Quantitative MRI-Guided Nanoembolization for Liver Cancer

描述（由申请人提供）：本提案的广泛、长期目标是改善不可切除肝细胞癌（HCC）患者的预后。对于这些患者，经动脉化疗栓塞（TACE）是最广泛接受的局部治疗方法，因为它已被证明对保留肝功能的患者有生存益处。然而，对晚期疾病或肝功能不良患者的益处仍然有限。TACE的最佳剂量也是未知的。为了满足扩大患者资格和优化TACE给药方案的需求，研究人员提出：a)通过使用纳米颗粒（NP）作为阿霉素（DOX）的药物递送载体来开发下一代TACE； 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药治疗的剂量。提出的改进TACE采用治疗性纳米颗粒（NP）的新程序，称为纳米栓塞（NE）。NE是将治疗性NPs与栓塞剂一起局部递送到肿瘤血液供应中，以增加肿瘤内药物的摄取。研究人员的NP平台采用了一个中央超顺磁氧化物（SPIO）核心，可以用MRI成像，包裹在一个金（Au）壳中，作为治疗剂附着在DOX上。该提案将测试mri监测系统在VX2兔肝细胞癌模型中递送au - spio的实用性。该系统可以在给药前进行剂量预测，在给药过程中进行实时监测，并在给药后进行反馈，以验证是否达到了所需的肿瘤内药物浓度。Specific Aim 1将开发一种模型，预测分娩前au - spio的组织浓度，并为剂量学提供成像参数。假设定量MRI参数可用于预测分娩前注射的au - spio的生物分布，并为NE提供剂量测定。与健康相关的是基于局部肿瘤灌注的个体化肝肿瘤治疗。专项目标2将开发一种实时投影MRI透视技术，可以在NE期间实时监测Au-SPIO的输送。假设Au-SPIO在NE期间可以通过动态投影MRI实时监测。与健康相关的是开发一种实时成像方法，以确保注射的NPs达到预期的肿瘤目标。特异性目的3将使用MRI来量化NE后au - spio的组织浓度。假设MRI R2*作图能准确量化NE后au - spio的组织浓度。与健康相关的是在给药过程中提供定量的程序内反馈，目标是最大化肿瘤内药物浓度，同时最大限度地减少对邻近肝组织的毒性。

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.