Light-Triggered Drug Release in Primed Pancreatic Tumors

胰腺肿瘤中的光触发药物释放

• 批准号: 9130825
• 负责人: Jonathan F Lovell
• 金额: $ 34.15万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130825
• 关键词: Address; Affect; American; Biocompatible; Biodistribution; Biological Availability; Blood; Blood Vessels; Blood flow; Cancer Model; Chemistry; Clinical; Computer Simulation; Data; Deposition; Diagnosis; Disease; Dose; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Kinetics; Drug resistance; Duct (organ) structure; Endocrine; Ensure; Excision; Exhibits; Exocrine pancreas; Exposure to; Extinction (Psychology); Extravasation; Fiber Optics; Formulation; Goals; Health; Heating; Injection of therapeutic agent; Intravenous; Laparoscopy; Lasers; Light; Lighting; Lipids; Liposomal Doxorubicin; Liposomes; Malignant neoplasm of pancreas; Measures; Modeling; Molecular; Monitor; Motivation; Mus; Nanotechnology; Nausea; Neoplasm Metastasis; Outcome; Pain; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Penetration; Perfusion; Pharmaceutical Preparations; Phospholipids; Physiological; Pilot Projects; Porphyrins; Primary Neoplasm; Property; Resected; Resistance; Resolution; Risk; SHH gene; Serum; Sonic Hedgehog Pathway; Staging; Structure; Surgical incisions; Survival Rate; Symptoms; Therapeutic; Time; Toxic effect; Transition Temperature; Vascularization; base; cancer diagnosis; cancer type; chemotherapy; controlled release; conventional therapy; efficacy testing; in vivo; inhibitor/antagonist; irradiation; minimally invasive; monomer; nanocarrier; nanomaterials; nanoparticle; nanoscale; nanosystems; neovascularization; novel; optical fiber; outcome forecast; pancreatic cancer cells; pancreatic neoplasm; particle; photonics; porphyrin a; prevent; screening; simulation; stem; subcutaneous; tomography; tumor; tumor eradication; tumor microenvironment; tumor progression

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.

描述（由申请人提供）：胰腺癌 (PaCA) 在所有主要癌症类型中预后最差，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%) 被诊断患有无法手术的胰腺癌。由于靠近关键的血管和消化管，很少进行肿瘤切除术。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引起的并发症，例如内分泌和外分泌功能受损以及疼痛。我们提出的方法利用了一种新的近红外光触发药物释放纳米技术以及 PaCA 肿瘤启动技术。临床场景可能涉及腹腔镜引导（已在 PaCA 中使用）将近红外发射光纤引导至原发肿瘤以触发药物释放。这种方法克服了光穿透的挑战，并且不会损坏关键的胰腺血管。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 sonic hedgehog 通路可以增强血管化和脂质体阿霉素的递送，从而延迟缺血管小鼠 PaCA 模型中的肿瘤进展。在这里，我们的目标是通过将肿瘤引发与负载阿霉素的光敏卟啉体（LS-卟啉体）相结合来实现完全根除肿瘤。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，可以将包埋的药物稳定地保留在血清中；但在近红外光照射下会完全快速释放其内容物。该释放机制涉及用高转变温度脂质掺杂卟啉双层，基于卟啉体独特的新型纳米级加热现象。该项目有三个具体目标： 具体目标 1：优化血清稳定、生物相容性载药 LS-卟啉体：我们将优化 LS-卟啉体化学和配方，以创建新型稳健的控释纳米系统，并检查 LS-卟啉体体内稳定性和毒性。具体目标 2：开发 LS-卟啉体的最佳 PaCA 肿瘤沉积策略：我们使用光声断层扫描非侵入性地确定声波刺猬启动条件如何增强肿瘤血管化和 LS-卟啉体向肿瘤微血管和实质的递送。具体目标 3：使用 LS-卟啉体测试多柔比星在 PaCA 肿瘤中释放的功效：LS-卟啉体能够在循环水平较高时（注射后立即）释放药物，但也足够稳定，可以在稍后的外渗后释放。我们将在分布和生存研究中比较这些方法，并确认胰腺功能不会受到负面影响。