(F-237) Platinum Nanoparticles' Mechanism of Action in Triple Negative Breast Cancer

Introduction:: Nanotechnology has emerged as a potential therapeutic for cancer treatment. Metallic nanoparticles, in particular, like gold and silver, have gained significant importance in nanomedicine. More importantly, platinum nanoparticles (Pt NPs) have shown promising anticancer activity while having low toxicity towards healthy cells. Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that metastasizes rapidly and currently only has toxic chemotherapeutics. Cisplatin, in particular, works by entering the cell, ionizing in the cell, binding to the DNA, and breaking the DNA, effectively disabling the cell’s ability to proliferate. Cell viability tests for TNBC, double positive breast cancer (DPBC), cisplatin-resistant uterine sarcoma, and cardiac fibroblasts indicate that Pt NPs works similarly to cisplatin, but only kills TNBC, leaving healthy cells unaffected (López et. al 2022). Literature also suggests that increased levels of reactive oxidative species (ROS) when Pt NPs are uptaken leads to cell death. However, due to platinum’s antioxidant properties, it is unlikely that Pt NPs are killing TNBC by way of ROS. Initial ROS studies with TNBC and uterine sarcoma show patterns of decreased levels of ROS after Pt NPs treatment. Additionally, the acidic environment of cancer cells can lead to more ionization of the Pt NPs, increasing the Pt NPs efficacy at killing TNBC. The mechanism of action of Pt NPs needs to be more fully understood and to do so, further reactive oxidative species studies, cellular uptake studies were conducted.


Materials and Methods:: Potassium tetrachloroplatinate (II), Brij-58, and L-ascorbic acid were used in the synthesis of Pt NPs. Platinum nanoparticles were prepared by chemical reduction following the mechanism by Shim et. al. 2017. Four cell lines were used: triple-negative breast cancer (TNBC) (MDA-MB-231), double positive breast cancer (DPBC) (T47D), uterine sarcoma resistant to cisplatin (MES-SA), and cardiac fibroblasts (HCF-V). ROS studies were conducted on all four cell lines and incubated at 37OC for 1, 3, and 5 days. Platinum ion release studies were performed using PBS and MES buffers. Cellular uptake of Pt NPs was measured using ICP-MS for all four cell lines.


Results, Conclusions, and Discussions:: ROS is produced because of oxidative stress when a cell uptakes any foreign particles. However, platinum is an antioxidant, and as such, it should not result in elevated levels of ROS production in cells. When treated with five concentrations of platinum for 1, 3, and 5 days, DPBC follows a similar pattern to TNBC and uterine sarcoma in production of ROS. There is a variable increase of ROS production in the first day when cells are initially incubated with Pt NPs, but a decrease in ROS production is observed after 3 and 5 days. Release of platinum ions in acidic and neutral environments was detected. Acidic environments promote more ionization and the release data shows that Pt NPs in MES, a buffer at pH 5, had highly variable release of platinum ions with the amount of Pt ions released varying between values similar to that in PBS or much higher. Additionally, uptake of Pt NPs by cancer cell lines and healthy fibroblasts was studied. Cancer cells are prone to devour more nutrients and resources than healthy cells, attributing to their increased proliferation rates. As such, it was expected that the cancer cell lines, TNBC, DPBC, and uterine sarcoma, would have high levels of Pt NPs uptake, especially the TNBC. Surprisingly, the healthy fibroblasts were observed to have higher uptake levels than the cancer cell lines, with TNBC having the lowest uptake of Pt NPs. Ongoing mice studies are being conducted as well to determine the efficacy of Pt NPs in vivo. Preliminary data does show non-toxicity to the mice, further supporting Pt NPs low toxicity towards healthy cells.


Acknowledgements (Optional): : This research was funded by the New Jersey Health Foundation and NJIT’s Undergraduate Research Innovation Grant. This research was also advised by Dr. Aida Lopez-Ruiz and Dr. Kathleen McEnnis. Pt NPs formation was conducted by Prova Joy Mehedi, Darshan Danak, and Pranav Prabhu. Ion release studies were conducted by Noshin Siddiq.


References (Optional): : Shim et. al. 2017; López et. al. 2022