LIPOSOMAL DRUG DELIVERY: TUMOR GROWTH DELAY AND MR IMAGING OF DISTRIBUTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 长期以来，化疗一直被用来在癌症治疗过程中提供肿瘤控制。然而，化疗有几个局限性。首先，免费的化疗药物往往分布在全身，导致与化疗相关的常见治疗副作用。其次，缺乏一种非侵入性的方法来评估治疗后化疗药物的浓度，这阻碍了药物分布/剂量如何影响肿瘤控制的研究。温度敏感脂质体(TSL)可能提供一种克服这两个障碍的方法，因为它们定位于肿瘤部位的药物释放，并允许非侵入性成像药物浓度分布。然而，为了进行局部药物释放和药物浓度的准确测量，必须采用局部热疗(HT)，并且必须准确地测量温度。高温会导致脂质体的脂膜破裂，而随着绝对温度的增加，渗透性的增加会定量地影响从成像接收的信号。因此，我们提出的项目将有助于解释组织温度和药物释放之间的关系，因为在以前的实验中，热疗设备的温度是估计的，但没有测量。 我们TSL研究的主要目标是开发一种可以从实验室/动物领域转移到临床/人类领域的技术。我们与Viglianti等人的CIVM的初步工作。2004年和2006年证明，我们可以对使用TSL的药物分布进行成像和量化。从这项工作中，测量的信号除了温度外，还依赖于药物/TSL的浓度。来自没有成像的动物的温度数据允许我们对动物的温度做出假设，这是将测量的信号转换为药物绝对浓度所必需的。虽然是第一近似值，但以前的工作允许庞塞等人。(2007)，以证明在TSL的疗效中，温度分布与给药总量同样重要。这可以通过改变应用热疗的顺序和TSL的给药来实现。 在我们的实验中，由于多种原因，羟色胺的影响是必要的。从生物学上讲，羟色胺会使肿瘤的血管系统变得更加“渗漏”，并增加肿瘤的灌注量。这种效应在临床上被用来改善肿瘤的氧合，这反过来又导致了更好的辐射反应。为了最大限度地发挥这一效果的好处，准确的温度监控至关重要。目前正在尝试以非侵入性的方式做到这一点。适合我们的方法是利用随温度变化而发生的质子共振频率(PRF)漂移。为此，我们将在稳态(变质草)脉冲序列中使用损坏的梯度回忆采集。通过使用给定ROI的加热前后的相位数据和来自油品标准的与温度无关的相位数据，可以推导出组织的温度。之所以使用油标准，是因为它们允许我们绘制磁场不均匀图，并校正磁体中样品的相位漂移。 在我们的实验中，热疗是通过TSL释放来靶向脂质体的含量。大鼠在磁铁内接受高温治疗，高温后注射LTSL。我们提出的这项研究克服了Viglianti等人以前研究的主要局限性之一。(2004,2006)通过主动监测动物的温度，而不是使用稳态热流方程来估计它。通过非侵入性地监测脂质体内容物释放期间组织的温度，我们可以看到组织的温度图将如何帮助预测化疗药物释放的最终目的地。这可能使人们能够通过改变温度图将化疗药物“涂”到肿瘤上，从而获得所需的阿霉素浓度。 我们提出的项目使用的是热疗前注射脂质体的大鼠纤维肉瘤模型。然后，我们将尝试将从2T磁体中损坏的梯度回波脉冲序列获得的非侵入性温度图与基于T1的DOX浓度测量相关联，以更好地了解加热如何影响体内药物浓度，并进一步展示可成像脂质体系统向临床的转化。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chemotherapy has long been used to provide tumor control during cancer treatment. However, there are several limitations of chemotherapy. First, free chemotherapeutic agents tend to distribute to the whole body, causing the familiar treatment side effects associated with chemotherapy. Second, a lack of a noninvasive manner to assess chemotherapy drug concentration post treatment has hindered study of how drug distribution/dose affects tumor control. Temperature sensitive liposomes (TSLs) may provide a way to overcome both of these hurdles because they localized drug release at the tumor site and allow noninvasive imaging of the drug concentration distribution. However, in order to have local drug release, and accurate measurement of drug concentration, local hyperthermia (HT) must be applied and the temperature must be accurately measured. The hyperthermia causes the lipid membrane of the liposome to break down, and the increased permeability in concert with the absolute temperature quantitatively influence the signal received from the imaging. Consequently, the project we are proposing will help explain the relationship between tissue temperature and drug release were in previous experiments the temperature from the hyperthermia device was estimated but not measured. The primary goal of our TSL research is to develop a technology that can be moved from the lab/animal domain into the clinic/human domain. Our initial work with the CIVM in Viglianti et al. 2004 and 2006 demonstrated that we could image and quantify drug distribution delivered with TSL. From this work the measured signal was dependent on drug/TSL concentration in addition to temperature. Temperature data from animals that were not imaged allowed us to make assumptions about the animal's temperature that were necessary to convert the measured signal to absolute concentration of drug. Although a first approximation, the previous work allowed Ponce et al. (2007) to demonstrate that the temperature distribution was just as important as total drug delivered in the efficacy of TSL. This was possible by changing the sequence of the applied hyperthermia and the administration of the TSL. In our experiment, the effects of HT are necessary for multiple reasons. Biologically, HT causes the vascular system of the tumor to become more "leaky" and increased the perfusion of the tumor. This effect is taken advantage of in the clinic in order to improve tumor oxygenation, which in turn leads to improved radiation response. To maximize the benefits of this effect, accurate temperature monitoring is essential. Attempts to do this non-invasively are currently on going. The method that is suitable for our purposes utilizes the proton resonant frequency (PRF) shift that occurs with changing temperature. To do this, we will use a spoiled gradient recalled acquisition in steady state (spoiled GRASS) pulse sequence. By using the pre and post heating phase data of a given ROI and the temperature independent phase data from an oil standard, the temperature of the tissue can be derived. The oil standards are used because they allow us to map the field inhomogenity and to correct for phase drift of the sample in the magnet. In our experiment hyperthermia is used for targeting of the liposome contents through TSL release. The rat will be treated with HT while inside the magnet, and the LTSL will be injected after HT. The study that we are proposing overcomes one of the main limitations of previous studies by Viglianti et al. (2004,2006) by actively monitoring the temperature of the animal instead of using steady state heat flow equations to estimate it. By noninvasively monitoring the temperature of the tissue during liposome content release, we can see how the temperature maps of the tissue will help predict the final destination of the chemotherapy drug release. This will potentially enable one to "paint" chemotherapy drug onto the tumor by altering the temperature maps so that the desired end doxorubicin concentration is received. The project that we are proposing uses a rat fibrosarcoma model with liposomes injected before hyperthermia. We will then attempt to relate a non-invasive temperature map obtained from a spoiled gradient recalled echo pulse sequence in a 2T magnet to the T1 based DOX concentration measurements in order to better understand how heating affects in vivo drug concentration and further demonstrate the translation of the imagable liposome system to the clinic.