Light-Triggered Drug Release in Primed Pancreatic Tumors

描述(申请人提供)：胰腺癌(PACA)是所有主要癌症类型中预后最差的，今年将夺走3.7万美国人的生命。根据临床表现，大多数患者(80%)被诊断为不能手术的胰腺癌。由于关键血管和消化血管的接近，肿瘤切除手术很少进行。切除原发的PACA肿瘤可以防止进一步的转移，并解决原发肿瘤引起的并发症，如内分泌和外分泌功能受损和疼痛。我们提出的方法利用了一种新的能够实现近红外光触发的药物释放纳米技术以及PACA肿瘤启动。一种临床方案可能涉及到腹腔镜引导(已经在PACA中使用)，将近红外发射光纤发射到原发肿瘤以触发药物释放。这种方法克服了光穿透带来的挑战，并将避免对关键胰腺血管的损伤。虽然PACA细胞对常规化疗很敏感，但治疗这种疾病的困难源于肿瘤血管生成不良。我们的初步数据表明，抑制声波Hedgehog通路可以促进血管形成和脂质体阿霉素的输送，导致低血管小鼠PACA模型中肿瘤进展的延迟。在这里，我们的目标是通过将肿瘤启动与阿霉素负载的光敏卟啉(LS-porPhyome)相结合来实现肿瘤的完全根除。多孔体是由一层卟啉双层形成的脂质体状颗粒，可以产生独特的纳米级光子性质。我们已经开发出了LS-孔体，它可以稳定地将被包裹的药物保留在血清中，但在近红外线照射下可以完全迅速地释放它们的内容物。这种释放机制是基于一种新的纳米尺度的加热现象，该机制涉及到掺杂具有高转变温度脂类的卟啉双层膜。本项目有三个具体目标：具体目标1：优化血清稳定、生物相容的载药LS-卟啉小体：我们将优化LS-卟啉小体的化学和处方，以创建一种新型的强健、可控释的纳米系统，并检测LS-卟啉小体在体内的稳定性和毒性。具体目标2：为LS-门静脉小体建立一种最佳的PACA肿瘤沉积策略：我们使用光声断层扫描来非侵入性地确定超声刺猬注射条件如何促进肿瘤血管的形成和LS-门静脉小体向肿瘤微血管和实质的输送。具体目标3：使用LS-孔体测试阿霉素在PACA肿瘤中的释放效果：LS-孔体在循环水平较高时(注射后立即)能够释放药物，但也足够稳定，也可以在以后的渗出后释放。我们将在分布和生存研究中比较这些方法，并确认胰腺功能没有受到负面影响。

DESCRIPTION (provided by applicant): Pancreatic cancer (PaCA) has the poorest prognosis amongst all major cancer types and will claim the lives of 37,000 Americans this year. Upon clinical presentation, most patients (80%) are diagnosed with inoperable pancreatic cancer. Tumor removal is rarely performed due to the proximity of critical blood and digestive vessels. Resection of primary PaCA tumors can prevent further metastasis and address primary tumor-induced complications such as impaired endocrine and exocrine function and pain. Our proposed approach makes use of a new enabling near infrared light- triggered drug release nanotechnology along with PaCA tumor priming. A clinical scenario might involve laparoscopy guidance (already used in PaCA) of a near infrared emitting optical fiber into the primary tumor to trigger drug release. This approach overcomes challenges with light penetration and will spare damage to critical pancreatic vessels. Although PaCA cells are sensitive to conventional chemotherapies, difficulty in treating the disease stems from poor tumor vascularization. Our preliminary data demonstrate that inhibition of the sonic hedgehog pathway can enhance vascularization and delivery of liposomal doxorubicin, leading to a delay in tumor progression in a hypovascular mouse PaCA model. Here, we aim to achieve complete tumor eradication by combining tumor priming with doxorubicin-loaded, light-sensitive porphysome (LS-porphysomes). Porphysomes are liposome-like particles formed from a porphyrin bilayer that gives rise to unique nanoscale photonic properties. We have developed LS-porphysomes that stably retain entrapped drug in serum; yet completely rapidly release their contents upon near infrared light exposure. The release mechanism, which involves doping porphyrin bilayers with high transition temperature lipids, is based on a novel nanoscale heating phenomenon unique to porphysomes. This project has three specific aims: Specific Aim 1: Optimize serum-stable, biocompatible drug-loaded, LS-porphysomes: We will optimize LS-porphysome chemistry and formulation to create a new type of robust, controlled release nanosystem and examine LS-porphysome in vivo stability and toxicity. Specific Aim 2: Develop an optimal PaCA tumor deposition strategy for LS-porphysomes: We use photoacoustic tomography to non-invasively determine how sonic hedgehog priming conditions enhance tumor vascularization and LS-porphysome delivery to both tumor microvessels and parenchyma. Specific Aim 3: Test the efficacy of doxorubicin release in PaCA tumors using LS-porphysomes: LS-porphysomes enable drug release while circulating levels are high (immediately following injection) but are also stable enough to also enable later, post-extravasation release. We will compare these approaches in distribution and survival studies and confirm that pancreatic function is not negatively affected.