Glioblastoma PDT Design: Nanoagent Uptake and Tumor Oxygenation based dosimetry

胶质母细胞瘤 PDT 设计：纳米制剂摄取和基于肿瘤氧合的剂量测定

基本信息

批准号：
8717609
负责人：
Srivalleesha Mallidi
金额：
$ 5.7万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8717609
关键词：
3-Dimensional Address Algorithms Animal Model Biodistribution Cancer Biology Cell Line Cells Cetuximab Chloride Ion Chlorides Clinical Clinical Research Disease Distant Dose Drug Kinetics Encapsulated Epidermal Growth Factor Receptor Evaluation Excision Feedback Fluorescence Glioblastoma Hypoxia Hypoxia Inducible Factor Image Imaging Techniques In Vitro Lasers Light Liposomes Literature Malignant Neoplasms Measurement Mediating Mentors Methods Modality Monitor Monoclonal Antibody C225 Mus Nanotechnology Nature Necrosis Operative Surgical Procedures Optics Outcome Oxygen Oxygen Consumption Patients Photochemistry Photochemotherapy Photosensitizing Agents Phototoxicity Procedures Property Publishing Radiation therapy Research Research Personnel Resolution Survival Rate System Techniques Testing Therapeutic Therapeutic Agents Time Tissues Training Translations Treatment Efficacy Treatment outcome Tumor Biology Tumor Oxygenation Tumor Tissue Tumor Volume Tumor Weights U251 Ultrasonics Variant Vascular Endothelial Growth Factors Washington absorption active method aqueous base brain tissue cancer cell career chemotherapy cytotoxic design dosimetry effective therapy fluorescence imaging improved in vivo molecular marker mouse model neoplastic cell optical imaging overexpression photoacoustic imaging public health relevance receptor receptor expression success targeted delivery therapy design therapy resistant treatment response treatment strategy tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is an aggressive cancer with dismal survival rates and few new treatment options. Fluorescence guided resection of GBM followed by photodynamic therapy (PDT) has shown promise in several chemo- or radiotherapy non-responsive GBM treatments clinically. PDT is an emerging light and photosensitizer (PS) mediated cytotoxic method. However, as with other therapeutic modalities, the outcomes are variable largely due to the non-personalization of dose parameters and the highly localized nature of conventional PDT that ignores distant disease. The variability can primarily be attributed to the inter-patient differences in two key parameters - PS concentration and tumor oxygenation. These need to be incorporated in the design of patient-specific PDT. Also, because PDT has built in dual selectivity (confinement of light and localization of PS), using targeted PS would impact distant disease,an approach not yet exploited in GBM PDT. Building upon our previous findings, we propose a strategy for addressing these issues by establishing 3D PS tumoral uptake and oxygenation using photoacoustic imaging (PAI). The variation in PS uptake is addressed by adjusting the light dose while the tumor oxygenation variation is compensated by adjusting the light irradiance and using a combination of oxygen-dependent and oxygen-independent PSs. These PSs are co-delivered to the tumor in a targeted liposome for enhanced selectivity and impact on distant disease. The research will be accomplished in three specific aims: (1) Synthesis and characterization of Targeted Dual photosensitizer Encapsulation Liposomes (TDELs) for enhanced PDT. (2) Establish in-vivo pharmacokinetics and tumoral uptake of TDELs in orthotopic GBM tumors and (3) Evaluation of the TDELs and customized image guided PDT dosimetry impact on treatment response in vivo. Major deliverables will be (a) reproducible, well-characterized TDELs for targeted co-delivery of two PSs with optimized therapeutic agent payload; (b) a platform for determining the optimal interval between TDEL and light administration (c) irradiance for PDT that causes least decrease in tumor oxygenation status and (d) establishment of the benefit of customized active on-line PDT dosimetry compared to conventional "one size fits all" passive dosimetry approach in tumor volume reduction and survival. The findings of this study will form the basis for customized GBM treatments and serve as a platform for treatment of other cancers. A mentoring committee has been assembled to offer scientific guidance and career advice to the applicant in her translation to being an independent investigator. She will obtain extensive training in the fields of nanotechnology, photochemistry, tumor biology and GBM PDT strategies. The committee comprises of Dr. T. Hasan (PDT, targeted delivery and cancer biology), Dr. B. Pogue (quantitative image-guided algorithms and PDT dosimetry), Dr. X. Breakefield (GBM tumor biology and animal models), Dr. R. Martuza (clinical translational aspects of GBM-PDT) and Dr. L. Wang at Univ. of Washington (PAI and imaging tumor hypoxia).

描述（由申请人提供）：胶质母细胞瘤（GBM）是一种侵袭性癌症，其生存率很低，并且几乎没有新的治疗选择。荧光引导 GBM 切除术随后进行光动力疗法 (PDT) 在临床上对几种化疗或放疗无反应的 GBM 治疗中显示出了希望。 PDT 是一种新兴的光和光敏剂 (PS) 介导的细胞毒方法。然而，与其他治疗方式一样，结果存在差异，很大程度上是由于剂量参数的非个性化以及传统 PDT 的高度局部性而忽略了远处的疾病。这种变异性主要归因于两个关键参数（PS 浓度和肿瘤氧合）的患者间差异。这些需要纳入患者特异性 PDT 的设计中。此外，由于 PDT 具有双重选择性（光限制和 PS 定位），因此使用靶向 PS 会影响远处的疾病，这是 GBM PDT 中尚未采用的方法。基于我们之前的发现，我们提出了一种通过使用光声成像 (PAI) 建立 3D PS 肿瘤摄取和氧合来解决这些问题的策略。 PS 摄取的变化可通过调整光剂量来解决，而肿瘤氧合变化则可通过调整光辐照度并结合使用氧依赖性和氧非依赖性 PS 来补偿。这些 PS 通过靶向脂质体共同递送至肿瘤，以增强选择性和对远处疾病的影响。该研究将实现三个具体目标：（1）用于增强PDT的靶向双光敏剂封装脂质体（TDEL）的合成和表征。 (2) 建立原位 GBM 肿瘤中 TDEL 的体内药代动力学和肿瘤摄取；(3) 评估 TDEL 和定制图像引导 PDT 剂量测定对体内治疗反应的影响。主要交付成果将是 (a) 可重复、特征良好的 TDEL，用于靶向共同交付两种具有优化治疗剂有效负载的 PS； (b) 用于确定 TDEL 和光照射之间最佳间隔的平台 (c) 导致肿瘤氧合状态下降最少的 PDT 辐照度，以及 (d) 与传统的“单剂量”相比，确定定制主动在线 PDT 剂量测定的益处尺寸适合所有”被动剂量测定方法减少肿瘤体积和提高生存率。这项研究的结果将构成定制 GBM 治疗的基础，并作为治疗其他癌症的平台。已经成立了一个指导委员会，为申请人成为一名独立研究者提供科学指导和职业建议。她将获得纳米技术、光化学、肿瘤生物学和 GBM PDT 策略领域的广泛培训。该委员会由 T. Hasan 博士（PDT、靶向递送和癌症生物学）、B. Pogue 博士（定量图像引导算法和 PDT 剂量测定）、X. Breakefield 博士（GBM 肿瘤生物学和动物模型）、 . R. Martuza（GBM-PDT 的临床转化方面）和大学的 L. Wang 博士。华盛顿大学（PAI 和肿瘤缺氧成像）。