Biophysical Analysis of Folic Acid-Folate Binding Protein Interaction

描述(申请人提供)：拟议研究的目的是检查叶酸(FA)结合物和叶酸受体之间相互作用的生物物理性质，叶酸受体是模型药物传递系统的识别组件。了解药物输送系统的各个组成部分对于癌症靶向治疗的发展至关重要。作为实现这一目标的一步，将使用整体测量方法(如表面等离子体共振(SPR)和等温滴定热法(ITC))和单分子方法(如拉力光谱)对叶酸和叶酸结合蛋白(FBP)之间的相互作用进行生物物理表征。从这项研究获得的物理性质将被用作FA-FBP相互作用的基线测量。这项研究的结果将有助于解释FA和FBP之间多价相互作用的数据。该项目的具体目标是：1)用SPR和ITC测量FA-FBP相互作用的基线物理性质，2)用单分子方法测量FA-FBP相互作用的动力学和热力学参数，3)研究FA和FBP之间的多价相互作用。这项研究的结果有望成为进一步研究的基础，这些研究将阐明与模型叶酸受体结合所需的叶酸单元的最佳数量，并提供有助于更好地设计靶向给药系统的动力学和热力学信息。 与公共卫生相关：许多医疗治疗，特别是化疗药物的局限性是，它们是系统地给药，导致疾病细胞和健康细胞的破坏。一种能够针对病态细胞中的作用部位的设备显然是首选的，而且最有可能将副作用降至最低。

DESCRIPTION (provided by applicant): The purpose of the proposed study is to examine the biophysical properties of the interaction between a folic acid (FA) conjugate and folate receptors, which are recognition components of a model drug delivery system. Understanding the various components of the drug delivery system is crucial for the development of targeted therapeutics for cancer. As a step towards that goal, a biophysical characterization of the interaction between folic acid and folate binding protein (FBP) will be undertaken using bulk measurement methods such as surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) and single molecule methods such as force pulling spectroscopy. Physical properties obtained from this study will be used as baseline measurements for the FA-FBP interaction. The results from this study will aid in the interpretation of data from multivalent interactions between FA and FBP. The specific aims of the project are to: 1) measure baseline physical properties for the FA-FBP interaction by SPR and ITC, 2) measure kinetic and thermodynamic parameters for the FA-FBP interaction by single molecule approaches, 3) investigate multivalent interactions between FA and FBP. The results of this study are expected to form the basis for further studies that will clarify the optimal number of folic acid units required for binding to a model folate receptor and provide kinetic and thermodynamic information that will lead to better designs of targeted drug-delivery systems. PUBLIC HEALTH RELEVANCE: A limitation of many medical treatments, particularly chemotherapeutics is that they are administered systemically resulting in the destruction of both sick and healthy cells. A device capable of targeting the site of action in a sick cell would be clearly preferred and most likely minimize side-effects.