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.

项目概要/摘要 尽管实施了肝细胞癌（HCC）早期诊断的监测计划， 目前大多数患者被诊断已处于疾病的中期或晚期阶段，而目前尚无有效的治疗方法。 治疗性干预措施。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、肝功能不良或耐药性而获益。 HCC 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 的发病率正在稳步上升。近年来天然Omega-3脂肪酸， 二十二碳六烯酸 (DHA) 已被证明具有良好的抗癌特性及其食用量 与降低 HCC 风险有关。膳食 DHA 对已形成的实体瘤的影响是 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基于低密度脂蛋白（LDL）的新型 用未酯化的 DHA（本文称为 LDL-DHA）重构的纳米颗粒。在治疗上，我们 已表明 LDL-DHA 纳米颗粒能够以不伤害的剂量选择性杀死啮齿动物 HCC 细胞 原代肝细胞。此外，在同基因大鼠 HCC 模型中，局部区域递送 LDL-DHA 纳米颗粒（通过手术暴露和肝动脉插管实现）能够诱导 使HCC肿瘤广泛坏死（>80%）并阻碍肿瘤生长（3倍）而不损伤周围 正常肝脏。这种治疗选择性与 HCC 密切相关，因为 HCC 是中期和晚期肝病的背景。 晚期 HCC 通常容易出现治疗引起的损伤。本提案的目标是评估 用于治疗 HCC 的实用图像引导微创局部 LDL-DHA 治疗。致地址 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功效 在透视引导下将 LDL 纳米粒子局部递送至 HCC； 2) 研究有效性 透视引导下局部 LDL-DHA 治疗诱导 HCC 肿瘤坏死； 3）评估角色 酰胺质子转移磁共振成像作为一种新颖的分子成像方法，可以定量 评估肿瘤对 LDL-DHA 治疗的反应。在该项目完成后，我们预计合并后的 这些目标的工作将： (i) 优化 LDL-DHA 的微创图像引导局部递送 纳米颗粒以实现最大程度的肿瘤摄取和肿瘤根除； (ii) 非侵入性地量化肿瘤 LDL-DHA 治疗后的反应并预测患者的长期结果。 LDL-DHA治疗 该策略将具有重要意义，因为它提供了一种治疗 HCC 的新方法，且不会对肝脏造成二次损伤。 肝脏周围。最终，我们努力将这项技术带给人类患者，预计 通过为患者提供安全的治疗方案，对当前不可切除的 HCC 的治疗产生重要影响 以及治疗这种侵袭性癌症的可行方法。

项目成果

Profiling Carbohydrate Metabolism in Liver and Hepatocellular Carcinoma with [13C]-Glycerate Probes.

使用 [13C]-甘油酸盐探针分析肝脏和肝细胞癌中的碳水化合物代谢。

• DOI: 10.1002/anse.202100034
• 发表时间: 2021-11
• 期刊: Analysis & sensing
• 作者: Chen, Jun;LaGue, Evan;Li, Junjie;Yang, Chendong;Hackett, Edward P.;Mendoza, Manuel;Alger, Jeffry R.;DeBerardinis, Ralph J.;Corbin, Ian R.;Billingsley, Kelvin L.;Park, Jae Mo
• 通讯作者: Park, Jae Mo