Microvesicle-mediated delivery of transforming growth factor β1 siRNA for the suppression of tumor growth in mice

• Published in: Biomaterials 2014-05, Vol.35 (14), p.4390-4400
• Main Authors: Zhang, Yaqin, Li, Limin, Yu, Jianxiong, Zhu, Dihan, Zhang, Yujing, Li, Xihan, Gu, Hongwei, Zhang, Chen-Yu, Zen, Ke
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Apoptosis; Argonaute Proteins - metabolism; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dentistry; Gene Transfer Techniques; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Male; Mice; Mice, Inbred BALB C; Microvesicle; Neoplasms - metabolism; Neoplasms - pathology; Phosphorylation; RNA, Small Interfering - metabolism; siRNA; Smad2 Protein - metabolism; Systemic delivery; TGF-β1; Transforming Growth Factor beta1 - metabolism; Tumor therapy; Unilamellar Liposomes - chemistry
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2014.02.003

Abstract Cell-derived microvesicles (MVs) have been recently shown as an efficient carrier to deliver small RNAs into the target cells. In the present study, we characterized the inhibitory effect of TGF-β1 siRNA delivered by mouse fibroblast L929 cell-derived MVs (L929 MVs) on the growth and metastasis of murine sarcomas 180 cells both in vitro and in vivo . We found that, comparing to the same concentration of free TGF-β1 siRNA, TGF-β1 siRNA delivered by L929 MVs much more efficiently decreased the level of TGF-β1 in the recipient tumor cells. Functionally, MVs containing TGF-β1 siRNA significantly decreased the viability and migration of sarcomas 180 cells and promoted the apoptosis of tumor cells. Co-immunoprecipitation with Argonaute 2 (AGO2) via anti-AGO2 antibody indicated that the majority of TGF-β1 siRNA in the MVs were associated with AGO2 complex. A tumor implantation mouse model further showed that intravenous injection of TGF-β1 siRNA-containing MVs strongly suppressed TGF-β1 expression and TGF-β1 signaling downstream in the implanted tumor cells, and thus inhibited the growth and lung metastases of tumor cells. In conclusion, our results collectively demonstrate that the delivery of therapeutic TGF-β1 siRNA by cell-derived MVs provides an effective strategy to control tumor cell growth and metastasis.