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（由申请人提供）：胰腺癌是美国癌症相关死亡的第四大原因，手术切除提供了唯一的治愈机会，其 5 年生存率约为 20%，但超过 80% 的患者患有胰腺癌。晚期不可切除的疾病。所有类型胰腺癌的总体 5 年生存率低于 5%，部分原因是胰腺肿瘤具有致密的基质抑制。高强度聚焦超声 (HIFU) 可用于诱导靶向热疗，从而增加灌注，从而可能增强对脉管系统缺陷的胰腺肿瘤的靶向药物输送 (TDD)。破坏基质导致胰腺肿瘤致密基质的通透性增加，HIFU 增强 TDD 的一大挑战是缺乏非侵入性评估治疗效果。磁共振成像（MRI）和磁共振波谱（MRS）由于其与其他成像方式相比具有良好的空间分辨率，已被广泛用作临床肿瘤诊断和治疗随访的关键无创方法。对于胰腺肿瘤，传统 MRI 已用于定性检测病理区域以进行诊断和治疗随访，但分辨率有限且无法使用小鼠模型进行临床前研究定量，因此，需要更有效的高磁共振（MR）生物标志物。需要分辨率来监测荷瘤小鼠中经 HIFU 治疗的肿瘤的治疗反应，我们步骤 1) HIFU 诱导的高温将增强目标区域的 TDD 和胰腺肿瘤细胞死亡，定量 MR 将能够评估治疗效果 2) 脉冲 HIFU 将实现治疗效果的评估。破坏胰腺肿瘤的基质层，MRI/MRS 将评估基质层破坏的过程。本研究的总体目标是 1) 产生有效的 HIFU 诱导热疗以进行靶向治疗。为与人类胰腺癌非常相似的胰腺肿瘤小鼠模型 (KPC) 进行化疗药物输送，2) 基于 HIFU 增强 TDD，使用高位无创定量 MRI 和 MRS 方法准确监测轻度热疗和对胰腺肿瘤治疗的反应为了实现研究目标，我们提出了三个具体目标：1）使用先进的 MR 方法评估 KPC 小鼠模型的胰腺肿瘤进展，2）评估灌注和程度。 HIFU 后基质层破坏的情况以及 3) 评估对 HIFU 介导的化疗治疗的反应。无创 MR 生物标志物、脉冲 HIFU 方法和有效的 KPC 小鼠模型的开发对于增进对这种致命疾病的了解至关重要，并有潜力。用于评估临床前和临床试验中有前途的疗法。