Monodispersed Biocompatible Magnetic Nanoprobes for Improved Diagnostic Imaging

描述(申请人提供)：磁共振成像(MRI)是一个有吸引力的医学成像平台，因为它既不使用有害的辐射，也不使用昂贵的放射性示踪剂；然而，即使在合适的造影剂的帮助下，MRI也受到来自宿主组织的背景噪声的困扰，并且缺乏准确量化给定位置存在多少造影剂的能力。尽管造影剂在更大范围内成像和区分异常组织(肿瘤)和健康组织是有用的，但由于缺乏对比剂来区分肿瘤和周围的健康组织，早期发现数千个癌细胞是困难的。此外，疾病部位细胞的量化对于开发更具部位特异性的造影剂至关重要，这将使图像引导治疗的未来发展成为可能。因此，迫切需要开发磁性分子探针，与造影剂不同，它可以直接成像，而不受周围组织的影响，并且可以同时针对疾病部位进行早期诊断成像。我们的目标是使用磁粒子成像(MPI)，这是飞利浦最近推出的一种新的医学成像技术，它利用磁性纳米颗粒在交变磁场中的磁弛豫，产生纳米颗粒在组织中分布的三维图像。与核磁共振中使用的质子的顺磁性相比，磁性纳米粒子在MPI中的信号将增加100万倍。皇家飞利浦和Bruker Biospin联合宣布开发临床前MPI硬件和成像系统，将于2011/12年度上市。然而，商业上可用的磁铁矿配方在信号强度和空间分辨率方面都严重不足MPI。事实上，如果现在不开发这种关键组件，即合适的磁铁矿纳米颗粒分子探针，这种探针具有生物相容性和表面功能化，便于生物结合，并为最佳性能量身定做，那么MPI的巨大潜力可能永远不会实现。根据我们的技术诀窍，我们建议以最及时的方式开发分子探针技术，这是MPI成功的关键。我们的三个特定目标(SA)将专注于(SA1)开发单分散和生物兼容的磁性纳米颗粒(MNPs)作为分子探针，以优化MPI中使用的任何特定驱动频率，(SA2)使MNPs功能化，以特异性靶向肿瘤细胞和周围血管，并确定体外的靶向有效性，以及(SA3)展示MPI在体外使用自制磁光谱仪检测和定量我们的靶向MNPs的能力，从而为涉及体内成像和定量的第二阶段工作奠定基础。 与公共卫生相关：医学成像有多种形式，是临床医生用于诊断疾病和为患者确定正确的治疗方案的关键技术。癌症是一种疾病，仅在2010年就在美国造成了超过55万人的死亡(国家癌症研究所；www.ancer.gov)，诊断癌症特别困难，通常在患者存活率很低的较晚阶段才被发现。为了早期检测几千个细胞，重要的是使用纳米级的探头(1纳米=十亿分之一米)，这种探头可以专门针对癌细胞并直接成像，而不会受到患者身体的任何干扰或噪音。在这个项目中，我们将开发功能化的基于磁性纳米颗粒的分子探测器，其信号比核磁共振中使用的核顺磁性多一百万倍，用于使用一种名为磁粒子成像(MPI)的新技术来早期检测癌症。我们的技术将补充MPI的发明者飞利浦正在开发的硬件。这项技术如果成功，将优于目前的磁共振成像(MRI)等成像技术，并有可能实现早期诊断，让患者在抗击癌症的斗争中领先一步。

DESCRIPTION (provided by applicant): Magnetic Resonance Imaging (MRI) is an attractive platform for medical imaging because it uses neither harmful radiation nor expensive radio-tracers; however, MRI, even with the aid of suitable contrast agents, is plagued by background noise from the host tissue and lacks the ability to quantify exactly how much contrast agent is present at a given location. Despite the fact that contrast agents are useful in imaging and differentiating abnormal tissues (tumors) from healthy tissues at much larger scales, early detection of a few-thousand cancer cells is difficult due to the lack of contrast differentiating the tumor from surrounding healthy tissue. Additionally, quantification of cells at the disease site is crucial for development of more site-specific contrast agents that will enable future developments in image-guided therapeutics. Thus, there is a critical need to develop magnetic molecular probes that, unlike contrast agents, can be directly imaged, irrespective of the surrounding tissue, and can be simultaneously targeted to disease sites for early diagnostic imaging. Our goal is to use Magnetic Particle Imaging (MPI), a new medical imaging technology recently introduced by Philips that uses the magnetic relaxation of magnetite nanoparticles in alternating fields, to produce three-dimensional images of the distribution of the nanoparticles in the tissue. The magnetic nanoparticles will have a million times more signal in MPI compared to the nuclear paramagnetism of protons used in MRI. Royal Philips and Bruker Biospin, have jointly announced the development of a preclinical MPI hardware and imaging system, to be marketed in 2011/12. However, commercially available magnetite formulations are grossly inadequate for MPI, both in terms of signal intensity and spatial resolution. In fact, if this critical component, i.e. appropriate magnetite nanoparticle-based molecular probes, that are biocompatible and surface functionalized for facile bioconjugation, and tailored for optimal, performance, are not developed now the enormous potential of MPI may never be realized. Based on our knowhow, we propose to develop the technology of the molecular probes crucially required for the success of MPI in a most timely manner. Our three specific aims (SA) will focus on (SA1) development of monodispersed and biocompatible magnetic nanoparticles (MNPs) as molecular probes optimized for any specific driving frequency used in MPI, (SA2) functionalize the MNPs for specific targeting to tumor cells and the surrounding vasculature and determine the targeting effectiveness in vitro, and (SA3) demonstrate MPI's ability to detect and quantify our targeted MNPs in vitro using a home-built magnetic spectrometer, thereby setting the stage for Phase II work involving in vivo imaging and quantification. PUBLIC HEALTH RELEVANCE: Medical imaging, in its many forms, is a crucial technique used by clinicians for diagnosing diseases and determining the correct treatment options for patients. Diagnosis of cancer, a disease that has resulted in over 550,000 deaths in the United States in 2010 alone (National Cancer Institute; www.cancer.gov), is especially difficult and often detected at much later stages when patient survival chances are low. For early detection of a few-thousand cells, it is important to use nanometer-scale probes (1 nanometer = 1 billionth of a meter) that can specifically target cancer cells and be directly imaged, without any interference or noise from the patient's body. In this project, we will develop functionalized magnetic nanoparticle-based molecular probes, with a million times more signal than nuclear paramagnetism used in MRI, for early detection of cancer using a new and emerging technique called Magnetic Particle Imaging (MPI). Our technology will complement the hardware being developed by Philips, the inventors of MPI. This technology, if successful, will be superior to current imaging techniques such as Magnetic Resonance Imaging (MRI) and has the potential to enable early diagnosis, giving patients a head start in the fight against cancer.