MR-HIFU induced drug delivery for pancreatic cancer treatment

MR-HIFU 诱导药物输送用于胰腺癌治疗

• 批准号: 8874729
• 负责人: Donghoon Lee
• 金额: $ 55.84万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-12 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874729
• 关键词: Accounting; Aftercare; Biological Markers; Calibration; Cancer Etiology; Cancer Patient; Cell Death; Cessation of life; Clinical; Clinical Trials; Detection; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Drug Delivery Systems; Evaluation; Excision; Focused Ultrasound; Focused Ultrasound Therapy; Gadolinium; Genetic; Genetically Engineered Mouse; Goals; Human; Hyperthermia; Induced Hyperthermia; Injection of therapeutic agent; Liposomes; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant neoplasm of pancreas; Measurement; Mediating; Methodology; Methods; Modeling; Monitor; Mus; Noise; Operative Surgical Procedures; Pancreatic Ductal Adenocarcinoma; Pathologic; Patients; Penetration; Perfusion; Permeability; Pharmaceutical Preparations; Physiologic pulse; Preparation; Process; Resectable; Resolution; Sampling; Signal Transduction; Survival Rate; System; Treatment Efficacy; Ultrasonography; United States; Unresectable; anticancer research; base; cancer therapy; chemotherapeutic agent; chemotherapy; cold temperature; contrast enhanced; follow-up; gadolinium oxide; gemcitabine; imaging modality; in vivo; mouse model; neoplastic cell; pancreatic neoplasm; pre-clinical; preclinical study; public health relevance; radiofrequency; response; therapeutic development; treatment response; tumor; tumor progression

 DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. Surgical resection offers the only chance of cure with an about 20% 5-year survival but more than 80% of patients present with advanced unresectable disease. The overall 5-year survival rate for all types of pancreatic cancer is less than 5%. Pancreatic tumor therapy has been ineffective partly because pancreatic tumors have a dense stroma inhibiting penetration of chemotherapeutic drugs into the tumor. High intensity focused ultrasound (HIFU) can be used to induce targeted hyperthermia leading to increased perfusion potentially enhancing targeted drug delivery (TDD) to pancreatic tumors with deficient vasculature. In addition, pulsed HIFU has potential to mechanically disrupt stroma resulting in increased permeability of the dense stroma in pancreatic tumors. One major challenge with the HIFU-enhanced TDD is the absence of noninvasively assessing treatment efficacy following the HIFU application. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) have been widely used as key noninvasive methodologies for clinical tumor diagnosis and treatment follow-up due to their good spatial resolution compared to other imaging modalities. However, with respect to pancreatic tumors, conventional MRI has been used for qualitative detection of pathologic regions for diagnosis and treatment follow-up with limited resolution and inability of quantification for preclinical studies using mouse models. Therefore, more effective magnetic resonance (MR) biomarkers with high resolution are needed to monitor treatment responses of tumors treated with HIFU in tumor bearing mice. We hypothesize 1) HIFU induced hyperthermia will enhance TDD and pancreatic tumor cell death in a targeted region and quantitative MR will enable assessment of the treatment 2) pulsed HIFU will disrupt stromal layers in pancreatic tumor and MRI/MRS will assess the process of stromal layer disruption. The overall goal of this study is 1) to generate effective HIFU induced hyperthermia for targeted chemotherapeutic drug delivery for a pancreatic tumor mouse model (KPC) that closely resembles human pancreatic cancer and 2) to accurately monitor both mild hyperthermia and responses to pancreatic tumor treatments based on the HIFU-enhanced TDD using noninvasive and quantitative MRI and MRS methods at high resolution. To accomplish the study goal we propose three specific aims: 1) to assess pancreatic tumor progression for the KPC mouse model with advanced MR methods, 2) to evaluate perfusion and degree of stromal layer disruption after HIFU and 3) to assess responses to chemotherapeutic treatments mediated by HIFU. The development of noninvasive MR biomarkers, pulsed HIFU method and effective KPC mouse model will be essential to advance the understanding of this deadly disease and has the potential to be used to assess promising therapies in pre- clinical and clinical trials.

 描述（由适用提供）：胰腺癌是美国与癌症相关死亡的第四个主要原因。手术切除提供了约20％的5年生存的唯一治愈机会，但超过80％的患者患有晚期无法切除的疾病。所有类型的胰腺癌的总体5年生存率小于5％。胰腺肿瘤治疗的部分原因是胰腺肿瘤具有致密的基质抑制性化疗药物的密集抑制作用。高强度聚焦超声（HIFU）可用于诱导靶向高温，从而导致灌注增加有可能增强靶向药物递送（TDD）到缺乏脉管系统的胰腺肿瘤。此外，脉冲HIFU具有机械破坏基质的潜力，从而导致胰腺肿瘤致密基质的渗透率增加。 HIFU增强的TDD的一个主要挑战是在应用HIFU后没有非侵入性评估治疗效率。磁共振成像（MRI）和磁共振光谱（MRS）已被广泛用作临床肿瘤诊断和治疗随访的关键无创方法，因为它们与其他成像方式相比，它们的空间分辨率良好。然而，关于胰腺肿瘤，常规MRI已用于对病理区域进行定性检测，用于诊断和治疗随访，使用小鼠模型有限分辨率和无能为力的临床前研究。因此，需要具有高分辨率的更有效的磁共振（MR）生物标志物来监测用肿瘤轴承小鼠用HIFU治疗的肿瘤的治疗反应。我们假设1）HIFU诱导的高温将增强靶向区域中的TDD和胰腺肿瘤细胞死亡，而定量MR将能够评估治疗2）脉冲HIFU将破坏胰腺肿瘤中的脉冲基质层，MRI/MRS/MRS将评估间质层干扰的过程。这项研究的总体目标是1）生成有效的HIFU诱导的胰腺肿瘤小鼠模型（KPC）的有效的化学治疗药物递送（KPC），该模型与人类胰腺癌紧密相似，以准确地监测了轻度热点和基于胰腺肿瘤治疗的轻度和反应，并基于胰腺肿瘤治疗，并使用量级的MR MR MR MR MR MRININTINT TOD TDD DD DD DD DD DD DD DD DD DD DD DD DD DD DD DD DD DD DD。 高分辨率。为了实现研究目标，我们提出了三个具体目的：1）用高级MR方法评估KPC小鼠模型的胰腺肿瘤进展，2）评估HIFU后的灌注和基质层破坏程度和3）评估对HIFU介导的化学治疗治疗的反应。非侵入性MR生物标志物，脉冲HIFU方法和有效KPC小鼠模型的发展对于提高对这种致命疾病的理解至关重要，并且有可能用于评估临床和临床试验中的有希望的疗法。