Li Yaqing, Chen Yinting, Li Jiajia, Zhang Zuoquan, Huang Chumei, Lian Guoda, Yang Kege, Chen Shaojie, Lin Ying, Wang Lingyun, Huang Kaihong, Zeng Linjuan
Department of Gastroenterology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China.
Cancer Sci. 2017 Jul;108(7):1493-1503. doi: 10.1111/cas.13267. Epub 2017 Jun 13.
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 (scFv ) 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 scFv -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.
肿瘤转移在胰腺癌中自然发生，化疗效果通常较差。精准医学将靶基因下调与化疗药物相结合，有望提高治疗效果。因此，我们使用靶向共递送纳米颗粒（NP）载体开发了一种微小RNA-21反义寡核苷酸（ASO-miR-21）与吉西他滨（Gem）的联合疗法，并研究了其对胰腺癌细胞转移和生长的协同抑制作用。聚乙二醇-聚乙烯亚胺-磁性氧化铁纳米颗粒用于共递送ASO-miR-21和Gem。使用抗CD44v6单链可变片段（scFv）包被颗粒以实现主动靶向递送。我们的结果表明，ASO下调致癌性miR-21导致肿瘤抑制基因PDCD4和PTEN上调，并抑制上皮-间质转化，从而在体外抑制胰腺癌细胞的增殖并诱导其克隆形成、迁移和侵袭。与单独使用ASO-miR-21或Gem处理相比，ASO-miR-21和Gem的共递送在体外诱导了更多的细胞凋亡，并更大程度地抑制了胰腺癌细胞的生长。在动物试验中，与非靶向纳米颗粒相比，更多的scFv-PEG-聚乙烯亚胺/ASO-磁性氧化铁NP/Gem聚集在肿瘤部位，并有效抑制肿瘤增殖和转移。使用磁共振成像观察纳米颗粒的肿瘤归巢情况。这些结果表明，使用scFv功能化的NP载体进行miR-21基因沉默与Gem疗法的联合对胰腺癌细胞具有协同抗肿瘤作用，这是一种有前景的胰腺癌治疗策略。
