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

用于治疗肝细胞癌的低密度脂蛋白-二十二碳六烯酸纳米颗粒的图像引导递送和评估 - Diversity Supplement

• 批准号: 10309058
• 负责人: Ian Ronald Corbin
• 金额: $ 8.11万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-07 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10309058
• 关键词: Address; Amides; BAY 54-9085; Carcinoma; Catheterization; Catheters; Chemoembolization; Consumption; Diagnosis; Disease; Docosahexaenoic Acids; Dose; Drug resistance; Early Diagnosis; Engineering; Evaluation; Extensive Necrosis; Fluoroscopy; Funding Opportunities; Goals; Hepatic artery; Hepatocyte; Human; Incidence; Injury; Lipoproteins; Liver; Liver diseases; Liver neoplasms; Low-Density Lipoproteins; Magnetic Resonance Imaging; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Methods; Modeling; Molecular; National Institute of Biomedical Imaging and Bioengineering; Necrosis; Omega-3 Fatty Acids; Operative Surgical Procedures; Patient-Focused Outcomes; Patients; Primary carcinoma of the liver cells; Property; Protons; Rattus; Risk; Rodent; Role; Solid Neoplasm; Surveillance Program; Survival Rate; Technology; Therapeutic; Treatment-related toxicity; United States; Unresectable; Work; anti-cancer; base; cancer cell; curative treatments; dietary; image guided; image-guided drug delivery; imaging approach; liver function; minimally invasive; molecular imaging; nanoparticle; novel; novel therapeutics; reconstitution; response; treatment strategy; tumor; tumor eradication; tumor growth; uptake

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.

项目摘要/摘要 尽管实施了用于早期诊断肝细胞癌（HCC）的监视计划，但 目前，大多数患者在疾病的中期或晚期被诊断出来 治愈性干预措施。这些患者要么接受跨性化学栓塞或分子治疗， 索拉非尼。尽管这些疗法已被证明可以延长某些患者的生存，但许多疗法未能接受任何 由于治疗毒性，肝功能不良或耐药性而导致的益处。 HCC患者的长期生存 仍然很差，5年的存活率<12％。迫切需要针对HCC的新型疗法作为 在美国，HCC的发病率正在稳步增加。近年来，天然omega-3脂肪酸， 已显示二十六六烯酸（DHA）具有有希望的抗癌特性及其消耗量 与降低HCC的风险有关。饮食DHA对既定实体瘤的影响是 名义。为了解决这个问题，我们的实验室最近设计了一种基于新型的低密度脂蛋白（LDL） 用未酯化的DHA（以下称为LDL-DHA）重构的纳米颗粒。从治疗上，我们 已经表明，LDL-DHA纳米颗粒能够以不伤害的剂量选择性地杀死啮齿动物的HCC细胞 原发性肝细胞。此外，在HCC的合成大鼠模型中，LDL-DHA的局部递送 纳米颗粒（通过手术暴露和肝动脉导管实现）能够诱导 HCC肿瘤的广泛坏死（> 80％），并阻碍肿瘤的生长（3倍），而没有受伤 正常肝脏。这种治疗性选择性是对HCC的隐密性，作为中级背景肝病和 晚期HCC通常容易受到治疗损伤。本提案的目的是评估 实用图像引导的最低侵入性局部LDL-DHA疗法用于HCC的管理。解决 我们将研究以下特定目的：1）优化基于导管的肿瘤靶向功效 在荧光镜检查指导下，LDL纳米颗粒向HCC的局部区域递送； 2）研究的功效 透视镜引导的局部LDL-DHA治疗在HCC中诱导肿瘤坏死； 3）评估 酰胺质子转移磁共振成像是一种新颖的分子成像方法 评估肿瘤对LDL-DHA疗法的反应。该项目完成时，我们希望合并 这些目的的工作将：（i）优化LDL-DHA的最小侵入性图像引导的局部区域输送 纳米颗粒可达到最大的肿瘤摄取和消除肿瘤； （ii）非侵入性量化肿瘤 LDL-DHA治疗后的反应和预测长期患者结果。 LDL-DHA处理 策略将是重要的，因为它提供了一种新的方法来治疗HCC而无需对 周围的肝脏。最终，我们将这项技术带给人类患者是我们的努力， 通过为患者提供安全的情况，对当前无法切除的HCC的管理产生重要影响 以及可行的治疗这种侵略性癌症的方法。