Collaborative research: Developing cancer-specific targeting near-IR photosensitizers for in vitro theranostic photodynamic therapy and photothermal therapy

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Non-Technical SummaryPhototherapy involves the use of light to treat disease. Photodynamic therapy (PDT) and photothermaltherapy (PTT) are specialized forms of phototherapy that employ a light-responsive molecule to createreactive oxygen species (ROS) or heat, respectively, to treat cancer. In contrast to traditionalchemotherapy, PDT/PTT is highly selective because light can be delivered specifically at the tumor andthus confines the toxicity to the tumor. The widespread use of PDT for cancer treatment has been limited,in part, by the drawbacks associated with the photosensitizing molecules approved for this therapy. Theytend to require shorter wavelengths of light that do not penetrate tissue as well as near-infrared light, cannottreat oxygen-deprived tumors, cause prolonged cutaneous sensitivity to sunlight, and are poorly soluble inaqueous solutions. PDT could become more widely available as an adjuvant cancer therapy if betterphotosensitizers can be developed. This project will address some of these challenges with novelphotosensitizers based on the transition metal iridium (Ir). These new molecules will be activatable withnear-infrared light and able to generate ROS even when tumors oxygenation is low. The proposed Irmolecules are unique in that they are equipped with special functional groups designed to shift the activationwavelength of the molecules into the near-infrared while maintaining good ROS generation efficiency.Meanwhile, these near-infrared absorbing Ir molecules will also produce heat that will further maintainphototoxic effects in the absence of oxygen through PTT. The combination of PDT with PTT couldsignificantly enhance the cancer treatment efficiency, especially toward oxygen-deficient tumors. Inaddition, folic acid will be attached to the Ir molecules for added discrimination for certain types of tumors,such as triple negative breast cancer.The proposed research and educational and outreach activities will boost biomaterials research at NorthDakota State University (NDSU) and the University of Texas at Arlington (UTA), and will have broaderimpacts on the biomedical field in general. The scientific community will benefit from a deeperunderstanding of heavy transition-metal complexes and their application as near-infrared photosensitizersin the field of phototherapy. The interdisciplinary nature of this project will provide the involved graduateand undergraduate students with training opportunities in synthesis, spectroscopy, and photobiology, whichwill prepare these students for the future biomaterials workforce. The proposed outreach activitiesinvolve/expose tribal college students, high school students, and underrepresented AfricanAmerican/Hispanic students in/to modern biomaterial research and technology transfer, which will increasethe diversity of the future workforce in biomaterials field. The two female PIs can serve as role models forfemale students and encourage more female students to pursue scientific careers.Technical SummaryThis project aims to develop dual-action novel Ir(III) complex photosensitizers (PSs) for combinedphotodynamic therapy (PDT) and photothermal therapy (PTT) of cancers. The proposed PSs are bis-terpyridineIr(III) complexes equipped with a chalcogenophene-substituted diketopyrrolopyrrole (DPP) unitand folic acid. These PSs will be NIR (700-850 nm) activatable, exhibit cancer-specific targeting, andgenerate efficient ROS and/or hyperthermia for treating hypoxic solid tumors such as triple negative breastcancer (TNBC). The PIs posit that attaching a chalcogenophene-substituted DPP motif to one of theterpyridine ligands will shift the absorption of the PSs to the NIR regions while maintaining the long-livedDPP localized 3pi,pi* state as the lowest-energy triplet excited state. It is anticipated that the long-lived tripletstate will provide sufficient time for bimolecular interactions with oxygen for efficient ROS generation evenunder hypoxia. In addition, the strong NIR absorbing PSs are expected to generate hyperthermia effectsfor PTT as an alternate relaxation pathway due to the much lower-energy triplet states associated with NIRPSs. The combination of PDT with PTT could significantly enhance the cancer treatment efficiency,especially toward hypoxic tumors. Folic acid will be introduced to the other terpyridine ligand for specifictargeting of cancers with overexpressed folic acid receptors. The photophysics of these new and improvedIr(III) PSs will be systematically investigated according to their absorption and emission profiles and tripletexcited state lifetimes. The effectiveness of the proposed PSs as in vitro PDT/PTT agents and thephotosensitization mechanism(s) and subcellular targets will be explored using the TNBC MDA-MB-231cell line. The proposal addresses the major challenges to current PS development, i.e. high dark toxicity,inability to be activated by tissue penetrating NIR light, low ROS generation efficiency in hypoxic solidtumors, low cancer selectivity, and water insolubility. The success of this study could benefit the biomedicalfield of phototherapy by providing a deeper understanding of heavy transition-metal complexes and theirapplication as NIR PSs, which would eventually enable PDT/PTT to be applied to deep-seated, high-volumetumors, leading to more effective cancer therapies for some hard-to-treat solid tumors, such as TNBC.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.