Monodispersed Biocompatible Magnetic Nanoprobes for Improved Diagnostic Imaging

描述（由申请人提供）：磁共振成像（MRI）是一种有吸引力的医学成像平台，因为它既不使用有害辐射，也不使用昂贵的放射性示踪剂;然而，即使在适当造影剂的帮助下，MRI也会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。尽管造影剂可用于以大得多的尺度成像和区分异常组织（肿瘤）与健康组织，但由于缺乏区分肿瘤与周围健康组织的造影剂，几千个癌细胞的早期检测是困难的。此外，疾病部位的细胞定量对于开发更多部位特异性造影剂至关重要，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，其与造影剂不同，可以直接成像，而不考虑周围组织，并且可以同时靶向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，它利用磁铁矿纳米颗粒在交变场中的磁弛豫，来产生组织中纳米颗粒分布的三维图像。与MRI中使用的质子的核顺磁性相比，磁性纳米粒子在MPI中的信号将增加一百万倍。皇家飞利浦公司和布鲁克Biospin公司联合宣布开发一种临床前MPI硬件和成像系统，将于2011/12年上市。然而，市售的磁铁矿配方是严重不足的MPI，无论是在信号强度和空间分辨率。事实上，如果这种关键组分，即适当的基于磁铁矿纳米颗粒的分子探针，其是生物相容的和表面官能化的以便于生物缀合，并且针对最佳性能定制，现在不开发MPI的巨大潜力可能永远不会实现。基于我们的专业知识，我们建议以最及时的方式开发MPI成功所必需的分子探针技术。 我们的三个具体目标（SA）将集中在（SA 1）开发单分散和生物相容的磁性纳米颗粒（MNP）作为分子探针，针对MPI中使用的任何特定驱动频率进行优化，（SA 2）功能化MNP，以特异性靶向肿瘤细胞和周围血管系统，并确定体外靶向有效性，和（SA 3）证明MPI的能力，检测和定量我们的目标MNP在体外使用自制的磁分光计，从而设置阶段II的工作，涉及在体内成像和定量。 公共卫生相关性：医学成像以其多种形式是临床医生用于诊断疾病和确定患者正确治疗方案的关键技术。癌症是一种仅在2010年就在美国导致超过550，000人死亡的疾病（国家癌症研究所; www.cancer.gov），其诊断尤其困难，并且通常在患者存活机会低的较晚阶段才被检测到。对于几千个细胞的早期检测，重要的是使用纳米级探针（1纳米=十亿分之一米），可以特异性地靶向癌细胞并直接成像，而不会受到患者身体的任何干扰或噪音。在这个项目中，我们将开发基于功能化磁性纳米颗粒的分子探针，其信号比MRI中使用的核顺磁性高100万倍，用于使用称为磁性颗粒成像（MPI）的新兴技术早期检测癌症。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，将上级目前的成像技术，如磁共振成像（MRI），并有可能实现早期诊断，使患者在与癌症的斗争中处于领先地位。

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.