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

项目摘要/摘要 尽管实施了肝细胞癌(HCC)早期诊断监测计划， 大多数患者目前被诊断为疾病的中晚期，目前还没有 治疗性干预。这些患者要么接受经动脉化疗栓塞术，要么接受分子治疗， 索拉非尼。虽然这些疗法已被证明延长了一些患者的生存时间，但许多人却没有得到任何帮助。 因治疗毒性、肝功能不佳或耐药而受益。肝细胞癌患者的长期生存 仍然很穷，5年存活率只有12%。迫切需要抗肝癌的新疗法，因为 在美国，肝癌的发病率正在稳步上升。近年来天然的omega-3脂肪酸， 二十二碳六烯酸(DHA)已被证明具有良好的抗癌性能及其消费 与降低肝细胞癌的风险有关。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 与未酯化的DHA(这里称为低密度脂蛋白-DHA)重组的纳米颗粒。从治疗上讲，我们 已经证明，低密度脂蛋白-DHA纳米颗粒能够选择性地杀死啮齿动物肝癌细胞，剂量不会造成伤害 原代肝细胞。此外，在同基因大鼠肝细胞癌模型中，低密度脂蛋白-DHA的局部递送 纳米颗粒(通过外科手术暴露和肝动脉插管获得)能够诱导 肝细胞癌肿瘤广泛坏死(&gt；80%)，阻碍肿瘤生长(3倍)而不损伤周围 肝脏正常。这种治疗选择性与肝细胞癌密切相关，作为中晚期肝病的背景。 晚期肝细胞癌往往容易发生治疗后的损伤。本提案的目标是评价 实用影像引导下局部微创低密度脂蛋白-DHA治疗肝细胞癌致信地址 为此，我们将考察以下具体目标：1)优化基于导管的肿瘤靶向效率 透视引导下低密度脂蛋白纳米粒局部区域给药；2)研究 透视引导下局部低密度脂蛋白-DHA治疗在诱导肝癌肿瘤坏死中的作用 酰胺质子转移磁共振成像作为一种新的定量检测分子成像方法 评估肿瘤对低密度脂蛋白-DHA治疗的反应。在这个项目完成后，我们预计合并后的 这些目标的工作将：(I)优化低密度脂蛋白-DHA的微创图像引导局部区域递送 纳米粒子，以实现最大限度的肿瘤摄取和肿瘤根除；以及(Ii)非侵入性量化肿瘤 低密度脂蛋白-DHA治疗后的反应和预测患者的长期结果。低密度脂蛋白-DHA治疗 策略将具有重要意义，因为它提供了一种新的治疗肝癌的方法，而不会对 周围的肝脏。归根结底，我们将努力将这项技术带给人类患者，这是我们所期待的 为不能切除的肝细胞癌患者提供安全的 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.