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: 7919651
• 负责人: Ravindra K. Pandey
• 金额: $ 6.26万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919651
• 关键词: Adjuvant Therapy; Animals; Avidity; Binding; Biodistribution; Biological; Biology; Brain; Brain Neoplasms; Cancer Patient; Cells; Characteristics; Charge; Clinical; Clinical Data; Clinical Trials; Complement; Complex; Data; Detection; Development; Diagnostic Neoplasm Staging; 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; 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; Play; Porfimer Sodium; Porphyrins; Positron-Emission Tomography; Primary Brain Neoplasms; Process; Production; Property; RGD (sequence); Radiation therapy; Radioisotopes; Radiopharmaceuticals; Recurrence; Research; Role; Singlet Oxygen; Site; Skin; Specificity; Staging; Survival Rate; Therapeutic; Tissues; Toxic effect; Tracer; Treatment Efficacy; Validation; Work; absorption; advanced disease; analog; base; brain tissue; cancer therapy; chemotherapy; chromophore; conventional therapy; cyanine dye; design; flexibility; fluorophore; image guided therapy; image visualization; imaging modality; improved; in vivo; irradiation; lipophilicity; malignant breast neoplasm; melanoma; mouse model; neoplastic cell; neovasculature; novel; novel strategies; optical fiber; optical imaging; outcome forecast; palliation; porphyrin a; pre-clinical; quantum; receptor; response; standard care; treatment site; treatment strategy; tumor; tumor specificity; 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（PDT）是一种基于肿瘤定位光敏剂的有效局部疗法 (PS) 由直接照射治疗部位的光激活。目前的光敏剂显示出一些肿瘤 选择性，光几乎可以通过细而柔韧的光纤传输到身体的任何地方。然而，对于 小的、大的或埋藏的病变，可能很难检测到恶性肿瘤和/或正确放置光学 纤维照亮肿瘤的全部范围。我们假设开发一种新的引导方法 利用高选择性光学和 PET 成像进行治疗，实现肿瘤可视化、图像引导 光纤的放置，以及随后对病变的光动力破坏。 我们的项目涉及新型肿瘤缀合物的合成、表征和临床前验证 avid PS 携带独特的近红外 (NIR) 荧光染料和长半衰期 PET 试剂 124I。初步的 工作表明这些缀合物提供非常高的体内肿瘤选择性，同时保持。我们将确定是否 通过连接肿瘤或新血管系统选择性分子可以进一步增强缀合物选择性 靶向配体，例如 v3 整联蛋白结合肽。此外，我们的方法可以扩展到多种 方式干预：结合物可以提供治疗性放射性同位素，PDT 可以超累加 加强放射治疗。 该项目的目标如下： 目标 1：制备并表征含有肿瘤亲和性长波长的多功能缀合物 与新型近红外花青染料连接的光敏剂，可选择 124I 标记和 RGD 肽 与整合素 (v3) 相关的肿瘤和新血管结合的部分。 目标 2：体外表征不同缀合物。 目标 3：在动物身上检查缀合物的成像和治疗潜力，并确定任何 整合素靶向缀合物用于成像和治疗的额外好处。 这种“即视即治”方法利用一种可以通过光和 放射成像，然后以不同的波长激活以破坏肿瘤。早期发现癌症很重要，因为它在癌症患者中起着至关重要的作用 管理，因为检测到 1 期癌症与 >90% 的 5 年生存率相关 速度。我们设计用于检测和治疗的“多模态代理”的方法 癌症的研究可能在癌症治疗中发挥重要作用。获得的初始生物学数据 在小鼠模型中提出的化合物在肿瘤成像方面非常有前景 肿瘤转移无任何明显毒性。因此，本研究保证 进一步调查。