Interstitial Chemophototherapy with Light-Activated Nanoparticulate Doxorubicin

摘要 我们的目标是推动间质化学-光疗(i-CPT)作为一种有效的抗肿瘤药物的商业化 局部晚期肿瘤的治疗选择。此应用程序将重点提供以下方面的概念证明 I-CPT在治疗局部晚期肝细胞癌中的作用患有疾病的患者 无法手术的局部晚期肝细胞癌预后较差，5年存活率仅为31%。这个 化疗和光疗的组合(CPT)包括给予单一的药物，如 一种新型的长循环阿霉素卟啉磷脂脂质体制剂。少校 PhotoDox的优点是：1)它是热不依赖的；2)在665 nm的光下可以快速释放药物 给药；3)长循环(~22小时半衰期)，血清稳定，其他如Doxil®；以及4)具有 已被证明在多种肿瘤模型中是有效的。美国国家癌症研究所对PhotoDox进行了检测 研究所纳米技术表征实验室，并被发现在体外毒性和在 体内药代动力学研究。 POP生物技术公司拥有PhotoDox的独家许可证。沙菲尔斯坦博士在罗斯威尔公园的团队 癌症研究所(RPCI)开发并验证了一种新系统，以提供特定的光剂量学在 巨大的肿瘤。在这个STTR应用程序中，POP BioTechnologies将把PhotoDox和Shafistein博士的 优化和指导I-CPT治疗局部晚期肝肿瘤的治疗计划方法 通过实现以下目标： 目的1：确定在HepG2皮下肿瘤中进行有效的I-CPT的光照强度和光通量。 PI验证的有限元方法将用于指导光剂量发现研究，以定义 PhotoDox I-CPT瘤内光照度和光通量的安全有效。我们将解决关键问题 问：使用PhotoDox的I-CPT的最佳肿瘤内光照度和光通量是多少？ 目的2：验证I-CPT在大鼠原位肝癌模型中的疗效。 我们将使用有限元将在小鼠肿瘤中确定的最佳间质光传递(目标1)转换为 较大的大鼠原位肝癌。我们将解决关键问题：我们能否提供有效的I-CPT 用PhotoDox制作原位肝肿瘤模型？ 此翻译第一阶段项目将提供必要的数据，以指导我们的团队将进行测试的第二阶段研究 和研究I-CPT与PhotoDox在自发性土拨鼠肝癌中的作用(可在RPCI处获得)，这与 在人类肝癌患者的背景下理解I-CPT治疗。如果成功，I-CPT与 PhotoDox将使大多数新发的肝癌患者受益，他们患有无法手术和有问题的 原发肿瘤。

SUMMARY Our goal is to advance the commercialization of interstitial chemo-phototherapy (I-CPT) as a potent antitumor therapeutic option for locally advanced tumors. This application will focus on providing a proof of concept for the benefit of I-CPT in the treatment locally advanced hepatocellular carcinoma (HCC). Patients with inoperable locally advanced HCC have a poor prognosis with a 5-year survival rate of just 31%. The combination of chemotherapy and phototherapy (CPT) involves administering a single agent such as PhotoDox, a novel long-circulating, doxorubicin in porphyrin-phospholipid liposome formulation. The major advantages of PhotoDox are: 1) it is thermally independent; 2) has rapid drug release upon 665-nm light administration; 3) is long-circulating (~22 hour half-life), serum stable, and otherwise like DOXIL®; and 4) has been demonstrated to be effective in multiple tumor models. PhotoDox was tested by the National Cancer Institute Nanotechnology Characterization Lab, and was found to be similar to DOXIL® in in vitro toxicity and in vivo pharmacokinetic studies. POP Biotechnologies, Inc. has an exclusive license for PhotoDox. Dr. Shafirstein's team at Roswell Park Cancer Institute (RPCI) has developed and validated a novel system to provide specific light dosimetry in large tumors. In this STTR application, POP Biotechnologies will combine PhotoDox with Dr. Shafirstein’s treatment planning approach to optimize and guide I-CPT for effective therapy of locally advanced liver tumors by accomplishing the following aims: Aim 1: To define light irradiance and fluence for effective I-CPT in subcutaneous HepG2 tumors. The PI validated finite element method approach will be used to guide a light dose finding study to define a safe and effective intratumoral light irradiance and fluence for I-CPT with PhotoDox. We will address the key question: What is the optimal intratumoral light irradiance and fluence for I-CPT with PhotoDox? Aim 2: Demonstrate the effectiveness of I-CPT in an orthotopic liver cancer rat model. We will use the FEM to translate the optimal interstitial light delivery determined in murine tumors (Aim 1) to larger orthotopic liver cancer in rats. We will address the key question: Can we deliver an effective I-CPT with PhotoDox to an orthotopic model of liver tumor? This translational Phase I project will provide required data to guide a Phase II study where our teams will test and study I-CPT with PhotoDox in a spontaneous woodchuck HCC (available at RPCI) that is relevant to understanding I-CPT treatment in the context of human liver cancer patients. If successful, I-CPT with PhotoDox stands to benefit the majority of new liver cancer patients, who have inoperable and problematic primary tumors.