Graphene Oxide Nanoplatforms to Enhance Cisplatin-Based Drug Delivery

<b>INTRODUCTION</b><br/>Glioblastoma is a very aggressive type of cancer with a very poor life expectancy for patients and breast cancer often metastasizes into the liver, lungs, brain, and, in 70% of cases, to bones^1,2. Chemotherapy is largely used to treat cancer and it is based on the use of molecules targeting the high cancer cell proliferation metabolism³. Platinum (Pt) and three of its isoforms (cisplatin, carboplatin, and oxaliplatin) are some of the most successful metal-based drugs to cure breast cancer and glioblastoma^4,5. Despite Pt-based chemotherapeutics being effective, their side effects (high degradation before entering the cells, the off-target organs toxicity, and cell resistance) remain great drawbacks^6-9. In this work, it was developed a Graphene Oxide (GO) nanoplatform functionalized with Pt as a promising smart delivery system that could increase the Pt cellular uptake reducing the Pt amount needed for cancer treatment and consequently the side effects. <br/><b>EXPERIMENTAL METHODS</b><br/>GO nanoplatforms were treated with 8-arm polyethylene glycol-amine (PEG) that permits to load Pt on the platform (GO-PEG-Pt) and an extensive <i>in vitro</i> screening was performed on two breast cancer cell lines with aggressive nature that lead to metastatic behavior (MDA-MB 231 and MDA-MB 468) and two glioblastoma cell lines (U87 and U118). The bioactivity of GO-PEG-Pt compared to Pt-free (15 μM, 30 μM, and 60 μM) was analyzed looking at the effect on cellular uptake (ICP-OES), viability (MTT Assay), morphology (DAPI and actin staining), and migration up to 72 hours (Scratch Assay).<br/><b>RESULTS AND DISCUSSION</b><br/>The cell viability was significantly lower in MDA-MB 468 and U118 cells at 30 μM for GO-PEG-Pt group compared to Pt-free (&lt;75%), and even the cell morphology seemed to be compromised. These results were highly related to the cellular uptake of GO-PEG-Pt which is significantly higher compared to Pt-free after 24 hours. This data confirmed that our nanoplatform promotes drug delivery directly inside the cells. In addition, GO-PEG-Pt mostly affected the cell migration compared to Pt-free, in particular, MDA-MB 231 showed a migration reduction of 60%, and this could be a great advantage in reducing the metastasis process. <br/><b>CONCLUSION</b><br/>This study demonstrated that the combination of Pt onto PEG-functionalized nano-sized GO provided numerous advantages for tumor therapy such as minimizing toxicity, enhancing the cellular uptake, and consequently we could reduce the side effects because a lower amount of Pt is necessary.<br/><b>REFERENCES</b><br/>1. Feng, Y. <i>et al.</i>, Genes Dis., 5(2):77-106, 2018<br/>2. Dymova, M.A. <i>et al.</i>, Int. J. Mol. Sci., 22(12):6385, 2021<br/>3. Schirrmacher, V., Int. J. Oncol., 54:407–19, 2019 <br/>4. Taghavi, M.S. <i>et al.</i>, In Vitro Cell. Dev. Biol.-Animal, 49:465–472, 2013 <br/>5. Martín, M., Clin. Breast Cancer, 2(3):190-208, 2001<br/>6. Bersini, S. <i>et al.</i>, J. Biomaterials, 35:2454–61, 2014 <br/>7. Lei, S. <i>et al.</i>, Cancer Commun., 12:4413, 2021 <br/>8. Rajaratnam, V. <i>et al.</i>, Cancers, 12(4):937, 2020 <br/>9. Liang, Y. <i>et al.</i>, Semin. Cancer. Biol., 60:14–27, 2020<br/><b>ACKNOWLEDGMENTS</b><br/>The authors would like to thank the Nano4Tarmed project (H2020-WIDESPREAD-2020-5, grant no: 952063) for providing financial support to this project.