Intrabiliary MR/RF-enhanced chemotherapy of malignant biliary obstructions

描述(申请人提供)：胰胆系恶性肿瘤合并胆道梗阻的预后一般很差，因为在发病时无法切除，对化疗和放射治疗的反应也很差。胆道内支架置入术是目前治疗大多数恶性胆道梗阻的最佳选择。然而，胆道支架的短期耐用性需要反复干预和较长的住院时间，并伴随着较高的经济负担。此外，目前的全身化疗技术不允许在不对其他器官系统造成严重不良毒性的情况下，在靶部位提供足够有效的剂量。 在本项目中，我们的目标是通过目前可用的治疗恶性胆总管(CBD)梗阻的内科和外科治疗来克服这些问题。基于我们先前在新的腔内磁共振成像(MRI)/射频加热(RFH)原型系统方面的丰富经验，我们将建立一种新的介入技术。这一创新方法包括：(A)在胆道内核磁共振引导下，将大剂量化疗药物局部输送到胆总管内壁和邻近组织；(B)在胆道内核磁共振引导下，对胆管恶性梗阻进行射频增强的局部化疗。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进入胆总管管壁和邻近组织的可行性；以及(Iii)将这项新技术转化为临床实践，用于治疗恶性胆道梗阻患者。 我们相信，该项目的成功将在使用MRI/RFH互动介入肿瘤学技术治疗恶性胆道疾病方面取得重大突破。这项新技术的进一步扩展将为临床转化研究的其他领域的进展铺平道路，包括热增强基因疗法、使用靶向纳米颗粒和多肽的温度敏感疗法、光动力疗法和放射疗法。最后，该项目的成功将为开发治疗其他腔系统梗阻性疾病的新技术奠定基础，如尿路和胃肠道。

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.