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Aurora kinase inhibitors attached to iron oxide nanoparticles enhances inhibition of the growth of liver cancer cells

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Abstract

We have developed a novel Aurora kinase inhibitor (AKI) AM-005, an analogue of pan-AKI AT-9283. To improve the intracellular efficacy of AM-005 and AT-9283, we utilized magnetite nanoparticles (NPs) to deliver AM-005 and AT-9283 into human SMMC-7721 and HepG2 liver cancer cells. The drug-loaded NPs were prepared through quasi-emulsion solvent diffusion of magnetite NPs with AM-005 or AT-9283. The encapsulated drugs were readily released from NPs, preferentially at low pHs. Upon exposure, cancer cells effectively internalized drug-loaded NPs into lysosome-like vesicles, which triggered a series of cellular changes, including the formation of enlarged cytoplasm, the significant increase of membrane permeability, and the generation of reactive oxygen species (ROS). The increased ROS synthesis sustained over 72 h, whereas that in the cells treated with free-form drugs declined rapidly after 48 h. However, chemical sequestration of the iron core of NPs had a minor influence on the generation of intracellular ROS. On the other hand, uncoupling of AM-005 uptake with NP internalization into cells failed to induce ROS synthesis. Overall, our approach achieved two-fold increase in suppressing the viability of tumor cells in vitro and the growth of tumors in vivo. We conclude that magnetite NPs can be used as pH responsive nanocarriers that are able to improve the efficacy of AKIs.

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Authors and Affiliations

  1. State Key Laboratory of Bioelectronics and Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science & Medical Engineering, Southeast University, Nanjing, 210096, People’s Republic of China

    Xiquan Zhang, Lina Song, Yu Zhang, Min Ji & Ning Gu

  2. Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, People’s Republic of China

    Li Xie

  3. Jiangsu Chai Tai Tianqing Pharmaceutical Co. Ltd., Building No.9, District 699-8, Xuanwu Ave, Nanjing, 210023, People’s Republic of China

    Xiquan Zhang, Ming Zheng, Juan Yao & Weiwei Chang

  4. The Center of Vascular and Inflammatory Diseases, The Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA

    Xi Zhan

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  1. Xiquan Zhang
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  2. Li Xie
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  3. Ming Zheng
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  7. Yu Zhang
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  8. Min Ji
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  9. Ning Gu
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Correspondence to Min Ji, Ning Gu or Xi Zhan.

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11051_2014_2708_MOESM1_ESM.ppt

S-Fig 1. Drug loaded NPs induced apoptosis. (A)HepG2 and SMMC-7721 cells were treated with NPs, AM-005 and AM-NPs, respectively, for 4 days, and stained with annexin V-FITC/PI. The stained cells were analyzed by flow cytometry. Quantification of the data is presented on the right. (B) HepG2 cells were treated as above except that AT-9283 and AT-NPs were used. (C) HepG2 cells were treated with the reagents as indicated for 4 days, and analyzed by Western blot for the expression of α-tubulin and caspase-3. The intensity of each band was converted to digital data and quantified by ImageJ. The value of caspase-3 was normalized to that of corresponding α-tubulin. S-Fig 2. AM-NPs promote LDH release. HepG2 (A) and SMMC-7721 (B) cells were treated with AM-005 and AM-NPs for 48 h at indicated concentrations. The amount of LDH present in the media was measured as described in Materials and Methods. S-Fig 3. AT-NPs increase ROS generation. HepG2 cells were treated with NPs, AT-9283 and AT-NPs, respectively, at either 250 ng/mL (A) or 500 ng/mL (B) for 24h, 48h and 72h as indicated. All the treated cells were subjected to ROS synthesis analysis as described in the legend of Fig 6. The data were presented as the mean ± SEM (n=3) of ROS levels as defined by DCF. **, p < 0.005; and ***; p < 0.0005 (t-test), referring to the differences as indicated. S-Fig 4. Analysis of ROS in tumors. HepG2 tumors were excised at different days after treatment with saline, NPs, AT-9283, and AT-NPs (A) or saline, NPs, AM-005 and AM-NPs (B). Isolated tumor cells were then subjected to ROS analysis by measuring the conversion of H2DCF-DA into DCF as described in the Materials and Methods. S-Fig 5. DSL analysis of stored AM-NPs and NPs. AM-NPs and NPs were prepared and stored in water at 4°C. After 4 months, they were re-analyzed by DLS. Supplementary material 1 (PPT 1796 kb)

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Zhang, X., Xie, L., Zheng, M. et al. Aurora kinase inhibitors attached to iron oxide nanoparticles enhances inhibition of the growth of liver cancer cells. J Nanopart Res 17, 247 (2015). https://doi.org/10.1007/s11051-014-2708-4

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