Intrabiliary MR/RF-enhanced chemotherapy of malignant biliary obstructions

描述（由申请人提供）：胰胆管恶性肿瘤伴胆道梗阻的预后通常很差，因为在就诊时不可切除，化疗和放疗反应差。胆道内支架植入术是目前治疗大多数恶性胆道梗阻的最佳选择。然而，胆道支架的短期耐久性需要反复干预和更长的住院时间，并伴随着较高的经济负担。此外，目前用于全身化疗的技术不允许递送足以在靶部位有效应答而对其他器官系统没有实质性不期望的毒性的剂量。 在本项目中，我们的目标是克服这些问题，目前可用的药物和手术治疗恶性胆总管（CBD）梗阻。基于我们之前使用新型腔内MR成像（MRI）/射频加热（RFH）原型系统的丰富经验，我们将建立一种新的介入技术。这种创新的方法包括（a）胆管内MRI引导的高剂量化疗剂局部递送到CBD壁和邻近组织中;和（B）胆管内MRI引导的、RFH增强的恶性CBD阻塞的局部化疗。为了实现这一目标，我们提出了三个里程碑：（i）优化新的胆道内MRI/RFH原型系统;（ii）临床前验证使用新技术引导和增强化疗药物递送到CBD壁和邻近组织的可行性;以及（iii）将这种新技术转化为临床实践，以治疗恶性胆道梗阻患者。 我们相信，该项目的成功可能会导致重大突破的恶性胆道疾病的管理使用MRI/射频互动介入肿瘤学技术。这项新技术的进一步扩展应该为临床转化研究的其他领域的进步铺平道路，包括热增强基因治疗，使用靶向纳米颗粒和肽的温度敏感性治疗，光动力治疗和放射治疗。最后，该项目的成功将为开发新技术治疗其他管腔系统（如泌尿道和胃肠道）的阻塞性疾病奠定基础。

DESCRIPTION (provided by applicant): The prognosis of pancreatobiliary malignancies with biliary obstructions is generally dismal because of unresectability at the time of presentation and poor response to chemotherapy and radiotherapy. Intrabiliary stenting is currently the best option for the treatment of most malignant biliary obstructions. However, the short term durability of biliary stents necessitates repeated interventions and longer hospital stays with associated high economic burden. In addition, current techniques for systemic chemotherapy do not permit delivery of doses sufficient for effective response at the target sites without substantial undesired toxicities to other organ systems. In the present project, we aim to overcome these problems with currently available medical and surgical treatments of malignant common bile duct (CBD) obstructions. Based on our previous extensive experience with a novel intraluminal MR imaging (MRI)/radiofrequency heating (RFH) prototype system, we are going to establish a new interventional technique. This innovative approach involves (a) intrabiliary MRI-guided local delivery of high-dose chemotherapeutic agents into the CBD wall and adjacent tissues; and (b) intrabiliary MRI-guided, RFH-enhanced local chemotherapy of malignant CBD obstructions. To achieve this goal, we propose three milestones: (i) optimization of the new intrabiliary MRI/RFH prototype system; (ii) preclinical validation of the feasibility of using the new technology to guide and enhance chemotherapeutic drug delivery into the CBD wall and adjacent tissues; and (iii) translation of this novel technology to clinical practice to treat the patients with malignant biliary obstructions. We are convinced that the success of this project could lead to significant breakthroughs in the management of malignant biliary diseases using MRI/RFH-interactive interventional oncologic techniques. Further expansion of this new technology should pave the road to advances in other areas of clinical translational research, including heat-enhanced gene therapy, temperature-sensitive therapies using targeted nanoparticles and peptides, photodynamic therapy, and radiation therapy. Finally, the success of this project should lay the groundwork for development of new technologies to treat obstructive diseases in other luminal systems such as the urinary tract and gastrointestinal tract.