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: 8211748
• 负责人: Ravindra K. Pandey
• 金额: $ 56.02万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8211748
• 关键词: Adjuvant Therapy; Animals; Avidity; Binding; Biodistribution; Biological; Biology; Brain; Brain Neoplasms; Breast Melanoma; 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; Treaty; 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.

光动力疗法是一种有效的肿瘤局部治疗方法 (PS)由照射在治疗部位的光激活。目前的光敏剂显示一些肿瘤 选择性，并且光可以通过薄的柔性光纤被输送到身体的几乎任何地方。但对于 小的、大的或埋藏的病变，可能难以检测恶性肿瘤和/或适当地放置光学显微镜。 纤维来照亮肿瘤的整个范围。我们假设开发一种新的方法来引导 利用高选择性光学和PET成像的治疗，允许肿瘤可视化，图像引导 光纤的放置和随后的病变的光动力破坏。 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带有独特的近红外（NIR）荧光染料和长半衰期PET试剂124 I。初步 研究表明，这些缀合物提供了非常高的体内肿瘤选择性，同时保持。我们将确定 通过连接肿瘤或新生血管选择性分子 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个- 模态干预：缀合物可以递送治疗性放射性同位素，并且PDT可以超叠加地 加强放射治疗。 该项目的目标如下： 目的1：制备和表征含有抗肿瘤长波长荧光蛋白的多功能偶联物 光敏剂与具有124 I标记和RGD肽选择的新型NIR花青染料连接 结合与整联蛋白（v3）相关的肿瘤和新血管形成的部分。 目的2：对不同的偶联物进行体外表征。 目的3：在动物中检查缀合物的成像和治疗潜力，并确定任何可能的缀合物。 整合素靶向缀合物用于成像和治疗的额外益处。 这种“看和治疗”的方法用一种可以被光检测到的试剂来靶向癌症， 放射成像，然后在不同的波长下激活以破坏肿瘤。早期发现癌症是非常重要的，因为它在癌症患者中起着关键作用。 由于检测到1期癌症与>90%的5年生存率相关， 率我们设计用于检测和治疗的多模态代理的方法 可以在癌症治疗中发挥重要作用。获得的初始生物学数据 在肿瘤成像中是非常有前途的， 肿瘤转移而无任何显著毒性。因此，这项研究保证 进一步调查

项目成果

Pluronic F-127: An Efficient Delivery Vehicle for 3-(1'-hexyloxy)ethyl-3-devinylpyropheophorbide-a (HPPH or Photochlor).

• DOI: 10.1111/php.13183
• 发表时间: 2020-05
• 期刊: PHOTOCHEMISTRY AND PHOTOBIOLOGY
• 影响因子: 3.3
• 作者: Cacaccio, Joseph;Durrani, Farukh;Cheruku, Ravindra R.;Borah, Ballav;Ethirajan, Manivannan;Tabaczynski, Walter;Pera, Paula;Missert, Joseph R.;Pandey, Ravindra K.
• 通讯作者: Pandey, Ravindra K.

Conjugation of cRGD peptide to chlorophyll a based photosensitizer (HPPH) alters its pharmacokinetics with enhanced tumor-imaging and photosensitizing (PDT) efficacy.

将CRGD肽与叶绿素A基光敏剂（HPPH）结合通过增强的肿瘤成像和光敏（PDT）功效来改变其药代动力学。

• DOI: 10.1021/mp200018y
• 发表时间: 2011-08-01
• 期刊: Molecular pharmaceutics
• 影响因子: 4.9
• 作者: Srivatsan A;Ethirajan M;Pandey SK;Dubey S;Zheng X;Liu TH;Shibata M;Missert J;Morgan J;Pandey RK
• 通讯作者: Pandey RK

Measurement of Cyanine Dye Photobleaching in Photosensitizer Cyanine Dye Conjugates Could Help in Optimizing Light Dosimetry for Improved Photodynamic Therapy of Cancer.

光敏剂氰染料偶联物中氰氨酸染料光漂白的测量可以帮助优化光剂量测定法，以改善癌症的光动力疗法。

• DOI: 10.3390/molecules23081842
• 发表时间: 2018-07-24
• 期刊: Molecules (Basel, Switzerland)
• 作者: James NS;Cheruku RR;Missert JR;Sunar U;Pandey RK
• 通讯作者: Pandey RK

Synthesis, photophysical, electrochemical, tumor-imaging, and phototherapeutic properties of purpurinimide-N-substituted cyanine dyes joined with variable lengths of linkers.

• DOI: 10.1021/bc200345p
• 发表时间: 2011-11-16
• 期刊: BIOCONJUGATE CHEMISTRY
• 影响因子: 4.7
• 作者: Williams, Michael P. A.;Ethirajan, Manivannan;Ohkubo, Kei;Chen, Ping;Pera, Paula;Morgan, Janet;White, William H., III;Shibata, Masayuki;Fukuzumi, Shunichi;Kadish, Karl M.;Pandey, Ravindra K.
• 通讯作者: Pandey, Ravindra K.

Multifunctional biodegradable polyacrylamide nanocarriers for cancer theranostics--a "see and treat" strategy.

• DOI: 10.1021/nn301633m
• 发表时间: 2012-08-28
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Wang, Shouyan;Kim, Gwangseong;Lee, Yong-Eun Koo;Hah, Hoe Jin;Ethirajan, Manivannan;Pandey, Ravindra K.;Kopelman, Raoul
• 通讯作者: Kopelman, Raoul