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

描述（由申请人提供）：30多年来，晚期发现和耐药性使卵巢癌（OvCa）的严峻统计数据保持不变（预计2010年将有21,880例新病例和13,850例死亡）。采用机制不同成分的联合疗法的新方法被认为是最有效的。然而，连续给药的多种治疗未能影响生存。该提案解决了这一问题以及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，将用于药物输送监测的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”（TPMILs）相结合，选择性地靶向并同时阻断与侵袭性OvCa相关的相互关联的生存途径。为了解决导致OvCa相关死亡的严重毒性和频繁复发，我们利用纳米技术计划制造tpmil，用于同时在细胞内递送靶向抑制剂，并提供与光动力疗法（PDT）的联合方案，光动力疗法是一种经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对化疗和放射耐药细胞有效，并与化疗和生物制剂协同作用，从而提高疗效。具体目标将实现在4个方面：(1)合成、优化和表征用于OvCa三联治疗的tpmil。(2)定制和校准hyperfme用于tpmil和微结节OvCa的在线、体内成像。(3)建立影像引导的ovca靶向PDT治疗方案。(4)评估使用tpmil和定制pdt剂量法对急性治疗反应和生存提高的影响。本提案的主要成果将是：(i)两种可重复的、特性良好的tpmil，用于多药递送，具有优化的靶向部分表面密度和治疗剂有效载荷；（ii）定制的高分辨率微创成像系统，用于在线肿瘤负荷和药物浓度定量校准；（iii）在最佳TPMIL - TNR下提供足够BPD积累的最佳药光间隔和PDT阈值剂量；（iv）确定定制剂量法对治疗耐受性、急性肿瘤减少和生存的益处；(v)确定最佳靶向片段（单抗与定制环肽）。这项研究的结果将影响晚期（II-IV期）和耐药OvCa患者以及接受挽救性治疗的患者的预后。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性的，因此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为未来患者定制治疗创造了可能。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.