Harnessing The Mechanical Power Of Nanomachines To Treat Cancer: Light-Activated Molecular Nanomachines Kill Melanoma And Oral Cancer Cells.

Abstract Introduction: Molecular nanomachines (MNMs) have been studied for their anti-tumor efficacy in a number of solid malignancies. They consist of small (1 nm) organic molecule-based motors that change conformation upon light activation and mechanically drill holes in the cell membrane resulting in cellular necrosis. That opens a novel way of molecular mechanical therapy. Recently, we generated a blue light spectrum (395-405 nm)-activated MNMs which showed promising results in pancreatic cancer cell lines. Herein, we evaluate the in vitro efficacy in various oral and skin cancers including squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and melanoma, a disease characterized by fast progression and therapeutic resistance. Methods: MNMs activated by the blue light spectrum were synthesized. In vitro efficacy of the activated MNMs (8 µM in 0.1% DMSO) was investigated in skin cancer cell lines. Cells were incubated with MNMs for 30 minutes, then treatment groups were subjected to 150 mW/cm2 blue light for 4 minutes or 300 mW/cm2 for 5 min. Control groups included MNMs without light, 0.1% DMSO (required for solubility of the MNMs) with light, and 0.1% DMSO without light. Cell viability was quantitatively evaluated utilizing propidium iodide (PI) and flow cytometry assay with each datapoint representing triplicates. Additionally, cells were grown and tested by clonogenic assay 1d and 9d following light and MNMs treatment. Results: B16-F10 (murine melanoma cancer cell line) treated with light-activated MNMs exhibited almost 100% loss in viability when treated with MNMs and light. Solution only (0.1% DMSO), unactivated MNMs and DMSO solution combined with light exhibited less than 5% change in cell viability suggesting that all the controls are non-cytotoxic evaluated by PI-flow cytometry at 3 h after treatment. Clonogenic assay 9 day post treatment confirmed 100% cell death for the MNMs + light treated cells, while showing nearly 80-90% survival of cells in the light only treatment control. Other treated cell lines include SCC cell lines (ROC 1 and ROC 3) showing 100% loss in cell viability when treated with MNMs and light. Conclusions: Light-activated MNM exhibit profound in vitro efficacy in multiple skin cancer cells lines. MNMs are a promising novel therapeutic modality for the treatment of oral and skin cancers, and there are no known resistance mechanisms for nanomechanical therapy. They are now being tested on murine tumor models of B16-F10 in C57BL/6 mice and further preclinical characterization of antitumor efficacy and tolerability are necessary in these studies. Citation Format: Ciceron Ayala-Orozco, Alexis van Venrooy, Dongdong Liu, Yewen Shi, Jacob Beckham, David Izhaky, James M. Tour, Jeffrey N. Myers, Roberto Rangel. Harnessing the mechanical power of nanomachines to treat cancer: Light-activated molecular nanomachines kill melanoma and oral cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 269.