Ovarian Cancer PDT: Multi-intracellular targeting and Image-guided dosimetry

描述（由申请人提供）：晚期检测和耐药性使卵巢癌（OvCa）的统计数据保持了30多年（预计2010年有21，880例新发病例和13，850例死亡）。新的方法，使用联合治疗与机械不同的组件被假设为是最有效的。然而，序贯给予多种治疗未能影响生存率。该提案解决了这一问题沿着OvCa治疗中的其他关键障碍。长期目标是开发、整合和验证关键平台技术，以将用于药物递送监测的联合收割机定量荧光成像和定制剂量测定与“靶向光毒性多抑制剂脂质体”（TPMIL）结合起来，TPMIL选择性靶向并同时阻断与侵袭性OvCa相关的相互关联的存活途径。为了解决导致OvCa相关死亡的剧烈毒性和频繁复发，我们利用我们的纳米技术计划来制造TPMIL，用于同时细胞内递送靶向抑制剂，并提供与光动力疗法（PDT）的组合方案，这是一种FDA批准的基于光化学的治疗方法，已显示出OvCa的临床前景。PDT对化疗和放射抗性细胞有效，并与化疗剂和生物制剂协同作用，从而提高疗效。本研究的主要目的是：（1）合成、优化和表征用于OvCa三联疗法的TPMIL。(2)定制和校准hyperCFME，用于TPMIL和微结节OvCa的在线体内成像。(3)建立OvCa靶向PDT的图像引导治疗计划。(4)评价使用TPMIL和定制PDT剂量测定对急性治疗反应和生存率提高的影响。该提案的主要交付成果将是（i）两种可重现的、表征良好的TPMIL，用于多药剂递送，具有优化的靶向部分表面密度和治疗剂有效载荷;（ii）定制的、高分辨率的、微创成像系统，经校准用于在线肿瘤负荷和药物浓度定量;（iii）在最佳TPMIL TNR下提供足够BPD累积的最佳药物-光间隔，以及阈值PDT剂量;（iv）确定定制的剂量测定对治疗耐受性、急性肿瘤减少和存活的益处;和（v）鉴定最佳靶向部分（mAb相对于定制的环肽）。这项研究的结果将影响晚期（II-IV期）和耐药OvCa患者以及接受挽救治疗的患者的结局。通过这种高度集成的方法开发的基础设施将创建一个新的框架，以快速评估和优化新的治疗策略，这些策略将适用于广泛的转移性肿瘤和分子靶点。由于分子表达和反应可能是特异质的，因此所提出的对生物标志物表达和治疗诱导的生物标志物变化的快速监测创造了未来患者定制治疗的可能性。该平台还将通过提供新的调查工具来影响科学研究。

DESCRIPTION (provided by applicant): Late detection and drug resistance have maintained the grim statistics for ovarian cancer (OvCa) for over 30 years (with a projected 21,880 new cases and 13,850 deaths in 2010). New approaches using combination therapies with mechanistically distinct components are hypothesized to be most effective. However, sequential administration of multiple therapies has failed to impact survival. This proposal addresses this issue along with other key barriers in the treatment of OvCa. The long term goal is to develop, integrate and validate key platform technologies to combine quantitative fluorescence imaging for drug delivery monitoring and customized dosimetry with "Targeted Phototoxic Multi-Inhibitor Liposomes" (TPMILs) that selectively target and simultaneously block interconnected survival pathways associated with aggressive OvCa. To address the grueling toxicities and frequent recurrence that cause OvCa-related deaths, we leverage our nanotechnology program to fabricate TPMILs for simultaneous intracellular delivery of targeted inhibitors, and deliver combination regimens with photodynamic therapy (PDT), an FDA-approved photochemistry-based treatment that has shown clinical promise for OvCa. PDT is effective on chemo and radiation resistant cells and synergizes with chemotherapeutic and biologic agents resulting in improved efficacy. The goals will be realized in 4 specific aims: (1) Synthesize, optimize and characterize TPMILs for triple combination therapy of OvCa. (2) Customize and calibrate hyperCFME for online, in vivo imaging of TPMILs and micronodular OvCa. (3) Establish image-guided treatment planning for OvCa-targeted PDT. (4) Evaluate the impact of using TPMILs and customized PDT-dosimetry on acute treatment response and survival enhancement. Major deliverables of this proposal will be (i) two reproducible, well-characterized TPMILs for multi-agent delivery with optimized targeting moiety surface densities and therapeutic agent payloads; (ii) a custom built, high-resolution, minimally-invasive imaging system calibrated for online tumor burden and drug concentration quantification; (iii) the optimal drug-light interval that provides sufficient BPD accumulation at the best TPMIL TNR, and the threshold PDT dose; (iv) determination of customized dosimetry benefit to treatment tolerance, acute tumor reduction, and survival; and, (v) identification of the optimal targeting moiety (mAb versus customized cyclic peptide). The findings from this study will impact outcomes for patients with advanced (stage II-IV) and resistant OvCa and those receiving salvage therapies. The infrastructure developed through this highly integrated approach will create a new framework to rapidly evaluate and optimize new therapeutic strategies that will be adaptable to a broad array of metastatic tumors and molecular targets. Because molecular expressions and responses can be idiosyncratic, the proposed rapid monitoring of biomarker expression and treatment-induced biomarker changes creates the possibility of patient-customized treatments in the future. The platform will also impact scientific research by providing new investigative tools.