effects on pancreatic cancer cells metastasis and growth. Polyethylene glycol–polyethylenimine–magnetic iron oxide NPs were used to co‐deliver ASO‐miR‐21 and Gem. An anti‐CD44v6 single‐chain variable fragment (scFvCD 44v6) was used to coat the particles to obtain active and targeted delivery. Our results showed that the downregulation of the oncogenic miR‐21 by ASO resulted in upregulation of the tumor‐suppressor genes PDCD4 and PTEN and the suppression of epithelial–mesenchymal transition, which inhibited the proliferation and induced the clonal formation, migration, and invasion of pancreatic cancer cells in vitro. The co‐delivery of ASO‐miR‐21 and Gem induced more cell apoptosis and inhibited the growth of pancreatic cancer cells to a greater extent than single ASO‐miR‐21 or Gem treatment in vitro. In animal tests, more scFvCD 44v6‐PEG‐polyethylenimine/ASO‐magnetic iron oxide NP/Gem accumulated at the tumor site than non‐targeted NPs and induced a potent inhibition of tumor proliferation and metastasis. Magnetic resonance imaging was used to observed tumor homing of NPs. These results imply that the combination of miR‐21 gene silencing and Gem therapy using an scFv‐functionalized NP carrier exerted synergistic antitumor effects on pancreatic cancer cells, which is a promising strategy for pancreatic cancer therapy.