Light-Triggered Drug Release in Primed Pancreatic Tumors

胰腺癌（PaCA）是所有主要癌症类型中预后最差的，今年将夺走37，000名美国人的生命。根据临床表现，大多数患者（80%）被诊断为不可手术的胰腺癌。由于靠近重要的血液和消化血管，很少进行肿瘤切除。切除原发性PaCA肿瘤可以防止进一步转移并解决原发性肿瘤诱导的并发症，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近红外光触发的药物释放纳米技术沿着PaCA肿瘤引发。临床情况可能涉及腹腔镜引导（已用于PaCA）近红外发射光纤进入原发性肿瘤以触发药物释放。这种方法克服了光穿透的挑战，并将避免对关键胰腺血管的损伤。尽管PaCA细胞对常规化疗敏感，但治疗该疾病的困难源于肿瘤血管化不良。我们的初步数据表明，抑制音刺猬途径可以增强血管化和脂质体阿霉素的递送，导致在低血管小鼠PaCA模型中肿瘤进展的延迟。在这里，我们的目标是实现完全根除肿瘤相结合的肿瘤引发阿霉素负载，光敏卟啉（LS-卟啉）。卟啉囊泡是由卟啉双层形成的脂质体样颗粒，其产生独特的纳米级光子性质。我们已经开发了LS-卟啉囊泡，其稳定地将包埋的药物保留在血清中;但在近红外光照射下完全快速释放其内容物。释放机制，其中涉及掺杂卟啉双层高转变温度脂质，是基于一种新的纳米尺度加热现象，独特的卟啉囊泡。本项目有三个具体目标：具体目标1：优化血清稳定的、生物相容的载药LS-卟啉体：我们将优化LS-卟啉体的化学和配方，以创建一种新型的稳健的、控释的纳米系统，并检查LS-卟啉体的体内稳定性和毒性。具体目标二：开发LS-卟啉小体的最佳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声波刺猬引发条件如何增强肿瘤血管化和LS-卟啉小体向肿瘤微血管和实质的递送。具体目标3：使用LS-卟啉囊泡测试多柔比星在PaCA肿瘤中释放的功效：LS-卟啉囊泡能够在循环水平高时（注射后立即）释放药物，但也足够稳定，还能够在外渗后释放。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.