Temperature Modulated-Fluorescence Tomography: A New Modality for Cancer Imaging

描述(申请人提供)：根据美国疾病控制与预防中心的数据，在美国男性中，前列腺癌是最常见的癌症类型，是癌症死亡的第二大原因。由于前列腺癌的弥漫性，需要安全、廉价和便携的前列腺癌成像，而MRI或核成像无法满足这一需求。作为体内最灵敏的分子成像手段之一，荧光成像在临床前和临床研究中发挥着重要的作用。事实上，活体荧光光学成像 应用范围广泛，从细胞到器官层面。不幸的是，在器官水平的应用中，由于生物组织的高散射特性，特别是在深层组织中，荧光成像的分辨率很低。在过去的十年里，学术界和工业界的研究小组为提高荧光断层扫描(FT)的分辨率付出了大量的努力。然而，如果荧光靶点不能在解剖图像中定位，则将FT与其他解剖成像手段(如MRI或CT)相结合的方法不能很好地执行。有几种技术试图使用超声波来调制荧光信号，以实现更高的分辨率。然而，低的调制效率和极低的信噪比是导致这些技术难以实现的两个主要因素。因此，荧光成像的低定量准确性和分辨率仍然是这一强大技术临床应用的主要障碍。为了克服这些限制，我们在这项建议中的主要目标是开发一种全新的方法-温度调制荧光断层扫描(TM-FT)，该方法可以在不牺牲基于荧光的检测的特殊灵敏度的情况下，在深达6厘米的地方提供高分辨率图像。这种高度创新的方法有两个关键组件：a)温度敏感的荧光分子探测器(热点)和b)基于高强度聚焦超声(HIFU)的高空间分辨率的组织温度调制(仅3-50℃)。焦斑的小尺寸(~1 mm)使这些温度敏感剂的分布不仅具有高空间分辨率，而且具有高的定量精度。这一新系统的开发将包括：TM-FT重建算法的开发和优化，TM-FT系统的开发和模型研究的评估，最后是体内研究的验证。这项培训计划是为了首次对这种新的成像方式进行体内可行性研究。这项提议的结果可能是一种无辐射、成本效益高和便携式的肿瘤成像系统。携带原位前列腺癌模型的小鼠将被用来检验这样的假设：与独立的FT系统相比，TM-FT将提供更定量的更准确和更高分辨率的荧光图像。如果成功，结果将是一种新的成像方式的开始。

DESCRIPTION (provided by applicant): According to the CDC, among US men, cancer of the prostate is the most common type of cancer and the second leading cause of cancer death. Due to the diffuse nature of prostate cancer, there is a need for safe, inexpensive, and portable prostate tumor imaging, which MRI or nuclear imaging cannot satisfy. As one of the most sensitive in vivo molecular imaging modalities, fluorescence imaging has great potential to play an important role in preclinical and clinical studies. Indeed, in vivo fluorescence optical imaging extends across a wide range of applications, from cellular to organ levels. Unfortunately, in organ level applications, fluorescence imaging suffers from low resolution due to the high scattering nature of the biological tissue especially in deep tissue. Extensive effort has been spent to improve the resolution of fluorescence tomography (FT) by research groups from academia and industry in the last decade. However, approaches such as integrating FT with other anatomic imaging modalities such as MRI or CT does not perform well if the fluorescent target cannot be localized in the anatomical image. There are several techniques that attempt to modulate fluorescence signals using ultrasound to achieve higher resolution. However, low modulation efficiency and extremely low signal to noise ratio (SNR) are the two primary factors that make the implementation of these techniques difficult. Therefore, the low quantitative accuracy and resolution of fluorescence imaging remain as the main barriers for clinical translation of this powerful technique. To overcome these limitations, our main goal in this proposal is to develop an entirely new approach "Temperature-modulated fluorescence tomography (TM-FT)" that can provide high resolution images at depths up to 6 cm without sacrificing the exceptional sensitivity of fluorescence-based detection. There are two key components to this highly innovative approach: a) Temperature sensitive florescent molecular probes (thermo-dots) and b) High Intensity Focused Ultrasound (HIFU) based modulation of tissue temperature (only 3-50C) with high spatial resolution. The small size of the focal spot (~1mm) allows imaging the distribution of these temperature sensitive agents with not only high spatial resolution but also high quantitative accuracy. Development of this novel system will include: development and optimization of the TM-FT reconstruction algorithm, development of the TM-FT system and evaluation with phantom studies, and finally, validation with in vivo studies. This training proposal is geared toward the first in vivo feasibility studies of this nove imaging modality. The outcome of this proposal could be a radiation free, cost-effective, and portable tumor imaging system. Mice bearing orthotopic prostate cancer model will be used to test the hypothesis that "TM-FT will provide quantitatively more accurate and higher resolution fluorescence images compared to a stand-alone FT system". If successful, the outcome will be the beginning of a new imaging modality.