Light-Triggered Drug Release in Primed Pancreatic Tumors

描述（由申请人提供）：胰腺癌（PaCA）是所有主要癌症类型中预后最差的，每年将夺去37,000名美国人的生命。根据临床表现，大多数患者（80%）被诊断为不能手术的胰腺癌。肿瘤切除很少进行，因为接近关键的血液和消化血管。切除原发性PaCA肿瘤可以防止进一步转移，解决原发性肿瘤引起的并发症，如内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以及PaCA肿瘤启动。临床场景可能包括腹腔镜引导（已经在PaCA中使用）近红外发射光纤进入原发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，但由于肿瘤血管化不良，治疗困难。我们的初步数据表明，抑制sonic hedgehog途径可以增强阿霉素脂质体的血管化和递送，从而延迟低血管小鼠PaCA模型的肿瘤进展。在这里，我们的目标是通过将肿瘤启动与负载阿霉素的光敏卟体（ls -卟体）相结合来实现完全的肿瘤根除。卟啉体是由卟啉双层形成的脂质体样颗粒，具有独特的纳米级光子特性。我们开发了ls -卟啉体，它能稳定地保留血清中的包裹药物；但在近红外光照射下完全迅速释放其内容物。该释放机制是基于卟啉体特有的一种新型纳米加热现象，涉及到用高转变温度脂质掺杂卟啉双层。本项目有三个具体目标：1 .优化血清稳定、生物相容性载药的ls -卟啉体：我们将优化ls -卟啉体的化学和配方，以创建一种新型的鲁棒、可控释放的纳米系统，并研究ls -卟啉体的体内稳定性和毒性。具体目标2：为ls -卟体开发最佳的PaCA肿瘤沉积策略：我们使用光声断层扫描非侵入性地确定超声hedgehog基因启动条件如何增强肿瘤血管化和ls -卟体向肿瘤微血管和实质的传递。特异性目的3：使用ls -卟啉体测试阿霉素在PaCA肿瘤中的释放效果：ls -卟啉体在循环水平较高（注射后立即）时使药物释放，但也足够稳定，可以在体外渗滤后释放。我们将在分布和生存研究中比较这些方法，并证实胰腺功能不会受到负面影响。

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.