Quantitative MRI-Guided Nanoembolization for Liver Cancer

描述（由申请人提供）：该提案的广泛长期目标是改善不可切除的肝细胞癌（HCC）患者的预后。对于这些患者，经动脉化疗栓塞术（TACE）是最广泛接受的局部治疗，因为它在肝功能保留的患者中证明了生存获益。然而，对晚期疾病或肝功能差的患者的益处仍然有限。TACE的最佳剂量也仍然未知。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递送治疗的剂量学。对TACE的拟议改进在称为纳米栓塞（NE）的新程序中采用治疗性纳米颗粒（NP）。NE是将治疗性NP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，可以用MRI成像，封闭在一个金（Au）壳内，该壳连接到DOX作为治疗剂。该提案将测试MRI监测系统在HCC的VX 2兔模型中递送Au-SPIO的效用。该系统将能够在药物递送之前预测剂量测定，在药物递送期间实时监测，以及在递送之后反馈以验证已经达到期望的肿瘤内药物浓度。具体目标1将开发一个模型，预测输送前Au-SPIO的组织浓度，并提供剂量测定的成像参数。假设定量MRI参数可用于预测递送前注射的Au-SPIO的生物分布，并提供NE的剂量测定。健康相关性将是基于局部肿瘤灌注为患者提供个性化的肝肿瘤治疗。Specific Aim 2将开发一种实时投影MRI荧光透视技术，可在NE期间真实的实时监测Au-SPIO输送。假设可以用动态投影MRI实时监测NE期间的Au-SPIO递送。健康相关性是开发一种实时成像方法，确保注射的NP到达其预期的肿瘤靶点。Specific Aim 3将使用MRI量化NE后Au-SPIO的组织浓度。假设MRI R2* 映射准确地定量NE后Au-SPIO的组织浓度。健康相关性是在药物输送期间提供定量的术中反馈，目标是最大化肿瘤内药物浓度，同时最小化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.