Exploiting a new endoplasmic reticulum targeting BODIPY-Scaffold for detection of organelle stress and exploration of chemotherapeutic transport - Exploiting a new endoplasmic reticulum targeting BODIPY-Scaffold for the examination of the role ER-stress plays in non-small cell lung cancer NSCLC Shawn Swavey (Department of Chemistry, University of Dayton) Kristen Krupa (Department of Chemical and Materials Engineering, University of Dayton) PROJECT SUMMARY & ABSTRACT The American Cancer Society estimates that in 2022 more than 230,000 new cases of lung cancer were diagnosed with over 130,000 deaths from lung cancer in the United States alone; making it the leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) is the most predominant form of lung cancer, constituting 85-90% of all cases. Developing improved therapeutic and diagnostic tools for various malignancies has recently revolved around a better understanding of the cellular organelles. The endoplasmic reticulum (ER), has recently garnered particular interest due to its major role played within tumor cells. The ER manages the augmented cellular stress associated with the rapid proliferation of cancer cells by initiating mechanisms that return the cell to homeostasis. However, sustained or uncontrolled ER stress (ERS) will ultimately lead to cell death and tumor destruction, making ERS levels a viable therapeutic target. Moreover, it has been suggested that following actuation by an external trigger, augmented ERS can initiate the self- destructive immunogenic cell death (ICD) response; thereby creating a secondary ERS-dependent cytotoxic mechanism. The overarching goal of this project is to generate ER-targeting fluorescent imaging agents to characterize the role of ERS in NSCLC and develop directed cancer therapeutics based on observed responses. The Swavey laboratory has recently developed a two-step synthetic route to generate a family of ER-targeting boron dipyrrin (BODIPY) fluorescent probes. The synthetic simplicity and versatility of this process allow for the easy configuration of these probes with specific constituents without affecting their ability to localize within the ER; thereby allowing for the synthesis of a myriad of compounds. Following synthesis and characterization of the BODIPY probes, their efficacy as NSCLC therapeutics will be explored through three mechanisms; Aim 1) as real-time monitors of ER stress and cancer by sensing microviscosity changes, Aim 2) via targeted delivery of cisplatin, a renowned anticancer therapeutic, to the ER and Aim 3) as photodynamic therapy (PDT) agent via light-activated reactive oxygen species production within the ER to trigger ICD. As our preliminary data has demonstrated the versatile BODIPY core is responsible for ER-targeting capabilities and allows for easy functionalization, we hypothesize that a series of BODIPY dyes will successfully be synthesized capable of carrying out their desired functions in the ER, whether it is serving as a real-time, molecular probe for viscosity changes or delivering cancer therapeutics. However, the efficacy of these applications will depend on the constituent chemical formulation. Moreover, due to its distinctive attributes, it is believed that the BDP-1I BODIPY dye will be able to successfully destroy NSCLC cells through ICD induction following photo-stimulation. Our three-pronged approach will help us develop future strategies for the detection and potential treatment of NSCLC, with our ultimate goal of creating a collaborative center in the area of fluoroprobes at the University of Dayton, driven by our diverse faculty and students.
