Phototherapy involves the use of light to treat disease. Photodynamic therapy (PDT) and photothermal therapy (PTT) are specialized forms of phototherapy that employ a light-responsive molecule to create reactive oxygen species (ROS) or heat, respectively, to treat cancer. In contrast to traditional chemotherapy, PDT/PTT is highly selective because light can be delivered specifically at the tumor and thus 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. They tend to require shorter wavelengths of light that do not penetrate tissue as well as near-infrared light, cannot treat oxygen-deprived tumors, cause prolonged cutaneous sensitivity to sunlight, and are poorly soluble in aqueous solutions. PDT could become more widely available as an adjuvant cancer therapy if better photosensitizers can be developed. This project will address some of these challenges with novel photosensitizers based on the transition metal iridium (Ir). These new molecules will be activatable with near-infrared light and able to generate ROS even when tumors oxygenation is low. The proposed Ir molecules are unique in that they are equipped with special functional groups designed to shift the activation wavelength 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 maintain phototoxic effects in the absence of oxygen through PTT. The combination of PDT with PTT could significantly enhance the cancer treatment efficiency, especially toward oxygen-deficient tumors. In addition, 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 North Dakota State University (NDSU) and the University of Texas at Arlington (UTA), and will have broader impacts on the biomedical field in general. The scientific community will benefit from a deeper understanding of heavy transition-metal complexes and their application as near-infrared photosensitizers in the field of phototherapy. The interdisciplinary nature of this project will provide the involved graduate and undergraduate students with training opportunities in synthesis, spectroscopy, and photobiology, which will prepare these students for the future biomaterials workforce. The proposed outreach activities involve/expose tribal college students, high school students, and underrepresented African American/Hispanic students in/to modern biomaterial research and technology transfer, which will increase the diversity of the future workforce in biomaterials field. The two female PIs can serve as role models for female students and encourage more female students to pursue scientific careers.
This project aims to develop dual-action novel Ir(III) complex photosensitizers (PSs) for combined photodynamic therapy (PDT) and photothermal therapy (PTT) of cancers. The proposed PSs are bis-terpyridine Ir(III) complexes equipped with a chalcogenophene-substituted diketopyrrolopyrrole (DPP) unit and folic acid. These PSs will be NIR (700-850 nm) activatable, exhibit cancer-specific targeting, and generate efficient ROS and/or hyperthermia for treating hypoxic solid tumors such as triple negative breast cancer (TNBC). The PIs posit that attaching a chalcogenophene-substituted DPP motif to one of the terpyridine ligands will shift the absorption of the PSs to the NIR regions while maintaining the long-lived DPP localized 3pi,pi* state as the lowest-energy triplet excited state. It is anticipated that the long-lived triplet state will provide sufficient time for bimolecular interactions with oxygen for efficient ROS generation even under hypoxia. In addition, the strong NIR absorbing PSs are expected to generate hyperthermia effects for PTT as an alternate relaxation pathway due to the much lower-energy triplet states associated with NIR PSs. 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 specific targeting of cancers with overexpressed folic acid receptors. The photophysics of these new and improved Ir(III) PSs will be systematically investigated according to their absorption and emission profiles and triplet excited state lifetimes. The effectiveness of the proposed PSs as in vitro PDT/PTT agents and the photosensitization mechanism(s) and subcellular targets will be explored using the TNBC MDA-MB-231 cell 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 solid tumors, low cancer selectivity, and water insolubility. The success of this study could benefit the biomedical field of phototherapy by providing a deeper understanding of heavy transition-metal complexes and their application as NIR PSs, which would eventually enable PDT/PTT to be applied to deep-seated, high-volume tumors, 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.
