Chemophototherapy with Porphyrin-phospholipid Liposomes Permeabilized by Red Light

项目总结 胰腺癌(PACA)是所有主要癌症类型中预后最差的，并声称 2016年，超过4.1万名美国人的生命。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，要么延迟进展，要么缓解。 由于肿瘤的血管稀少，化疗通常无效。肿瘤切除是 由于靠近大血管，常常是不可行的，这也使热消融复杂化。 程序。我们寻求开发化学光疗法作为一种新的消融方式治疗PACA。这 一种将光疗和化疗结合在一起的方法，使用单一的试剂，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 发现当加入少量的卟啉-磷脂(即2摩尔百分比)时 与传统的隐形脂质体相比，保持了稳定性和长时间的血液循环特性。在之前 使用阿霉素，在啮齿动物体内循环25小时，但脂质体迅速释放它们 内容物(在几分钟内)暴露在临床相关的红光下。这会产生一个订单 更多的药物沉积在肿瘤中，导致有效的消融。我们将对此进行调整 开发一种长循环、光激活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，通过结合Small 不饱和脂类的数量，以及POP。我们将在#年评估IRI POP配方 患者来源的异种移植模仿临床疾病的特征，以及在原位模型中 来自这种疾病的基因工程小鼠模型。处理参数，如 将评估药物剂量、光剂量和药物-光间隔。我们将制定和评估 光纤放置的间隙光治疗和计算机辅助治疗规划，基于 MR扫描使用光传播模型，这将是将化学光疗法应用于临床所必需的 学习。我们将描述消融测量和治疗的深度 大鼠肿瘤中的间质纤维。最后，为了评估这项技术的适用性 在许多PACA肿瘤中发现的关键血管，我们将描述药物和光剂量的功能 啮齿类动物体内大静脉、体外绵羊颈动脉和脱细胞胶原的反应 船只。

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.