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，存活率很低，几乎没有新的治疗选择。在荧光引导下切除基底膜，然后进行光动力疗法(PDT)，在临床上已显示出在几种化疗或放疗无效的基底膜治疗中的应用前景。光动力疗法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，结果是不同的，主要是由于剂量参数的非个性化以及传统PDT的高度局部化性质而忽略了远处的疾病。这种可变性主要归因于患者之间在两个关键参数上的差异-PS浓度和肿瘤氧合。这些都需要结合到针对患者的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将影响远处疾病，这一方法尚未在GBM PDT中使用。基于我们之前的发现，我们提出了一种策略，通过使用光声成像(PAI)建立3D PS肿瘤的摄取和氧合来解决这些问题。PS摄取的变化通过调整光剂量来解决，而肿瘤氧合变化通过调整光照度和使用氧依赖和氧非依赖PSS的组合来补偿。这些PS在靶向脂质体中共同传递到肿瘤上，以增强选择性和对远处疾病的影响。本研究将在以下三个方面完成：(1)用于增强型光动力治疗的靶向双光敏剂包埋脂质体的合成与表征。(2)建立TDELs在原位GBM肿瘤中的体内药代动力学和肿瘤摄取；(3)评价TDELs和定制图像引导的PDT剂量学对体内治疗反应的影响。主要交付成果将是：(A)用于靶向联合递送两个PS的可重复性、特性良好的TDEL，以及优化的治疗剂有效载荷；(B)用于确定TDEL和光疗之间的最佳间隔的平台；(C)使肿瘤氧合状态下降最小的PDT的辐照度；(D)与传统的“一刀切”被动剂量学方法相比，定制的主动式在线PDT剂量学方法在肿瘤体积缩小和存活率方面的益处。这项研究的结果将形成定制的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，为申请者提供科学指导和职业建议，帮助她将自己转变为一名独立调查员。她将在纳米技术、光化学、肿瘤生物学和GBM PDT策略方面获得广泛的培训。该委员会由T.Hasan博士(PDT、靶向传递和癌症生物学)、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的临床翻译方面)和L.Wang博士组成。(PAI和肿瘤乏氧成像)。 公共卫生相关性：胶质母细胞瘤是一种毁灭性的疾病，存活率很低。该项目旨在提高光动力治疗胶质母细胞瘤的疗效(一种高度特异的治疗策略，与化疗或放射治疗不同，对周围健康脑组织造成的损害较小)。该项目整合了(1)纳米技术平台，以在“正确的时间”和“正确的地点”提供成像和治疗剂，以及(2)光学成像技术，以指导治疗剂量学，以获得有效的治疗结果。

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). PUBLIC HEALTH RELEVANCE: Glioblastoma is a devastating disease with dismal survival rates. This project aims to improve the efficacy of photodynamic treatment (a highly specific treatment strategy that causes less damage to surrounding healthy brain tissue unlike chemo or radiotherapy) for glioblastoma. The project integrates (1) nanotechnology platforms to deliver imaging and therapeutic agents at the "right time" and to the "right place" and (2) optical imaging techniques to guide therapy dosimetry for obtaining effective treatment outcome.