Multifunctional Photosensitizers for Image-guided PDT of Brain Tumors

用于脑肿瘤图像引导 PDT 的多功能光敏剂

• 批准号: 7373099
• 负责人: Ravindra K. Pandey
• 金额: $ 55.62万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7373099
• 关键词: Adjuvant Therapy; Animals; Avidity; Binding; Biodistribution; Biological; Biology; Brain; Brain Neoplasms; Cancer Patient; Caring; Cells; Characteristics; Charge; Clinical; Clinical Data; Clinical Trials; Complement; Complex; Data; Detection; Development; Diagnostic Neoplasm Staging; Disease; Drug Kinetics; Excision; Failure; Fluorescence; Fluorescent Dyes; Fluorochrome; Generations; Glioma; Goals; HPPH; Half-Life; Image; In Vitro; Individual; Integrin Binding; Integrins; Intervention; Invaded; Investigation; Label; Laboratory Study; Lesion; Ligands; Light; Link; Local Therapy; Localized; Location; Magnetic Resonance Imaging; Malignant Glioma; Malignant Neoplasms; Mammary Neoplasms; Measures; Modality; Modeling; Molecular; Molecular Target; Mus; Neoplasm Metastasis; Normal tissue morphology; Operative Surgical Procedures; Optics; Patients; Peptides; Photochemotherapy; Photosensitizing Agents; Phototoxicity; Placement; Play; Porfimer Sodium; Porphyrins; Positron-Emission Tomography; Process; Production; Property; RGD (sequence); Radiation therapy; Radioisotopes; Radiopharmaceuticals; Range; Rate; Recurrence; Research; Role; Singlet Oxygen; Site; Skin; Specificity; Staging; Standards of Weights and Measures; Survival Rate; Therapeutic; Tissues; Title; Toxic effect; Tracer; Treatment Efficacy; Tumor-Associated Vasculature; Validation; Work; absorption; analog; base; brain tissue; cancer therapy; chemotherapy; chromophore; cyanine dye; design; fluorophore; image guided therapy; image visualization; improved; in vivo; irradiation; lipophilicity; malignant breast neoplasm; melanoma; mouse model; neoplastic cell; novel; novel strategies; optical fiber; optical imaging; outcome forecast; porphyrin a; pre-clinical; quantum; receptor; response; treatment site; tumor; uptake

Photodynamic therapy (PDT) is an effective local therapy based on a tumor localizing photosensitizer (PS) activated by light directed at the treatment site. Current photosensitizers demonstrate some tumor selectivity, and light can be delivered almost anywhere in the body by thin, flexible optical fibers. However, for small, bulky, or buried lesions, it may be difficult to detect the malignancies and/or to properly place the optical fibers to illuminate the full extent of the tumor. We hypothesize development of a new approach to guided therapy utilizing highly selective optical and PET imaging, allowing tumor visualization, image-guided placement of the optical fibers, and subsequent photodynamic destruction of the lesions. Our project involves synthesis, characterization and pre-clinical validation of novel conjugates of tumor- avid PS carrying unique, near infrared (NIR) fluorescent dyes and the long half-life PET agent 124I. Preliminary work shows these conjugates provide very high in vivo tumor selectivity, while maintaining. We will determine if the conjugate selectivity can be further enhanced by linking tumor- or neovasculature-selective molecular targeting ligands such as an v3 integrin binding peptide. In addition, our approach can be extended to multi- modality interventions: The conjugate can deliver therapeutic radioisotopes, and PDT can super-additively potentiate radiotherapy. The aims of this project are as follow: Aim 1: To prepare and characterize multi-functional conjugates containing a tumor-avidlong -wavelength photosensitizer linked to novel NIR cyanine dyes with the option of a 124I-label and a RGD peptide moiety that binds to tumor and neovasulature associated with integrin (v3). Aim 2: To characterize the different conjugates in vitro. Aim 3: To examine in animals the imaging and therapeutic potential of the conjugates and determine any added benefits of integrin targeted conjugates for imaging and therapy. This ¿see and treat¿ approach targets cancers with an agent that can be detected by light and radioimaging, and then activated at a different wavelength to destroy the tumors. It is important to detect cancer at early stage as it plays critical role in cancer patient management since detection of stage 1 cancer is associated with a >90% 5 year survival rate. Our approach of designing ¿Multimodality Agents¿ for the detection and treatment of cancer could play a major role in cancer therapy. The initial biological data obtained from the proposed compounds in mice model are quite promising in imaging tumors and tumor metastases without any significant toxicity. Therefore, this research warrants further investigation.

光动力疗法是一种基于肿瘤定位光敏剂的有效局部治疗方法。 (PS)由直射到治疗部位的光激活。目前的光敏剂显示了一些肿瘤 这种光纤具有良好的选择性，可以通过细长的柔性光纤将光传输到人体内几乎任何地方。然而，对于 小的、大的或埋藏的病变，可能很难发现恶性肿瘤和/或正确放置光学元件 纤维可以照亮肿瘤的整个范围。我们假设了一种新的引导方法的发展 使用高选择性光学和PET成像的治疗，允许肿瘤可视化，图像引导 放置光纤，以及随后对病变进行光动力破坏。 我们的项目涉及新型肿瘤结合物的合成、表征和临床前验证。 Avid PS具有独特的近红外(NIR)荧光染料和长半衰期的PET试剂124I。初步 研究表明，这些结合物在体内提供了非常高的肿瘤选择性，同时保持了。我们将确定是否 通过连接肿瘤或新生血管选择性分子可以进一步提高偶联选择性 靶向配体，如v3整合素结合肽。此外，我们的方法还可以扩展到多个- 模式干预：结合物可传递治疗性放射性同位素，光动力疗法可超加成 加强放射治疗。 该项目的目标如下： 目的1：制备和表征含抗肿瘤长波的多功能偶联物 可选择~(124)I标记和RGD多肽的新型近红外菁染料光敏剂 与肿瘤和与整合素相关的新生血管结合的部分(V3)。 目的2：研究不同结合物的体外性质。 目标3：在动物身上检查结合物的成像和治疗潜力，并确定任何 用于成像和治疗的整合素靶向结合物的额外好处。 这种治疗癌症的方法是用一种可以被光检测和治疗的试剂来治疗癌症 放射成像，然后在不同的波长激活以摧毁肿瘤。癌症的早期诊断非常重要，因为它在癌症患者中起着至关重要的作用。 自发现1期癌症以来的治疗与90%的5年生存率相关 费率。我们设计用于检测和治疗的“多模式试剂”的方法 癌症的研究可能在癌症治疗中发挥重要作用。获得的初始生物数据 从所建议的化合物在小鼠模型中非常有希望在肿瘤成像和 肿瘤转移无任何明显毒性。因此，这项研究证明了 进一步调查。