Microvesicle-mediated delivery of transforming growth factor β1 siRNA for the suppression of tumor growth in mice
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.
Journal: Biomaterials - Volume 35, Issue 14, May 2014, Pages 4390–4400