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: 9125788
• 负责人: Donghoon Lee
• 金额: $ 50.27万
• 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/9125788
• 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; Health; 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; 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，5年生存率约为20%，但超过80%的患者存在晚期不可切除的疾病。所有类型胰腺癌的5年生存率均低于5%。胰腺肿瘤治疗一直是无效的，部分原因是胰腺肿瘤具有致密的基质，抑制化疗药物渗透到肿瘤中。高强度聚焦超声（HIFU）可用于诱导靶向热疗，导致灌注增加，从而可能增强血管缺陷胰腺肿瘤的靶向药物递送（TDD）。此外，脉冲HIFU具有机械破坏间质的潜力，导致胰腺肿瘤中致密间质的渗透性增加。HIFU增强TDD的一个主要挑战是在HIFU应用后缺乏无创评估治疗效果。磁共振成像（MRI）和磁共振波谱（MRS）已被广泛用作临床肿瘤诊断和治疗随访的关键非侵入性方法，因为与其他成像方式相比，它们具有良好的空间分辨率。然而，对于胰腺肿瘤，常规MRI已被用于定性检测病理区域，用于诊断和治疗随访，分辨率有限，并且无法使用小鼠模型进行临床前研究的定量。因此，需要更有效的具有高分辨率的磁共振（MR）生物标志物来监测荷瘤小鼠中用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区域中的TDD和胰腺肿瘤细胞死亡，并且定量MR将能够评估治疗2）脉冲HIFU将破坏胰腺肿瘤中的基质层，并且MRI/MRS将评估基质层破坏的过程。本研究的总体目标是1）为与人类胰腺癌非常相似的胰腺肿瘤小鼠模型（KPC）产生有效的HIFU诱导的高温，用于靶向化疗药物递送，2）准确监测轻度高温和对胰腺肿瘤治疗的反应基于HIFU增强的TDD，使用无创和定量MRI和高分辨率的MRS方法。为了实现研究目标，我们提出了三个具体目标：1）用先进的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，3）评估对HIFU介导的化疗治疗的反应。非侵入性MR生物标志物、脉冲HIFU方法和有效KPC小鼠模型的开发对于促进对这种致命疾病的理解至关重要，并有可能用于评估临床前和临床试验中有前途的治疗方法。