Glioblastoma PDT Design: Nanoagent Uptake and Tumor Oxygenation based dosimetry

描述（由申请人提供）：胶质母细胞瘤（GBM）是一种侵袭性癌症，生存率低，几乎没有新的治疗选择。荧光引导切除GBM后进行光动力学治疗（PDT）已显示出在临床上几种化疗或放疗无反应GBM治疗中的前景。PDT是一种新兴的光和光敏剂（PS）介导的细胞毒性方法。然而，与其他治疗方式一样，由于剂量参数的非个性化和传统PDT的高度局部化性质，忽略了远处疾病，结果在很大程度上是可变的。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（光的限制和PS的定位），使用靶向PS将影响远处疾病，这是GBM PDT中尚未开发的方法。基于我们以前的研究结果，我们提出了一种解决这些问题的策略，通过建立三维PS肿瘤吸收和氧合使用光声成像（派）。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性和氧非依赖性PS的组合来补偿。这些PS在靶向脂质体中共同递送至肿瘤，以增强选择性和对远处疾病的影响。 本论文的主要研究内容包括三个方面：（1）靶向双光敏剂脂质体（TDEL）的合成与表征。(2)在原位GBM肿瘤中建立TDEL的体内药代动力学和肿瘤摄取，以及（3）评价TDEL和定制的图像引导PDT剂量测定对体内治疗反应的影响。主要可交付成果将是（a）用于靶向共递送两种PS和优化的治疗剂有效载荷的可再现的、良好表征的TDEL;（B）用于确定TDEL和光施用之间的最佳间隔的平台，（c）引起肿瘤氧合状态的最小降低的PDT辐照度，和（d）与传统的“一刀切”相比，建立定制的主动在线PDT剂量测定的益处被动剂量学方法在肿瘤体积减小和存活中的应用。这项研究的结果将成为定制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，为申请人成为独立调查员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博士组成。Hasan（PDT，靶向递送和癌症生物学），B博士。Pogue（定量图像引导算法和PDT剂量测定），X.布雷克菲尔德（GBM肿瘤生物学和动物模型），R。Martuza（GBM-PDT的临床转化方面）和L.华盛顿大学的Wang（派和肿瘤缺氧成像）。

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).