MR-HIFU induced drug delivery for pancreatic cancer treatment

 描述(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，大约20%的5年存活率，但超过80%的患者存在晚期不能切除的疾病。所有类型的胰腺癌的总体5年生存率都不到5%。胰腺肿瘤的治疗一直无效，部分原因是胰腺肿瘤有致密的间质，抑制了化疗药物对肿瘤的渗透。高强度聚焦超声(HIFU)可用于诱导靶向热疗，从而增加灌注，潜在地增强靶向给药(TDD)到血管缺陷的胰腺肿瘤。此外，脉冲HIFU有可能机械地破坏胰腺肿瘤的间质，导致致密间质的渗透性增加。HIFU增强TDD的一个主要挑战是在HIFU应用后缺乏对治疗效果的非侵入性评估。磁共振成像(MRI)和磁共振波谱(MRS)因其良好的空间分辨率而被广泛用于临床肿瘤诊断和治疗随访的关键无创性方法。然而，对于胰腺肿瘤，常规MRI一直被用于定性检测病理区域以进行诊断和治疗随访，分辨率有限，无法使用小鼠模型进行临床前研究。因此，需要更有效、高分辨率的磁共振(MR)生物标志物来监测HIFU治疗荷瘤小鼠的治疗反应。我们假设1)HIFU诱导的热疗将增加TDD和胰腺肿瘤细胞在靶区的死亡，定量MR将使治疗评估成为可能。2)脉冲HIFU将破坏胰腺肿瘤的间质层，MRI/MRS将评估间质层破坏的过程。本研究的总体目标是：1)为与人胰腺癌相似的胰腺肿瘤小鼠模型(KPC)产生有效的HIFU诱导的热疗，用于靶向化疗药物输送；2)使用高分辨率的无创定量MRI和MRS方法，准确监测基于HIFU增强TDD的轻度热疗和胰腺肿瘤治疗的反应。为了实现这一研究目标，我们提出了三个具体的目标：1)用先进的MR方法评估KPC小鼠模型胰腺肿瘤的进展；2)评估HIFU后的灌注和间质层破坏的程度；3)评估HIFU介导的化疗的反应。无创磁共振生物标记物、脉冲HIFU方法和有效的KPC小鼠模型的发展将对促进对这种致命疾病的理解至关重要，并有可能在临床前和临床试验中用于评估有前景的治疗方法。

 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.