Abplatin(IV) inhibited tumor growth on a patient derived cancer model of hepatocellular carcinoma and its comparative multi-omics study with cisplatin

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  Scheme 1. Schematic illustration showing Abplatin(IV) inhibited the tumor growth on a patient-derived tumor xenograft model of hepatocellular carcinoma (PDXHCC) and its comparative multi-omics study with cisplatin. A Abplatin(IV) was prepared by the physical encapsulation of a hydrophobic CisPt(IV) with HSA. B Subsequently, Abplatin(IV) was intraveneously (i.v.) injected into the mice bearing PDXHCC. Abplatin(IV) could be accumulated at the tumor site via blood circulation and internalized by the cancer cells via endocytosis. C The possible mechanism of Cisplatin (Left panel) and Abplatin(IV) (Right panel). The Pt(II) in cisplatin might directly bind to DNA to cause cell apoptosis. However, Abplatin(IV) was believed to be reduced by intracellular reducing agents such as glutathione(GSH) and ascorbic acid to release Pt(II) for DNA binding. Transcriptomics and metabolomics study on the mechanism of Abplatin(IV) revealed Abplatin(IV) significantly disturbed the purine metabolism pathway. Up-regulated and down-regulated metabolites were represented in red and blue, respectively. Lipidomics study showed that Abplatin(IV) induced the disorder of glycerophospholipids and sphingolipids

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  Fig. 1. Characterization of Abplatin(IV). A Representative transmission electron microscope (TEM) image of Abplatin(IV), scale bar = 200 nm. B Hydrodynamic diameter of Abplatin(IV) by dynamic light scattering (DLS). C Particle size of Abplatin(IV) following incubation in PBS for 7 days. D Element mapping of Abplatin(IV) by scanning transmission electron microscope (STEM), scale bar = 100 nm. E Representative drug release profile of Abplatin(IV) under various conditions

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  Fig. 2. Intracellular uptake and in vitro anticancer efficacy of Abplatin(IV). A Intracellular uptake of Abplatin(IV)@Cy5.5 by BEL-7404 cells via confocal laser scanning microscope (CLSM), scale bar = 40 µm. B Semi-quantitative study of the intracellular uptake of Abplatin(IV)@Cy5.5 via flow cytometry. C Intracellular Pt uptake of the cells treated with various drugs (10 μM Pt) for 1, 4, and 7 h respectively via ICP-MS. D Pt-DNA adducts of cells treated with cisplatin, CisPt(IV), and Abplatin(IV) via ICP-MS. E Fluorescence distribution of Abplatin(IV)@Cy5.5 at 12 h in different focal planes of 3D tumor sphere, scale bar = 100 µm. F In vitro anticancer activity of cisplatin, CisPt(IV) and Abplatin(IV). G Cell apoptosis in 3D tumor sphere induced by various drugs (10 µM) in 3D tumor spheres at 24 h, scale bar = 200 µm

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  Fig. 3. Abplatin(IV) inhibited tumor growth on a PDXHCC model. A Schematic illustration showing the establishment of a PDXHCC model for in vivo studies. B In vivo biodistribution of Abplatin(IV) labeled with Cy7.5 via in vivo imaging and ex vivo imaging of major organs at 36 h. C The corresponding semi-quantification of the fluorescence signal of Abplatin(IV) over time and biodistribution of major organs. D Tumor growth inhibition curves of mice treated with PBS, cisplatin, and Abplatin(IV). E H&E staining and TUNEL of representative tumor tissues. Scale bar for H&E images = 200 µm, scale bar for TUNEL images = 100 µm. F H&E staining of major organs of mice treated by PBS and Abplatin(IV), scale bar = 100 µm

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  Fig. 4. Transcriptomic analysis of BEL-7404 cells treated with cisplatin and Abplatin(IV) by RNA-seq. A A Venn diagram revealed the number of genes transcribed in each treatment group. B, C Volcano plots displayed the differentially expressed genes. D A heat map showed the significant differential transcription genes. E Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis based on differential genes

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  Fig. 5. Lipidomic and metabolomic study on BEL-7404 cells treated with Abplatin(IV). A Differential lipids between PBS and Abplatin(IV) treated cells. B Differential metabolites between PBS and Abplatin(IV)-treated cells. C Overview of enriched metabolite sets in the cells treated with Abplatin(IV) and PBS. D Abplatin(IV) disturbed the purine metabolism, arginine biosynthesis, histidine metabolism, and glutathione metabolism in BEL-7404 cells. Up-regulated and down-regulated metabolites were represented in red and blue, respectively