Ultrasound-enhanced drug penetration for treatment of pancreatic cancer

项目总结 胰腺癌是美国癌症死亡的第四大原因，有效的很少 治疗选择。可切除肿瘤的中位存活率只有2年，而且系统性 吉西他滨化疗只能提供适度的生存益处。胰腺肿瘤的主要特征 化疗困难的原因是广泛的间质间质结缔组织增生症，它会减少血液。 灌注增加了肿瘤内的压力，阻碍了化疗的进行。破坏间质 屏障可增加肿瘤的灌注量和通透性，增强化疗的穿透性。在……里面 在我们最初的资助期间，我们成功地演示了使用脉冲高电波对基质进行机械破坏 强度聚焦超声(PHIFU)诱导的空化增强阿霉素在UP中的渗透 到4.5倍。这些结果是在体内基因工程小鼠模型(KPC小鼠)中获得的 胰腺导管腺癌，使用优化的超声引导PHIFU小动物治疗系统。 KPC模型与异种移植或皮下模型不同，它紧密地概括了临床上的基因突变 人类胰腺癌的症状和组织病理学。这些结果很容易翻译给患者 治疗。在这一新的应用中，我们建议评估KPC小鼠的肿瘤反应和生存 用PHIFU治疗，并全身应用吉西他滨。然后我们将开发一种新的超声波引导 PHIFU临床系统，结合气泡多普勒成像算法，实现对PHIFU的监测 心理治疗。该系统将按照FDA的指导方针进行设计、制造和表征。主要范式 与小动物研究不同的是，超声换能器的设计产生的聚焦较少， 影响较大组织区域的较低频率(亚兆赫)HIFU光束，可能具有不同的物理 与以前使用的高频、高聚焦换能器相比，空化成核的机理。 我们假设这一变化将：1)缩短治疗时间；2)提供更深的渗透深度；3) 允许使用较低的PHIFU压力幅度，从而提高安全性。的另一项重大创新 这项建议是我们团队发现的一种独特的空化测绘技术的进一步发展 在初始授权期和称为气泡多普勒的情况下，实现了基于超声的PHIFU监测 实时治疗。我们将完成PHIFU治疗的可行性和安全性的临床前评估 在一系列急性和短期存活研究中使用气泡多普勒监测猪胰腺。在……里面 同时，还将设计一项使用这种治疗设备的临床试验。将汇编所有相关报告以适用于 向美国FDA申请研究设备豁免(IDE)，以进行胰腺癌患者的临床试验 癌症。

PROJECT SUMMARY Pancreas cancer is the fourth leading cause of cancer mortality in the United States, with very few effective therapeutic options. The median survival rate for resectable tumors is only 2 years, and systemic chemotherapy with gemcitabine only offers a modest survival benefit. The main characteristic of pancreas tumors that makes chemotherapy treatment difficult is the extensive stromal desmoplasia, which decreases blood perfusion, increases the intratumoral pressure and impedes the delivery of chemotherapy. Disrupting the stromal barrier would both increase perfusion and permeabilize the tumor, enhancing penetration of chemotherapy. In our initial grant period we successfully demonstrated that mechanical disruption of the stroma using pulsed high intensity focused ultrasound (pHIFU)-induced cavitation resulted in enhanced penetration of doxorubicin by up to 4.5-fold. These results were obtained in an in vivo genetically engineered mouse model (KPC mouse) of pancreatic ductal adenocarcinoma, using an optimized ultrasound-guided pHIFU small animal treatment system. The KPC model, unlike xenograft or subcutaneous models, closely recapitulates the genetic mutations, clinical symptoms and histopathology found in human pancreatic cancer. These results are readily translatable to patient treatment. In this renewal application we propose to evaluate the tumor response and survival of KPC mice treated with pHIFU and systemic administration of gemcitabine. We will then develop a new ultrasound-guided pHIFU clinical system that incorporates Bubble Doppler imaging algorithms to enable monitoring of pHIFU therapy. The system will be designed, fabricated and characterized following FDA guidelines. The main paradigm shift compared to the small animal studies is the design of ultrasound transducers that produce less focused, lower frequency (sub-MHz) HIFU beams that affect larger tissue areas and may have a different physical mechanism of cavitation nucleation compared to high- frequency, highly focused transducers used previously. We hypothesize that this change will: 1) shorten treatment duration; 2) provide deeper penetration depth; 3) allow the use of lower pHIFU pressure amplitudes and therefore improve safety. The other major innovation of this proposal is the further development of a unique cavitation mapping technique, discovered by our group during the initial grant period and termed Bubble Doppler, which enables ultrasound-based monitoring of pHIFU therapy in real-time. We will complete preclinical evaluation of the feasibility and safety of pHIFU treatments using Bubble Doppler monitoring in porcine pancreas in a series of acute and short term survival studies. In parallel, a clinical trial using this therapy device will be designed. All relevant reports will be compiled to apply for an investigational device exemption (IDE) to US FDA to conduct a clinical trial in patients with pancreatic cancer.