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

合作研究：开发用于体外治疗诊断光动力疗法和光热疗法的癌症特异性靶向近红外光敏剂

• 批准号: 2317606
• 负责人: WENFANG SUN
• 金额: $ 34.05万
• 依托单位: University of Alabama Tuscaloosa
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2317606&HistoricalAwards=false
• 关键词: Collaborative; research; Developing; cancer; specific

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.

非技术摘要疗法涉及使用光治疗疾病。光动力疗法（PDT）和光热治疗（PTT）是使用光疗法的专门形式的光疗形式，分别采用轻度反应性分子来治疗癌症。与传统化学疗法相反，PDT/PTT具有很高的选择性，因为可以在肿瘤上专门递送光，并将其局限于肿瘤的毒性。 PDT在癌症治疗中的广泛使用受到了与批准用于该疗法的光敏分子相关的缺点。他们需要较短的光波长，这些波长不会穿透组织以及近红外光，无法处理氧气剥夺氧气的肿瘤，会导致对阳光的长时间敏感性，并且是溶解的溶液。如果可以开发出更好的photosensitizer，则PDT可以作为辅助癌症疗法更广泛地获得。该项目将基于过渡金属虹膜（IR）的新型photosensitizer来应对其中一些挑战。这些新分子将用near-in-infrared光进行激活，即使肿瘤氧合很低，也能够产生ROS。所提出的IRMOLECULES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产生效率。同样，这些近红外吸收的IR分子也将产生热量，从而进一步维持肾上腺素的效果，而在没有氧气的情况下通过Ptt ptt ptt。 PDT与PTT的组合可以显着提高癌症治疗效率，尤其是对缺氧肿瘤的效率。不结束，叶酸将附着在IR分子上，以增加某些类型的肿瘤（例如三重阴性乳腺癌）。拟议的研究以及教育和外展活动将促进北达科他州立大学（NDSU）（NDSU）和德克萨斯大学Arlington（UTA）的生物材料研究，并将在Arlington（UTA）上进行广泛的生物影响力。科学界将受益于重大过渡金属络合物的深刻理解，并将其作为光疗领域中的近红外摄影作用。该项目的跨学科性质将为涉及的毕业生本科生提供合成，光谱和光生物学的培训机会，这将使这些学生为未来的生物材料劳动力做好准备。在现代生物材料研究和技术转移中，拟议的外展活动Involve/揭露了部落大学的学生，高中生和代表性不足的非裔美国人/西班牙裔学生，这将增加生物材料领域未来劳动力的多样性。这两个女性PI可以作为榜样，并鼓励更多的女学生从事科学职业。所提出的PSS是配备了果糖基取代的二基吡咯吡咯（DPP）单位和叶酸的双基吡啶尼尔（III）配合物。这些PSS将是NIR（700-850 nm），可激活，表现出癌症特异性靶向，并产生有效的ROS和/或高温，用于治疗缺氧实体瘤，例如Triple阴性乳腺癌（TNBC）。 PI认为将硫烷酚基取代的DPP基序连接到硫吡啶配体中的一种将使PSS的吸收转移到NIR区域，同时保持长期寿命的DPP局部局部3PI，PI*状态为最低的Energy Emergy Trip兴奋的三重状态。可以预料，长期的三重态将为双重分子与氧相互作用提供足够的时间，以使有效的ROS生成均匀缺氧。此外，由于与NIRPS相关的能源较低的三胞胎状态，预期吸收强的NIR吸收PSS将对PTT产生高温效应。 PDT与PTT的组合可以显着提高癌症治疗效率，尤其是针对低氧肿瘤。叶酸将被引入其他terpyridine配体，以特异性地捕获过表达叶酸受体的癌症。这些新的和改进的PSS的光体物理学将根据其吸收和排放曲线以及三重态激发的状态寿命进行系统研究。拟议的PSS作为体外PDT/PTT药物以及photosensitization机制（S）和亚细胞靶标的有效性将使用TNBC MDA-MDA-MB-231CELL系列进行探索。该提案解决了当前PS发育的主要挑战，即高深色毒性，无法通过穿透NIR光线的组织激活，低氧固体效率低，低癌症的癌症选择性和水不溶性。这项研究的成功可以通过对重型过渡金属络合物的更深入了解及其作为NIR PSS的应用，从而使光疗的生物医学领域受益，这最终将使PDT/PTT适用于深层，高量化的高量化者，从而为一些较强的固体统计数据提供了更大的癌症，例如，诸如thement and Feareat and the thef and thef and thef。认为值得通过基金会的智力优点和更广泛影响的评论标准来评估值得支持。