Targeted Transcatheter Magneto-Mechanical Therapy for Hepatocellular Carcinoma

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。目前的治疗方法是姑息性的，在改善预后方面相对无效。迫切需要改进有效的治疗方法。我们最近的研究已经证明了一种新的实体肿瘤治疗方案的令人兴奋的潜力；我们提出的方法包括使用磁涡盘，在目标细胞膜的表面施加磁机械力来诱导细胞凋亡。我们提出了第一项体内研究，以验证磁机械疗法治疗肝癌的抗癌效果。磁性纳米盘将被制造并用于磁机械单元破坏的表征。我们将使用经导管输液将磁盘直接输送到目标肝脏肿瘤的血液供应中。经肝导管给药的体内靶向效率 动脉注射将通过MRI定量和组织学测量在肝细胞癌大鼠模型中进行研究。最后，我们将评估靶向经导管磁机械治疗癌症的体内治疗反应；我们将在啮齿动物模型中验证抗CD44结合磁性纳米盘诱导肝癌细胞凋亡的能力。通过一个合作项目，建立在我们在生物医学工程、放射学和癌症生物学方面的优势，我们寻求开发一种强大的新的磁力机械治疗方法来治疗肝细胞癌。我们提出的项目将解决以下具体目标：目标1：确定我们的纳米磁盘的靶向效率和成像特性任务1.1：以特定的几何比例制备各种纳米尺寸的磁旋涡磁盘(镀金铁盘)，使其在细胞膜上进行磁机械运动。任务1.2：磁盘的生物功能化和体外磁机械破坏肝癌细胞的有效性。任务1.3：描述磁共振成像(MRI)中磁性纳米盘浓度与T2/T2*弛豫速率之间的关系。目的2：验证经导管磁机治疗肝癌大鼠模型的肿瘤消退作用。任务2.1：使用体内定量MRI测量和尸检侵入性组织学测量来确定磁性纳米盘的体内靶向效率。任务2.2。目的：应用功能性磁共振成像技术和肿瘤细胞死亡的病理学分析，验证靶向经导管磁机械治疗的体内疗效。

DESCRIPTION (provided by applicant): The broad, long-term objective of this proposal is to improve the prognosis of patients with unresectable hepatocellular carcinoma (HCC). Current therapies are palliative and relatively ineffective for improving prognosis. There exists a critica need for improved methods for effective treatment. Our recent studies have demonstrated the exciting potential of an innovative new therapeutic option for solid tumors; our proposed approach involves using magnetic vortex disks that apply magneto-mechanical forces at the surface of targeted cell membranes to induce apoptotic cell death. We propose the first in vivo study to validate the anti-cancer efficacy of magneto-mechanical therapy for the treatment of HCC. Magnetic nanodisks will be fabricated and characterized for magneto-mechanical cell destruction. We will use transcatheter infusions to deliver the magnetic disks directly into the blood supply of the targeted hepatic tumors. In vivo targeting efficiency via transcatheter hepatic artery injection will be studied with MRI quantification and histological measurements in an HCC rat model. Finally, we will evaluate in vivo therapeutic responses of targeted transcatheter magneto-mechanical cancer therapy; we will validate the ability to induce apoptotic HCC cell death using anti-CD44 conjugated magnetic nanodisks in the rodent model. Through a collaborative project building upon our strengths in biomedical engineering, radiology, and cancer biology, we seek to develop a powerful new magneto-mechanical therapeutic method for the treatment of HCC. Our proposed project will address the following Specific Aims: Aim 1: To determine targeting efficiency and imaging characteristics of our nano magnetic disks Task 1.1: To fabricate various nano-sized magnetic spin-vortex disks (Au coated Fe disk) at a specific geometrical ratio for magneto-mechanical motion upon cell membrane. Task 1.2: Biofunctionalization of magnetic disks and validation of in vitro magneto-mechanical destruction of hepatocellular carcinoma cells. Task 1.3: To characterize relationship between magnetic nanodisks concentration and T2/T2* relaxations rates for magnetic resonance imaging (MRI). Aim 2: To validate that transcatheter magneto-mechanical cancer therapy leads to tumor regression in HCC rat models. Task 2.1: To determine in vivo targeting efficiency of magnetic nanodisks using both in vivo quantitative MRI measurements and invasive histological measurements at necropsy. Task 2.2. To demonstrate in vivo therapeutic responses to targeted transcatheter magneto-mechanical therapy with both functional MRI technique and pathological analysis of tumor cell death.