有机阴离子转运多肽调控的近红外吡啰红衍生物肿瘤荧光诊断与治疗试剂的开发及应用

Given their high-sensitivity, visualization, noninvasiveness, absence of ionizing radiation and real-time imaging ability in vivo even at the single living cell level, fluorescence-based imaging techniques have offered the exciting opportunity to diagnostics and treatment of tumor. Currently, indocyanine green (ICG) is a main imaging contrast agent used for tumor imaging in clinical trials. However, the application of ICG has been limited largely due to its nonspecific binding to proteins and the lack of targeting specificity. Recently, a class of near-infrared (NIR) heptamethine cyanine dyes were reported to be able to accumulate preferentially in a wide range of cancer cell types assisted by organic-anion transporting polypeptide (OATP) transporters overexpressed in many types of cancer cells. However, despite their successful applications in in vivo imaging of tumors, these cyanine dyes suffer from the poor photo-stability and low fluorescence quantum yield. More recently, we presented a phenol-functionalized O-pyronin dye as a new substrate of OATPs for diagnosing a wide range of cancer cell types. However, the excitation and emission wavelengths of the dye are in visible region, thus disadvantageous for tissue imaging application. In this project, a series of near-infrared (NIR) derivatives of O-pyronin, including C-pyronin, Si-pyronin, P-pyronin, and SO2-pyronin, are presented as the candidate substrates of OATPs for diagnosis of cancer cells/tissues. We hope that by adjusting the hydrophilic and lipophilic properties of the R substituents on the C-9 position of these NIR dyes, the NIR pyronin derivatives, difficult to penetrate normal cell membrane but able to penetrate cancer cell membrane assisted by OATPs, could be obtained, which would be applied to diagnosis of cancer or tumors. What's more, we would also exploit the OATPs-mediated anticancer and photodynamics therapy agents for tumors based on these NIR pyronin platforms, which would provide some ideas and references for the development of new anticancer drugs in future.

鉴于高敏感性、非侵袭性、可视化、无辐射等特点，荧光技术已在肿瘤的诊断与治疗方面显示了巨大的应用前景。然而，目前临床使用的吲哚青绿荧光诊断试剂的靶向性低，仅对个别肿瘤的诊断有效。尽管近年来发展的可被癌细胞膜过量表达的有机阴离子转运多肽（OATPs）所调控的花菁染料提高了肿瘤的靶向性和广谱性，但其光稳定性弱，荧光量子收率低。本课题组最近将OATPs调控的染料基质范围进一步拓展到了光物理性质优良的氧-吡啰红染料。为了克服该染料激发和发射波长短、不利于肿瘤荧光影像的缺点，本项目拟以该染料的近红外衍生物碳-吡啰红、硅-吡啰红、磷-吡啰红、砜-吡啰红为平台，通过取代基亲水亲油性的调整，开发出难以透过正常细胞膜，但能被OATPs转运而穿透癌细胞膜的广谱型肿瘤荧光诊断试剂，实现癌症的早期检测和肿瘤边界的精准定位，并进一步开发OATPs调控的肿瘤化疗和光动力治疗试剂，为新型肿瘤靶向药物的开发提供思路和参考。

癌症是目前危害人类健康的重大疾病，早期诊断和治疗将大大提升人类的生命健康水平。在各类癌症诊断治疗技术中，荧光技术及其衍生的光动力治疗技术因非侵入性、实时监控、高时空分辨率、无耐药性等特点，已在癌症诊断与治疗领域展示了大的应用前景。本项目围绕肿瘤荧光诊断试剂与光动力治疗试剂的开发开展研究，该两类试剂的构建基础为荧光染料，其光物理性质，如荧光量子收率和吸收/发射波长直接影响应用效果。因此，本项目第一项研究工作主要集中在近红外荧光染料的合成和光物理性能的提升方面，主要包括罗丹明家族荧光染料、氟硼二吡咯家族荧光染料、硅-恶嗪荧光染料，Cardipys荧光染料。本项目第二项研究工作是开发荧光探针，探究癌细胞机制，实现癌细胞及肿瘤的荧光诊断，包括癌细胞自我保护机制的探究，肿瘤相关巨噬细胞表型的荧光区分、耐药癌细胞的荧光甄别、癌细胞及组织的荧光诊断。本项目第三项工作是开发肿瘤靶向、可激活的光动力治疗试剂，实现肿瘤靶向的光动力治疗。通过本项目研究，获得了高荧光量子收率的可近红外罗丹明家族及氟硼二吡咯家族荧光染料，荧光量子收率可达0.8-0.99；获得了高对比度区分肿瘤组织和正常组织的荧光探针，荧光对比度超过了25；合成了高敏感性半胱氨酸荧光探针，揭示了癌细胞在缺乏细胞外胱氨酸补给的条件下能启动“谷胱甘肽-半胱氨酸”循环来抵抗氧化压力的自我保护机制；合成了高敏感性一氧化氮荧光探针和谷胱甘肽荧光探针，分别实现了肿瘤相关巨噬细胞M1、M2表型的荧光区分以及耐药癌细胞与癌细胞的荧光鉴别；获得了无重原子、可激活的、肿瘤靶向的光动力治疗光敏剂，实现了癌细胞/肿瘤的靶向光动力治疗，半致死量达到了亚微摩尔范围，并避免了治疗不足或过度治疗。此外，在本项目支持下，系统综述了铁、血红素及相关酶的荧光探针，为铁死亡相关抗癌药物开发提供了指导；系统综述了深红至近红外花色素荧光染料及荧光探针，为构建新型肿瘤荧光诊断及光动力治疗试剂提供了指导。

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