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Glutathione boosting the cytotoxicity of a magnetic platinum(iv) nano-prodrug in tumor cells.

ABSTRACT: Superparamagnetic iron oxide nanoparticles (SPIONs) are potential vehicles for targeted drug delivery and viable contrast agents for magnetic resonance imaging (MRI). A Pt^IV prodrug (HSPt) derived from functionalization of cisplatin with hydroxyl and succinate is conjugated with a poly(ethylene glycol) (PEG)-modified SPION for cancer therapy and monitoring of therapeutic responses. The relaxivity of HSPt-PEG-SPIONs is larger than that of commercial contrast agent Feridex, and a tumor-selective negative contrast is observed in MRI in a magnetic field. HSPt-PEG-SPIONs can be dissociated and reduced into Pt^II species by glutathione (GSH). Instead of forming DNA-Pt crosslinks, the reduced product induces direct DNA single- or double-strand breaks, which is uncommon for Pt drugs. The cytotoxicity of HSPt-PEG-SPIONs is positively correlated with the GSH level of tumor cells, which is opposite to the scenario of current Pt drugs. HSPt-PEG-SPIONs are as cytotoxic as cisplatin against cancer cells but are almost nontoxic towards normal cells. Since the mechanism of action of the nanocomposite is different from the established paradigm for Pt drugs, it may become a special theranostic agent for cancer treatment.

SUBMITTER: Zhu Z

PROVIDER: S-EPMC6054038 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Glutathione boosting the cytotoxicity of a magnetic platinum(iv) nano-prodrug in tumor cells.

Zhu Zhenzhu Z Wang Zenghui Z Hao Yigang Y Zhu Chengcheng C Jiao Yang Y Chen Huachao H Wang Yun-Ming YM Yan Jun J Guo Zijian Z Wang Xiaoyong X

Chemical science 20160120 4

Superparamagnetic iron oxide nanoparticles (SPIONs) are potential vehicles for targeted drug delivery and viable contrast agents for magnetic resonance imaging (MRI). A Pt<sup>IV</sup> prodrug (HSPt) derived from functionalization of cisplatin with hydroxyl and succinate is conjugated with a poly(ethylene glycol) (PEG)-modified SPION for cancer therapy and monitoring of therapeutic responses. The relaxivity of HSPt-PEG-SPIONs is larger than that of commercial contrast agent Feridex, and a tumor- ...[more]

PMID: 30090279

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Project description:Herein, thermo-responsive liposomes (TLs) loaded with Asp (Asp/TLs) were produced by self-assembling DPPC, DSPE-PEG2000, and cholesterol. The preparation variables were optimized using the Box-Behnken design (BBD). The optimized Asp/TLs exhibited an average particle size of 114.05 ± 1.56 nm, PDI of 0.15 ± 0.015, zeta potential of -15.24 ± 0.65 mV, and entrapment efficiency (EE%) of 84.08 ± 2.75%. In addition, under physiological conditions, Asp/TLs showed spherical shape, outstanding stability and thermo-triggered the release of Asp at 38 °C, reaching the maximum Asp release at 40 °C. The MTT assay showed that the optimal Asp/TLs exhibited the highest cytotoxic activity upon exposure to mild hyperthermia (40 °C) against the invasive triple-negative breast cancer cell line (MDA-MB-231) when compared to other preparations. The IC50 of Asp/TLs (40 °C) was estimated at 0.9 μg mL-1, while that of free Asp (40 °C) was 3.83 μg mL-1. As such, the optimal Asp/TLs were shown to increase the cytotoxic activity of Asp by 4-fold upon exposure to mild hyperthermia. The IC50 values of Asp and Asp/TLs without exposure to 40 °C were 6.6 μg mL-1 and 186 μg mL-1, respectively. This indicated that Asp was released only when placed at 40 °C. The apoptosis assay revealed that Asp/TLs (40 °C) caused a remarkable increase in the percentage of cell population among both the late apoptosis and necrosis quartiles, as well as a significant decline in the viable cell quartile (P ≤ 0.001) when compared to Asp (40 °C). Asp/TLs (40 °C) and Asp (40 °C) could stimulate the intrinsic apoptosis pathway by upregulating the apoptotic genes Bak and Bax, while downregulating the anti-apoptotic genes, BCL-xL and BCL-2. The free Asp (40 °C) increased the gene expression of Bak and Bax by 4.4- and 5.2-folds, while reducing the expression of BCL-xL and BCL-2 by 50% and 73%, respectively. The optimal Asp TLs (40 °C) manifested more potent effects as demonstrated by the upregulation of Bak, Bax, and P53 by 5.6-, 7.2-, and 1.3-folds, as well as the downregulation of BCL-xL and BCL-2 by 70% and 85%, respectively. As such, the optimal Asp TLs (40 °C) treatment displayed the most potent cytotoxic profile and induced both apoptosis and necrosis in MDA-MB-231.

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Glutathione boosting the cytotoxicity of a magnetic platinum(iv) nano-prodrug in tumor cells.

Publications

Glutathione boosting the cytotoxicity of a magnetic platinum(iv) nano-prodrug in tumor cells.

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