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

卵巢癌 PDT：多细胞内靶向和图像引导剂量测定

• 批准号: 8657916
• 负责人: Tayyaba Hasan
• 金额: $ 37.09万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-25 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657916
• 关键词: Acute; Address; Biodistribution; Biological; Biological Markers; Cancer Model; Cancer Patient; Cells; Cessation of life; Cetuximab; Clinic; Clinical; Combined Modality Therapy; Complex; Contrast Media; Custom; Cyclic Peptides; Cytotoxic agent; Detection; Disease; Disease Resistance; Disseminated Malignant Neoplasm; Dose; Drug Delivery Systems; Drug Kinetics; Drug resistance; Elements; Epidermal Growth Factor Receptor; Equilibrium; FDA approved; Feedback; Fluorescence; Future; Goals; Grant; Greater sac of peritoneum; Heterogeneity; Hour; Image; Imagery; Imaging Device; Kinetics; Label; Left; Life; Light; Liposomes; Malignant neoplasm of ovary; Maximum Tolerated Dose; Measures; Microscopic; Modality; Molecular; Molecular Target; Monitor; Monoclonal Antibodies; Mus; Nanotechnology; Neoplasm Metastasis; Nodule; Outcome; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Photochemistry; Photochemotherapy; Radiation; Recurrence; Regimen; Relative (related person); Research; Research Infrastructure; Resectable; Resistance; Resolution; Salvage Therapy; Signal Transduction; Site; Staging; Surface; System; Technology; Therapeutic; Therapeutic Agents; Therapeutic Index; Time; Tissues; Toxic effect; Tumor Burden; Tyrosine Kinase Inhibitor; Vascular Endothelial Growth Factor Receptor; Verteporfin; attenuation; base; cancer cell; cell killing; cytotoxic; density; dosimetry; fluorescence imaging; improved; in vivo; in vivo imaging; inhibitor/antagonist; instrument; minimally invasive; mouse model; neoplastic cell; novel strategies; novel therapeutics; outcome forecast; phase 2 study; programs; receptor; resistance mechanism; response; statistics; targeted delivery; tool; treatment planning; treatment response; tumor; uptake

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.

描述（由申请人提供）： 30 多年来，晚期检测和耐药性一直是卵巢癌 (OvCa) 的严峻统计数据（预计 2010 年将有 21,880 例新病例和 13,850 例死亡）。据推测，使用具有不同机制的成分的联合疗法的新方法是最有效的。然而，多种疗法的连续给药未能影响生存。该提案解决了这个问题以及 OvCa 治疗中的其他主要障碍。长期目标是开发、集成和验证关键平台技术，将用于药物输送监测和定制剂量测定的定量荧光成像与“靶向光毒性多抑制剂脂质体”（TPMIL）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问题，我们利用纳米技术计划来制造 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) 的联合治疗方案，光动力疗法 (PDT) 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 对化疗和放疗耐药细胞有效，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 三重联合治疗的 TPMIL。 (2) 定制和校准 hyperCFME，用于 TPMIL 和微结节 OvCa 的在线体内成像。 (3)建立影像引导的OvCa靶向PDT治疗计划。 (4) 评估使用 TPMIL 和定制 PDT 剂量测定对急性治疗反应和生存增强的影响。该提案的主要交付成果将是 (i) 两种可重复、特征良好的 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负载； (ii) 定制的高分辨率微创成像系统，针对在线肿瘤负荷和药物浓度定量进行校准； (iii) 在最佳 TPMIL TNR 下提供足够 BPD 积累的最佳药物-光照间隔，以及阈值 PDT 剂量； (iv) 确定定制剂量测定对治疗耐受性、急性肿瘤减少和生存的益处； (v) 确定最佳靶向部分（mAb 与定制环肽）。这项研究的结果将影响晚期（II-IV 期）和耐药 OvCa 患者以及接受挽救治疗的患者的结果。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，该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，因此对生物标志物表达和治疗引起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性。该平台还将通过提供新的调查工具来影响科学研究。