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: 8306721
• 负责人: Tayyaba Hasan
• 金额: $ 39.99万
• 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/8306721
• 关键词: Acute; Address; Biodistribution; Biological; Biological Markers; Borderline Personality Disorder; Bronchopulmonary Dysplasia; 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; 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）：晚期检测和耐药性已经维持了30多年的卵巢癌（OVCA）（OVCA）的严峻统计（预计2010年有21,880例新病例和13,850例死亡）。假设使用与机械上不同成分的组合疗法的新方法是最有效的。但是，多种疗法的顺序给药未影响生存。该提案与OVCA治疗的其他关键障碍有关此问题。长期目标是开发，整合和验证关键平台技术，以结合定量荧光成像，用于药物输送监测和定制的剂量测定法与“靶向光毒性多抑制剂脂质体”（TPMIL）（TPMILS）（TPMILS），这些（TPMIL）选择性地靶向并同时阻止与积极的OVCA相关的互联生存途径。为了解决引起OVCA相关死亡的艰苦毒性和频繁的复发，我们利用纳米技术计划来制造TPMIL，以同时对靶向抑制剂进行细胞内递送，并与光学治疗（PDT）（PDT）（PDT）（FDA-Apprate Phodagrate Prosipe for Prosipe Cloile for Prosipe Clinca for OOVCA）提供了组合方案。 PDT可有效地对化学和抗辐射抗性细胞有效，并与化学治疗和生物学剂协同作用，从而提高功效。目标将在4个特定目标中实现：（1）合成，优化和表征OVCA三重组合疗法的TPMIL。 （2）自定义和校准HyperCFME在线，在TPMIL和微型OVCA的体内成像。 （3）建立针对OVCA靶向PDT的图像引导的治疗计划。 （4）评估使用TPMIL和定制的PDT-毫米法对急性治疗反应和生存增强的影响。该提案的主要可交付成果将是（i）两个可再现的，良好的TPMIL，用于多代理交付，具有优化的靶向部分部分的部分表面密度和治疗剂有效载荷； （ii）一种定制的，高分辨率的，微创的成像系统，用于在线肿瘤负担和药物浓度定量； （iii）在最佳TPMIL TNR和阈值PDT剂量下提供足够的BPD积累的最佳药物灯间隔； （iv）确定定制的剂量法对治疗耐受性，急性肿瘤降低和存活的益处； （v）识别最佳靶向部分（MAB与自定义的环状肽）。这项研究的发现将影响患有晚期（II-IV期）和耐药性OVCA的患者以及接受打捞疗法的患者的结果。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，这些策略将适应广泛的转移性肿瘤和分子靶标。由于分子表达和反应可能是特殊的，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会在将来会产生患者抑制治疗的可能性。该平台还将通过提供新的调查工具来影响科学研究。