Image Guided Delivery and Evaluation of Low? Density Lipoprotein-Docosahexaenoic acid Nanoparticles for the Management of Hepatocellular Carcinoma

项目总结/摘要 尽管实施了肝细胞癌（HCC）早期诊断的监测计划， 大多数患者目前被诊断为处于疾病的中期或晚期， 治疗性干预。这些患者接受经动脉化疗栓塞或分子治疗， 索拉非尼。虽然这些疗法已被证明可以延长一些患者的生存期，但许多患者未能接受任何治疗。 由于治疗毒性、肝功能差或耐药性而获益。肝癌患者的长期生存 仍然很差，5年生存率<12%。迫切需要针对HCC的新疗法， 在美国，HCC的发病率稳步上升。近年来，天然omega-3脂肪酸， 二十二碳六烯酸（DHA）已被证明具有有希望的抗癌特性， 与降低HCC风险有关。膳食DHA对已建立的实体瘤的影响是 名义上的为了解决这个问题，我们的实验室最近设计了一种新的基于低密度脂蛋白（LDL）的 在一些实施方案中，本发明涉及用未酯化的DHA（本文中称为LDL-DHA）重构的纳米颗粒。治疗上，我们 已经表明，LDL-DHA纳米颗粒能够选择性地杀死啮齿动物HCC细胞，剂量不损害 原代肝细胞此外，在HCC的同系大鼠模型中，LDL-DHA的局部递送 纳米颗粒（通过手术暴露和肝动脉导管插入术实现）能够诱导 HCC肿瘤广泛坏死（>80%），并阻止肿瘤生长（3倍），而不损伤周围组织 正常肝脏这种治疗选择性与HCC密切相关，因为HCC是中度和中度肝病的背景。 晚期HCC通常易于发生治疗诱导的损伤。本提案的目的是评价 图像引导的微创局部LDL-DHA治疗HCC的实用性。解决 为了实现这一目标，我们将研究以下具体目标：1）优化基于导管的肿瘤靶向疗效 在荧光透视引导下将LDL纳米颗粒局部递送至HCC; 2）研究 荧光透视引导的局部LDL-DHA治疗在诱导HCC肿瘤坏死中的作用; 3）评估 酰胺质子转移磁共振成像作为一种新的分子成像方法， 评估肿瘤对LDL-DHA治疗的反应。在这个项目完成后，我们预计， 这些目标的工作将：（i）优化LDL-DHA的微创图像引导局部区域递送 纳米颗粒以实现最大肿瘤摄取和肿瘤根除;和（ii）非侵入性地定量肿瘤 反应和预测LDL-DHA治疗后的长期患者结局。LDL-DHA治疗 该策略将是重要的，因为它提供了一种治疗HCC而不对肝细胞造成继发性损伤的新方法。 肝脏周围。最终，我们将奋进将这项技术带给人类患者， 通过为患者提供一种安全的治疗方法， 治疗这种侵袭性癌症的可行方法。

PROJECT SUMMARY/ ABSTRACT Despite the implementation of surveillance programs for early diagnosis of hepatocelllular carcinoma (HCC), most patients are currently diagnosed at intermediate or advanced stage of the disease for which there are no curative interventions. These patients either receive transarterial chemoembolization or the molecular therapy, sorafenib. While these therapies have proven to prolong survival for some patients, many fail to receive any benefit due to treatment toxicities, poor liver function or drug resistance. The long term survival for HCC patients remains poor, with a 5-year survival rates <12%. Novel therapies against HCC are urgently needed as the incidence of HCC is steadily increasing in the United States. In recent years the natural omega-3 fatty acid, docosahexaenoic acid (DHA) has been shown to possess promising anticancer properties and its consumption has been implicated in reducing the risk of HCC. The effects of dietary DHA on established solid tumors is nominal. To address this issue, our lab has recently engineered a novel low-density lipoprotein (LDL) based nanoparticle that is reconstituted with unesterified DHA (herein referred to as LDL-DHA). Therapeutically, we have shown that the LDL-DHA nanoparticle is able to selectively kill rodent HCC cells at doses that do not harm primary hepatocytes. Furthermore, in a syngeneic rat model of HCC, locoregional delivery of LDL-DHA nanoparticles (achieved via surgical exposure and catheterization of the hepatic artery) is able to induce extensive necrosis (>80%) of HCC tumors and impede the tumor growth (3 fold) without injury to surrounding normal liver. This therapeutic selectivity is germane to HCC, as the background liver disease in intermediate and advanced HCC is often prone to treatment induced injury. The goal of the present proposal is to evaluate the utility image-guided minimally invasive locoregional LDL-DHA therapy for the management of HCC. To address this goal we will examine the following specific aims: 1) Optimize tumor targeting efficacy for catheter-based locoregional delivery of LDL nanoparticles to HCC under fluoroscopy guidance; 2) Investigate the efficacy of fluoroscopy-guided locoregional LDL-DHA treatment in inducing tumor necrosis in HCC; 3) Evaluate the role of amide proton transfer magnetic resonance imaging as a novel molecular imaging approach to quantitatively assess tumor response to LDL-DHA therapy. At the completion of this project, we expect that the combined work of these Aims will: (i) optimize the minimal invasive image-guided locoregional delivery of LDL-DHA nanoparticles to achieve maximum tumor uptake and tumor eradication; and (ii) to noninvasively quantify tumor response and forecast long term patient outcome following LDL-DHA treatment. The LDL-DHA treatment strategy will be significant because it offers a new method of treating HCC without secondary injury to the surrounding liver. Ultimately it is our endeavor to bring this technology to human patients, where it is anticipated to have an important impact on the current management of unresectable HCC by providing patients with a safe and viable approach to treating this aggressive cancer.