Glioblastoma PDT Design: Nanoagent Uptake and Tumor Oxygenation based dosimetry

描述（申请人提供）：胶质母细胞瘤（GBM）是一种侵袭性癌症，生存率低，很少有新的治疗选择。荧光引导切除GBM后光动力治疗（PDT）在临床上显示出一些化疗或放疗无反应的GBM治疗的前景。PDT是一种新兴的光和光敏剂介导的细胞毒方法。然而，与其他治疗方式一样，由于剂量参数的非个体化和传统PDT的高度局域性，忽略了远处的疾病，结果是可变的。这种可变性主要归因于患者之间两个关键参数的差异- PS浓度和肿瘤氧合。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（限制光和定位PS），使用靶向PS将影响远端疾病，这一方法尚未在GBM PDT中得到利用。基于我们之前的研究结果，我们提出了一种解决这些问题的策略，即利用光声成像（PAI）建立3D PS肿瘤摄取和氧合。PS摄取的变化通过调节光剂量来解决，而肿瘤氧合变化通过调节光辐照度和使用氧依赖型和氧依赖型PS来补偿。这些ps在靶向脂质体中共同递送到肿瘤中，以增强选择性和对远处疾病的影响。本研究将在三个方面完成：(1)用于增强PDT的靶向双光敏剂包封脂质体（TDELs）的合成和表征。(2)建立原位GBM肿瘤中TDELs的体内药代动力学和肿瘤摄取；(3)评估TDELs和定制图像引导的PDT剂量法对体内治疗反应的影响。主要成果将是：(a)可重复的、特性良好的TDELs，用于优化治疗剂载荷的两种PSs的靶向联合递送；(b)确定TDEL和光照之间的最佳间隔的平台(c) PDT的辐照度对肿瘤氧合状态的影响最小，(d)与传统的“一刀切”被动剂量法相比，定制的主动在线PDT剂量法在肿瘤体积缩小和生存方面的优势。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。一个指导委员会已经成立，为申请人在成为独立研究者的过程中提供科学指导和职业建议。她将在纳米技术、光化学、肿瘤生物学和GBM PDT策略等领域接受广泛的培训。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剂量学）、X. Breakefield博士（GBM肿瘤生物学和动物模型）、R. Martuza博士（GBM -PDT的临床转化方面）和华盛顿大学的L. Wang博士（PAI和肿瘤缺氧成像）组成。

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).