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)是光疗的专门形式，它们利用光响应分子分别产生活性氧(ROS)或热来治疗癌症。与传统的化疗不同，PDT/PTT具有高度的选择性，因为光可以特定地投射到肿瘤上，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了限制，部分原因是这种治疗方法所使用的光敏分子存在缺陷。它们往往需要较短波长的光，不像近红外光那样穿透组织，不能治疗缺氧的肿瘤，导致皮肤对阳光的长期敏感，并且是难于溶解的水溶液。如果能开发出更好的光敏剂，光动力疗法可能会作为癌症的辅助疗法得到更广泛的应用。这个项目将用基于过渡金属Ir(Ir)的新型光敏剂来解决其中的一些挑战。这些新分子可以在近红外光下被激活，即使在肿瘤含氧量较低的情况下也能产生ROS。所提出的红外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，这些近红外吸收的Ir分子也将产生热量，通过PTT在无氧的情况下进一步保持光毒效应。PDT联合PTT可显著提高肿瘤的治疗效率，尤其是对缺氧肿瘤的治疗。此外，叶酸将被连接到IR分子上，以增加对某些类型的肿瘤的区分，例如三阴性乳腺癌。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金属过渡金属络合物及其在光疗领域中作为近红外光敏剂的应用的深入了解。这个项目的跨学科性质将为相关的毕业生和本科生提供合成、光谱学和光生物学方面的培训机会，这将使这些学生为未来的生物材料劳动力做好准备。拟议的外联活动将使部落大学生、高中生和非洲裔/拉美裔学生参与/接触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。这两位女性PI可以作为女学生的榜样，鼓励更多的女学生追求科学事业。技术概述本项目旨在开发用于癌症的光动力疗法(PDT)和光热疗法(PTT)相结合的双作用新型Ir(III)复合光敏剂(PSS)。所建议的PSS是双三联吡啶Ir(III)与硫基苯二酮基吡咯(DPP)和叶酸的配合物。这些PSS将是近红外(700-850 nm)可激活的，具有癌症特异性靶向，并产生有效的ROS和/或热疗，用于治疗缺氧的实体肿瘤，如三阴性乳腺癌(TNBC)。PI假设将硫基取代的DPP基序连接到其中一个三联吡啶配体上，将PSS的吸收转移到近红外区域，同时保持长寿命的DPP局域3pi，pi*态作为最低能量的三重态激发态。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，以便即使在低氧条件下也能有效地产生ROS。此外，强吸收近红外的PSS有望为PTT产生高温效应，作为一种替代的弛豫途径，因为与NIR相关联的三重态能量要低得多。PDT联合PTT可显著提高肿瘤的治疗效率，尤其是对缺氧肿瘤的治疗。叶酸将被引入到另一种三联吡啶配体中，用于针对叶酸受体过度表达的癌症。这些新的和改进的Ir(III)PSS将根据它们的吸收和发射分布以及三重激发态寿命来系统地研究它们的光物理。我们将使用TNBC MDA-MB-231细胞株来研究PSS作为体外光动力疗法/PTT药物的有效性和光敏化机制(S)和亚细胞靶点。该提案解决了目前PS开发面临的主要挑战，即高暗毒性、不能被组织穿透近红外光激活、低氧固体肿瘤中ROS生成效率低、低癌症选择性和水不溶。这项研究的成功可能会使生物医学领域受益于光疗，因为它提供了对重过渡金属络合物及其作为近红外PSS的应用的更深层次的了解，最终使PDT/PTT能够应用于深层次、大体积的肿瘤，导致对一些难以治疗的实体肿瘤，如TNBC的更有效的癌症治疗。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.