Effect of mesoporous silica nanoparticles co‑loading with 17‑AAG and Torin2 on anaplastic thyroid carcinoma by targeting VEGFR2.

Abstract

Anaplastic thyroid carcinoma (ATC) is a highly aggressive tumor with a poor prognosis and a low median survival rate because of insufficient effective therapeutic modalities. Recently, mesoporous silica nanoparticles (MSNs) as a green non-toxic and safe nanomaterial have shown advantages to be a drug carrier and to modify the targeting group to the targeted therapy. To aim of the study was to explore the effects of MSNs co-loading with 17-allylamino-17-demethoxy-geldanamycin (17-AAG; HSP90 inhibitor) and 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2; mTOR inhibitor) by targeting vascular endothelial growth factor receptor 2 (VEGFR2) on the viability of human anaplastic thyroid carcinoma FRO cells. The cytotoxicity of 17-AAG and Torin2 were analyzed by MTT assay. The possible synergistic antitumor effects between 17-AAG and Torin2 were evaluated by CompuSyn software. Flow cytometry was performed to assess the VEGFR2 targeting of (17-AAG+Torin2)@MSNs-anti-VEGFR2 ab and uptake by FRO cells. An ATC xenograft mouse model was established to assess the antitumor effect of (17-AAG+Torin2)@MSNs-anti-VEGFR2 ab in vivo. The results revealed that the combination of 17-AAG and Torin2 inhibited the growth of FRO cells more effectively compared with single use of these agents. Additionally, the synergistic antitumor effect appeared when concentration ratio of the two drugs was 1:1 along with total drug concentration greater than 0.52 µM. Furthermore, in an ATC animal model, it was revealed that the (17-AAG+Torin2)@MSNs-anti-VEGFR2 ab therapy modality could most effectively prolong the median survival time [39.5 days vs. 33.0 days (non-targeted) or 27.5 days (control)]. Compared to (17-AAG+Torin2)@MSNs, the (17-AAG+Torin2)@MSNs-anti-VEGFR2 ab could not only inhibit ATC cell growth but also prolong the median survival time of tumor-bearing mice in vivo and vitro more effectively, which may provide a new promising therapy for ATC.