Chemophototherapy with Porphyrin-phospholipid Liposomes Permeabilized by Red Light

项目摘要 胰腺癌（PaCa）在所有主要癌症类型中预后最差， 2016年超过41，000名美国人的生命。根据临床表现，大多数患者被诊断为 局部晚期疾病，没有良好的治疗选择，无论是延迟进展或缓解。 化疗通常是无效的，因为肿瘤的血管少的性质。肿瘤切除是 由于靠近主要血管，这也使热消融复杂化， 程序.我们寻求发展化学光疗法作为一种新的消融方式的动脉瘤。这 这种方法结合了光疗和化疗，使用单一的药物，基于光激活 脂质体。最近，长循环脂质体伊立替康（IRI）被批准用于治疗PaCa。我们 已经发现当掺入少量的卟啉-磷脂（即2摩尔百分比）时 在常规的隐形脂质体中，保持了稳定性和长血液循环特性。于过往 使用阿霉素的工作，循环>25小时，在啮齿动物，但脂质体迅速释放他们的 内容（在几分钟内）暴露于临床相关的红光。这导致了一个命令 肿瘤中的药物沉积量更大，导致有效的消融。我们会把这个 开发一种长循环、光活化形式的伊立替康的方法。我们还将应用最近的 开发和评估超快光触发释放版本的方法， 我们将评估IRI PoP制剂， 患者来源的异种移植物，其模拟临床疾病的羽毛，以及原位模型 是从遗传工程小鼠模型中提取的。治疗参数，例如 将评估药物剂量、光剂量和药物-光间隔。我们将开发和评估 间质光治疗和计算机辅助治疗计划的光纤放置，基于 MR扫描与光传播建模，将需要在临床应用化学光疗法 问题研究我们将描述消融测量和治疗的深度， 大鼠肿瘤间质纤维。最后，为了评估该技术的适用性， 在许多PaCa肿瘤中发现的关键血管，我们将表征药物和光剂量功能 啮齿类动物体内大静脉、绵羊离体颈动脉和脱细胞胶原中的反应 船舶.

PROJECT SUMMARY Pancreatic cancer (PaCa) has the poorest prognosis amongst all major cancer types and claimed the lives of over 41,000 Americans in 2016. Upon clinical presentation, most patients are diagnosed with locally advanced disease without good treatment options, either to delay progression or for palliation. Chemotherapy is generally ineffective due to hypovascular nature of the tumor. Tumor removal is often unfeasible due to the proximity of major blood vessels, which also complicate thermal ablative procedures. We seek to develop chemophototherapy as a novel ablative modality for PaCa. This approach combines phototherapy and chemotherapy using a single agent, based on light-activated liposomes. Recently, long-circulating liposomal irinotecan (IRI) was approved for treating PaCa. We have found that when small amounts of porphyrin-phospholipid (i.e. 2 molar percent) are incorporated into conventional stealth liposomes, stability and long blood-circulating properties are retained. In prior work using doxorubicin, circulation was >25 hours in rodents, but the liposomes rapidly release their contents (in a couple of minutes) upon exposure to clinically relevant red light. This results in an order of magnitude greater drug deposition in the tumor, leading to potent ablation. We will adapt this approach to develop a long-circulating, light-activated form of irinotecan. We will also apply recent methodology to develop and assess an ultrafast light-triggered release version, by incorporating small amounts of unsaturated lipids, together with the PoP. We will assess the IRI PoP formulations in patient derived xenografts that mimic feathers of the clinical disease, as well as in an orthotopic model derived from a genetically engineered mouse model of the disease. Treatment parameters such as the drug dose, light dose, and drug-light interval will be assessed. We will develop and assess interstitial phototreatment and computer-aided treatment planning of optical fiber placement, based on MR scans with light propagation modeling that will be required to apply chemophototherapy in clinical studies. We will characterize the depth of ablation measurements and treatment with multiple interstitial fibers in large rat tumors. Finally, in order to asses the applicability of this technique near the critical vessels found in many PaCa tumors, we will characterize drug and light dose functional responses in large veins in rodents in vivo, in sheep carotid arteries ex vivo and in acellular collagen vessels.