Optical Measurement of Fast Drug Kinetics in Tumor

描述(由申请人提供)： 最初的资助项目名为“组织内药物浓度的非侵入性测量”，其目标已经成功实现。这导致了光学药代动力学(OP)方法的发展，该方法用于非侵入性地实时测量组织中药物或其他化合物的浓度，并通过动物肿瘤模型演示该技术在新药物的药代动力学研究中的应用。靶点药代动力学对化疗，尤其是光动力治疗非常重要，因为它是肿瘤组织和正常组织的剂量-反应曲线之间的差异，必须在治疗过程中加以利用。通过将OP方法扩展到快速测量序列，医学研究的其他领域也成为可能。这项竞争性续期赠款的目标是推进OP技术，并将其应用于评估血管生成和抗血管生成药物治疗的反应。光学造影剂首次通过动力学的OP测量将被用来评估微血管密度。在接下来的几十分钟内，进一步的OP测量将能够评估渗入细胞外液体空间的情况，并评估癌症区域的微血管通透性(因此，评估毛细血管的完整性)，目的是以一种非侵入性的方法来评估血管生成和抗血管生成治疗的反应。OP系统在几秒钟内进行多次测量的能力也将允许对浓度测量中的生物噪声进行评估。目的是证明，在浅表病变的情况下，OP方法能够提供通过CT和MRI技术以及使用小型、便携和廉价设备无法获得的信息。我们将设计和组装一个能够每秒测量3次的下一代OP系统，用于使用光纤探头确定本地毒剂浓度。我们将使用这个系统来记录第一次通过，以及随后的时间，用光学生色团和放射性示踪剂标记的测试化合物的特定地点的浓度。光学测量将以相同化合物上的放射性标记物的分析为基准。这将验证光学方法，便于与经批准的光学造影剂一起使用。在体外实验之后，我们将利用兔Vx2肿瘤来测试在受控条件下光学试剂和血红蛋白的首过和后续动力学的测量。我们将应用OP方法来估计微血管密度(光学试剂的峰值浓度和血红蛋白浓度)和表征毛细血管泄漏(使用三室动力学模型的内皮转移速率常数)，这是血管生成反应的两个指标。我们还将测试感知由肿瘤坏死因子-α和抗血管生成药物治疗后引起的通透性变化的能力。这种OP方法的应用可以改善对人类的治疗管理，特别是对于用目前的成像方法很难评估其动力学的浅表病变。

DESCRIPTION (provided by applicant): The goals of the original grant, titled "Noninvasive measurement of drug concentrations in tissue," have been successfully achieved. These entailed the development of the method of Optical Pharmacokinetics (OP) for noninvasive measurement in real time, and with site-specificity, of the concentrations of drugs or other compounds in tissue, and the demostration of the technology in pharmacokinetic studies of new agents with animal tumor models. Site-specific pharmacokinetics is important for chemotherapy, and especially for photodynamic therapy, since it is the difference between the dose-response curves of tumor tissue and normal tissue that must be exploited during treatment. By extending the OP method to rapid sequences of measurements, other areas of medical research are enabled. The goal of this Competing Renewal grant is to advance the OP technology and apply it to the assessment of angiogenesis and of the response to treatment by anti-angiogenic agents. OP measurements of the first-pass kinetics of optical contrast agents, administered in a short bolus, will be used to assess microvascular density. Further OP measurements over the subsequent tens of minutes will permit assessment of the leakage into the extracellular fluid space and evaluation of microvessel permeability (hence, assessing capillary integrity) in regions of cancer, with the goal of a noninvasive method to assess angiogenesis and response to anti-angiogenic treatment. The ability of the OP system to make a burst of many measurements within seconds will also permit evaluation of the biologic noise in concentration measurements. It is a goal to demonstrate that the OP method, in the case of superficial lesions, is able to provide information that is not available through CT and MRI techniques, and by use of a small, portable, and inexpensive device. We will design and assemble a next-generation OP system capable of >3 measurements per second, for determining local agent concentrations with fiber-optic probes. We will use this system to record the first-pass, and the subsequent-time, site-specific concentrations of test compounds that are labeled with both optical chromophores and radiotracers. Optical measurements will be benchmarked against the assay of the radioactive markers on the same compounds. This will verify the optical method, facilitating use with approved optical contrast agents. Following in-vitro experiments, we will utilize rabbit Vx2 tumors to test the measurement of the first-pass and following kinetics of optical agents and hemoglobin under controlled conditions. We will apply the OP method to estimate microvascular density (peak concentration of optical agent and hemoglobin concentration) and to characterize capillary leak (endothelial transfer rate constant using a tri-compartment kinetic model), two indices of the angiogenic response. We will also test the ability to sense changes in permeability caused by TNF-alpha and following treatment with anti-angiogenesis agents. Such application of the OP method can result in improved management of treatment in humans, especially for superficial lesions in which kinetics are difficult to assess by current imaging methods.