Quantitative MRI-Guided Nanoembolization for Liver Cancer

描述(由申请人提供)：这项建议的广泛、长期目标是改善不能切除的肝细胞癌(HCC)患者的预后。对于这些患者，经动脉化疗栓塞术(TACE)是被最广泛接受的局部治疗，因为它被证明对肝功能保留的患者有生存好处。然而，对晚期疾病或肝功能不佳的患者的益处仍然有限。TACE的最佳剂量也尚不清楚。为了满足扩大患者资格和优化TACE剂量方案的需求，研究人员建议：a)通过使用纳米颗粒(NP)作为阿霉素(DOX)的药物输送载体来开发下一代TACE，以及b)设计一种新的磁共振成像(MRI)系统来预测和监测这种局部给予疗法的剂量学。对TACE的拟议改进在一种名为纳米栓塞术(NE)的新程序中使用了治疗性纳米颗粒(NP)。NE是将治疗性NPs与栓塞剂一起局部输送到肿瘤血液供应中，以增加肿瘤内药物摄取。研究人员的NP平台采用了一个中央超顺磁性氧化物(SPIO)核心，该核心可以用磁共振成像，封闭在作为治疗剂附着在DOX上的金(Au)壳内。该提案将测试MRI监测系统在VX2兔肝细胞癌模型中输送Au-SPIO的实用性。该系统将能够在给药前预测剂量学，在给药期间进行实时监测，并在给药后进行反馈，以验证是否已达到所需的肿瘤内药物浓度。特定目标1将开发一个模型，在交付之前预测Au-SPIO的组织浓度，并为剂量学提供成像参数。推测定量MRI参数可用于预测分娩前注射的Au-SPIO的生物分布，并为NE提供剂量学依据。与健康相关的将是基于局部肿瘤灌注为患者提供个性化的肝肿瘤治疗。特定目标2将开发一种实时投影磁共振透视技术，可以在去甲肾上腺素期间实时监测Au-SPIO的输送。通过动态投射MRI可以实时监测NE时Au-SPIO的投放情况。与健康相关的是开发一种实时成像方法，确保注射的NPs达到预期的肿瘤目标。特殊目标3将使用磁共振成像来量化去甲肾上腺素后组织中Au-SPIO的浓度。推测MRI R2*图可以准确地定量去甲肾上腺素后组织中Au-SPIO的浓度。与健康相关的是在给药过程中提供量化的程序内反馈，目标是最大限度地提高肿瘤内的药物浓度，同时将对邻近肝组织的毒性降至最低。 公共卫生相关性：为了改善肝癌的治疗，这项提议设计了一种新的系统，用于磁共振成像(MRI)引导的治疗性纳米颗粒的输送。在动物实验中，我们将证明这种方法可以用来量化这种拟议疗法的剂量、输送和摄取。这一新的基于MRI的药物剂量学系统未来可能会被移植到接受各种实体器官肿瘤的局部治疗的患者身上。

DESCRIPTION (provided by applicant): The broad, long-term objective of this proposal is to improve the prognosis of patients with unresectable hepatocellular carcinoma (HCC). For these patients, transarterial chemoembolization (TACE) is the most widely accepted local treatment because of its proven survival benefit in patients with preserved liver function. However, benefit to patients with advanced disease or poor liver function is still limited. The optimal dose for TACE also remains unknown. To address the need to expand patient eligibility and optimize dosing protocols for TACE, the investigators propose: a) developing the next generation of TACE by using nanoparticles (NP) as drug delivery vehicles for doxorubicin (DOX) and b) devising a new magnetic resonance imaging (MRI) system to predict and monitor dosimetry for this locally delivered therapy. The proposed improvement to TACE employs therapeutic nanoparticles (NP) in a new procedure termed nanoembolization (NE). NE is local delivery of therapeutic NPs, together with embolic agents, into the tumor blood supply to increase intratumoral drug uptake. The investigators' NP platform employs a central superparamagnetic oxide (SPIO) core that can be imaged with MRI, enclosed within a gold (Au) shell that is attached to DOX as the therapeutic agent. The proposal will test the utility of an MRI-monitoring system for delivery of Au-SPIOs in the VX2 rabbit model of HCC. This system will enable prediction of dosimetry prior to drug delivery, real-time monitoring during drug delivery, and feedback after delivery to verify that desired intratumoral drug concentrations have been reached. Specific Aim 1 will develop a model that predicts tissue concentrations of Au-SPIOs before delivery and provides imaging parameters for dosimetry. It is hypothesized that quantitative MRI parameters can be used to predict the biodistribution of injected Au-SPIOs before delivery and to provide dosimetry for NE. The health relevance will be to personalize liver tumor therapies for patients based upon local tumor perfusion. Specific Aim 2 will develop a real-time projection MRI fluoroscopy technique that can monitor Au-SPIO delivery in real- time during NE. It is hypothesized that Au-SPIO delivery during NE can be monitored in real-time with dynamic projection MRI. The health relevance is to develop a real-time imaging method that ensures injected NPs reach their intended tumor target. Specific Aim 3 will use MRI to quantify tissue concentrations of Au-SPIOs after NE. It is hypothesized that MRI R2* mapping accurately quantifies tissue concentrations of Au-SPIOs after NE. The health relevance is to provide quantitative intra-procedural feedback during drug delivery, with the goal of maximizing intratumoral drug concentrations, while minimizing toxicity to adjacent liver tissue. PUBLIC HEALTH RELEVANCE: To improve the treatment of liver cancer, this proposal devises a new system for magnetic resonance imaging (MRI)-guided delivery of therapeutic nanoparticles. In animal studies, we will show that the method can be used to quantify dosing, delivery, and uptake of this proposed therapy. This new MRI-based drug dosimetry system may be translated in the future to patients undergoing local treatments for a variety of solid organ tumors.