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

描述(申请人提供)：晚发现和抗药性使卵巢癌(OvCa)的统计数据保持了30多年的严峻水平(预计2010年新增病例21,880例，死亡13,850例)。假设使用机械上不同成分的联合疗法的新方法是最有效的。然而，多种疗法的顺序给药并未影响存活率。这项建议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、集成和验证关键平台技术，将用于药物释放监测的定量荧光成像和定制剂量测定与“靶向光毒多抑制物脂质体”(TPMILs)相结合，TPMILs可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路径。为了解决导致OvCa相关死亡的令人精疲力竭的毒性和频繁的复发，我们利用我们的纳米技术计划制造TPMILs，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)的组合方案，光动力疗法是FDA批准的一种基于光化学的治疗方法，已显示出治疗OvCa的临床前景。PDT对化疗和辐射耐药细胞有效，并与化疗和生物制剂协同作用，从而提高疗效。这些目标将通过4个具体目标来实现：(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的在线活体成像。(3)建立OvCa靶向PDT的影像引导治疗计划。(4)评价使用TPMILs和定制PDT剂量计对急性治疗反应和提高生存的影响。这项建议的主要成果将是(I)两种可重复使用、特性良好的多制剂TPMIL，其靶向部分的表面密度和治疗剂有效载荷得到优化；(Ii)定制的、高分辨率、微创的成像系统，针对在线肿瘤负荷和药物浓度量化进行校准；(Iii)在最佳TPMIL TNR和PDT阈值剂量下提供足够BPD累积的最佳药物光间隔；(Iv)确定有利于治疗耐受性、急性肿瘤减少和生存期的定制剂量学；以及(V)确定最佳靶向部分(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患者以及接受抢救治疗的患者的预后。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殊的，拟议的对生物标记物表达和治疗诱导的生物标记物变化的快速监测为未来患者定制治疗创造了可能性。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.