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

非技术概述光疗涉及使用光来治疗疾病。光动力疗法（PDT）和光热疗法（PTT）是专门形式的光疗，其分别采用光响应分子来消除活性氧（ROS）或热来治疗癌症。与传统化疗相比，PDT/PTT具有高度选择性，因为光可以特异性地传递到肿瘤，从而限制了对肿瘤的毒性。PDT在癌症治疗中的广泛应用受到限制，部分原因是与批准用于这种治疗的光敏分子相关的缺点。它们往往需要较短波长的光，不能像近红外光那样穿透组织，不能治疗缺氧肿瘤，导致皮肤对阳光的长期敏感性，并且在水溶液中溶解性差。如果能开发出更好的光敏剂，PDT作为辅助癌症治疗可能会更广泛地应用。该项目将解决一些基于过渡金属铱（Ir）的新型光敏剂的挑战。这些新分子将被近红外光激活，即使肿瘤氧合较低，也能产生ROS。所提出的铱分子的独特之处在于，它们配备了特殊的官能团，旨在将分子的激活波长转移到近红外，同时保持良好的活性氧产生效率。同时，这些近红外吸收铱分子也会产生热量，从而进一步维持光毒性作用。在没有氧气的情况下，通过PTT。PDT与PTT联合应用可显著提高肿瘤的治疗效率，尤其是对缺氧肿瘤的治疗效果。此外，叶酸将连接到Ir分子上，以增加对某些类型肿瘤的鉴别，如三阴性乳腺癌。拟议的研究和教育及推广活动将促进北达科他州州立大学（NDSU）和德克萨斯大学阿灵顿分校（UTA）的生物材料研究，并将对生物医学领域产生更广泛的影响。深入了解重过渡金属配合物及其作为近红外光敏剂在光疗领域的应用，将使科学界受益匪浅。该项目的跨学科性质将为参与的研究生和本科生提供合成，光谱学和光生物学的培训机会，这将为未来的生物材料劳动力做好准备。拟议的外展活动涉及/暴露部落大学生，高中生和代表性不足的非洲裔美国人/西班牙裔学生/现代生物材料研究和技术转让，这将增加生物材料领域未来劳动力的多样性。这两位女研究员可以作为女学生的榜样，鼓励更多的女学生从事科学事业。技术概述本项目旨在开发用于联合光动力疗法（PDT）和光热疗法（PTT）治疗癌症的双作用新型Ir（III）配合物光敏剂（PS）。所提出的PS是双三联吡啶Ir（III）配合物，其配备有硫族苯取代的二酮基吡咯并吡咯（DPP）单元和叶酸。这些PS将是NIR（700-850 nm）可激活的，表现出癌症特异性靶向，并产生有效的ROS和/或热疗，用于治疗缺氧实体瘤，如三阴性乳腺癌（TNBC）。将硫族苯取代的DPP基序连接到三联吡啶配体上的PI将使PS的吸收转移到近红外区域，同时保持长寿命DPP局域的3 pi，pi* 态作为最低能量的三重激发态。预期长寿命的三重态将为双分子与氧的相互作用提供足够的时间，从而即使在缺氧的情况下也能有效地产生ROS。此外，强近红外吸收的PS预计会产生热效应的PTT作为一个替代的弛豫途径，由于低得多的能量三重态与NIRPS。PDT与PTT联合应用可显著提高肿瘤治疗效率，尤其是对缺氧肿瘤。叶酸将被引入到另一个三联吡啶配体中，用于特异性靶向叶酸受体过表达的癌症。这些新的和改进的Ir（III）PS的光物理将根据它们的吸收和发射轮廓和三重激发态寿命进行系统的研究。将使用TNBC MDA-MB-231细胞系探索所提出的PS作为体外PDT/PTT试剂的有效性以及光敏化机制和亚细胞靶点。该提案解决了当前PS开发的主要挑战，即高暗毒性，不能被组织穿透NIR光激活，低氧实体瘤中ROS生成效率低，癌症选择性低，以及水不溶性。这项研究的成功可以通过提供对重过渡金属络合物及其作为NIR PS的应用的更深入理解而有益于光疗的生物医学领域，这最终将使PDT/PTT能够应用于深层次的高体积肿瘤，从而为一些难以治疗的实体瘤提供更有效的癌症治疗，该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.