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的辐射，也不使用昂贵的放射性示踪剂；然而，MRI，即使有合适的造影剂的帮助，也会受到来自宿主组织的背景噪声的困扰，并且缺乏准确量化在给定位置存在多少造影剂的能力。尽管造影剂在成像和在更大范围内区分异常组织（肿瘤）和健康组织方面很有用，但由于缺乏将肿瘤与周围健康组织区分开来的造影剂，早期发现几千个癌细胞是困难的。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，与造影剂不同，它可以不考虑周围组织而直接成像，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颗粒成像（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松弛，产生纳米颗粒在组织中分布的三维图像。磁性纳米颗粒在MPI中的信号比在MRI中使用的质子的核顺磁性多一百万倍。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。事实上，如果这个关键成分，即适当的磁铁矿纳米颗粒分子探针，生物相容性和表面功能化，易于生物偶联，并为最佳性能量身定制，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，我们建议及时开发分子探针技术，这对MPI的成功至关重要。我们的三个具体目标（SA）将集中在（SA1）开发单分散和生物相容性磁性纳米颗粒（MNPs）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；（SA2）使MNPs功能化，以特异性靶向肿瘤细胞和周围血管，并确定体外靶向有效性；（SA3）证明MPI能够使用自制的磁谱仪在体外检测和量化我们的靶向MNPs。从而为涉及体内成像和量化的第二阶段工作奠定了基础。

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.