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

非技术摘要光疗涉及使用光来治疗疾病。光动力疗法 (PDT) 和光热疗法 (PTT) 是光疗的特殊形式，它们利用光响应分子分别产生活性氧 (ROS) 或热量来治疗癌症。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使用受到了部分限制，因为与批准用于该疗法的光敏分子相关的缺点。它们往往需要较短波长的光，这些光不能像近红外光那样穿透组织，不能治疗缺氧的肿瘤，导致皮肤对阳光的敏感性延长，并且在水溶液中溶解度较差。如果能够开发出更好的光敏剂，PDT 作为一种辅助癌症疗法可能会得到更广泛的应用。该项目将利用基于过渡金属铱 (Ir) 的新型光敏剂来解决其中一些挑战。这些新分子将可被近红外光激活，并且即使在肿瘤氧合作用较低时也能够产生ROS。所提出的Ir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ROS生成效率。同时，这些近红外吸收Ir分子还会产生热量，通过PTT在没有氧气的情况下进一步维持光毒性作用。 PDT与PTT的结合可以显着提高癌症治疗效率，特别是对于缺氧肿瘤。此外，叶酸将附着在 Ir 分子上，以增加对某些类型肿瘤（如三阴性乳腺癌）的区分。拟议的研究、教育和推广活动将促进北达科他州立大学 (NDSU) 和德克萨斯大学阿灵顿分校 (UTA) 的生物材料研究，并将对整个生物医学领域产生更广泛的影响。科学界将受益于对重过渡金属配合物及其在光疗领域作为近红外光敏剂的应用的更深入了解。该项目的跨学科性质将为所涉及的研究生和本科生提供合成、光谱学和光生物学方面的培训机会，这将为这些学生成为未来的生物材料劳动力做好准备。拟议的外展活动让部落大学生、高中生和代表性不足的非裔美国人/西班牙裔学生参与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。两位女PI可以为女学生树立榜样，鼓励更多女学生追求科学事业。 技术摘要该项目旨在开发双作用新型Ir(III)络合物光敏剂(PSs)，用于癌症的联合光动力疗法(PDT)和光热疗法(PTT)。所提出的 PS 是配备有硫属酚取代的二酮吡咯并吡咯 (DPP) 单元和叶酸的双三联吡啶 Ir(III) 配合物。这些 PS 将可在近红外 (700-850 nm) 范围内激活，具有癌症特异性靶向性，并产生有效的 ROS 和/或热疗，用于治疗缺氧实体瘤，例如三阴性乳腺癌 (TNBC)。 PI 认为，将硫属基酚取代的 DPP 基序连接到三联吡啶配体之一会将 PS 的吸收转移到 NIR 区域，同时保持长寿命的 DPP 局域 3pi,pi* 态作为最低能量三重激发态。预计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，以便即使在缺氧情况下也能有效产生ROS。此外，由于与 NIRPS 相关的能量低得多的三重态，强 NIR 吸收 PS 预计将产生 PTT 的热效应，作为替代的松弛途径。 PDT与PTT的结合可以显着提高癌症治疗效率，特别是对缺氧肿瘤。叶酸将被引入到其他三联吡啶配体中，以特异性靶向叶酸受体过度表达的癌症。这些新型改进的 Ir(III) PS 的光物理学将根据其吸收和发射曲线以及三激发态寿命进行系统研究。将使用 TNBC MDA-MB-231 细胞系探索所提出的 PS 作为体外 PDT/PTT 药物的有效性以及光敏机制和亚细胞靶标。该提案解决了当前 PS 开发的主要挑战，即高暗毒性、无法被组织穿透的近红外光激活、缺氧实体瘤中 ROS 生成效率低、癌症选择性低和水不溶性。这项研究的成功可以通过提供对重过渡金属配合物及其作为 NIR PS 的应用的更深入的了解而使光疗生物医学领域受益，这最终将使 PDT/PTT 能够应用于深部、大体积肿瘤，从而为一些难以治疗的实体瘤（例如 TNBC）提供更有效的癌症疗法。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力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.