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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.

SUBMITTER: Wang C

PROVIDER: S-EPMC7108023 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Wang Congcong C Zhang Ruiguo R Tan Jian J Meng Zhaowei Z Zhang Yueqian Y Li Ning N Wang Hanjie H Chang Jin J Wang Renfei R

Oncology reports 20200309 5

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 inhib ...[more]

PMID: 32323855

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Project description:BackgroundMesoporous silica (MPS) nanoparticles (NPs), which have a unique pore structure and extremely large surface area and pore volume, have received much attention because of their biomedical application potential. Using MPS NPs for biomedical devices requires the verification of their biocompatibility because the surface area of NPs is one of the most important determinants of toxicity, including the cellular uptake and immune response. We have previously reported that the cytotoxicity and inflammation potential of MPS NPs have been shown to be lower than those of general amorphous colloidal silica (Col) NPs in macrophages, but the low cytotoxicity does not guarantee high biocompatibility in vivo. In this study, we compared the in vivo immunotoxicity of MPS and Col NPs in the mouse model to define the effects of pore structural conditions of silica NPs.Materials and methodsBoth MPS and Col NPs (2, 20, and 50 mg/kg/day) were intraperitoneally administered in female BALB/c mice for 4 weeks, and clinical toxicity, lymphocyte population, serum IgG/IgM levels, and histological changes were examined.ResultsThere was no overt sign of clinical toxicity in either MPS- or Col-treated mice. However, MPS NPs led to significant increases in liver and spleen weight and splenocyte proliferation. Mice treated with MPS NPs showed altered lymphocyte populations (CD3(+), CD45(+), CD4(+), and CD8(+)) in the spleen, increased serum IgG and IgM levels, and histological changes. Despite slight changes in lymphocyte populations in the spleen, Col NPs did not alter other immunological factors.ConclusionThe results indicate that in vivo exposure to MPS NPs caused more damage to systemic immunity than that of Col NPs through the dysregulation of the spleen. The results for in vivo data are inconsistent with those for in vitro data, which show lower cytotoxicity for MPS NPs. These results suggest the importance of verifying biocompatibility both in vitro and in vivo during the design of new nanomaterials.

Dataset Information

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

Publications

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

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