ASSESSMENT OF DRUG UPTAKE AND PERMEABILITY PROPERTIES OF NOVEL ANTICANCER AGENT

新型抗癌剂的药物摄取和渗透性评估

• 批准号: 8168094
• 负责人: ANTONIE H RICE
• 金额: $ 12.13万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-19 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168094
• 关键词: Affinity; Alzheimer' s Disease; Antineoplastic Agents; Back; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Neoplasms; Cattle; Cell Culture System; Chemicals; Computer Retrieval of Information on Scientific Projects Database; Elements; Endothelial Cells; Funding; Grant; Institution; Link; Mediating; Methods; Microtubule stabilizing agent; Microtubules; Modification; Neuraxis; Neurodegenerative Disorders; P-Glycoprotein; P-Glycoproteins; Paclitaxel; Pathway interactions; Permeability; Pharmaceutical Preparations; Primary Cell Cultures; Property; Research; Research Personnel; Resources; Source; System; Taxane Compound; Therapeutic Agents; United States National Institutes of Health; Work; analog; functional group; high throughput screening; novel; overexpression; prevent; taxane; uptake; vector

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. The blood-brain barrier (BBB) effectively prevents microtubule stabilizing drugs from readily entering the central nervous system (CNS). A major limiting factor for these stabilizing drugs and anticancer agents permeation across the BBB is the active efflux back into the circulation by the overexpression P-glycoprotein (P-gp). This study focuses on strategies to overcome P-gp mediated efflux of new taxane analogues, and other microtubule (MT) stabilizing agents that could be used to treat brain tumors and potentially, neurodegenerative diseases such as Alzheimer's disease. We hypothesize that taxane analogues can be prepared that elude the MDR transporter by altering and/or deleting functional groups that are recognition elements for the transporter. Also, we hypothesize that analogues produced by covalently linking known vectors with carriers in the endothelial cells of the BBB will be delivered to the brain with the aid of these transport systems. Our previous studies demonstrate the feasibility of making small chemical modifications to taxol to generate new analogues with reduced affinity for P-gp but retention of pharmacological activity. Upon successfully demonstrating that our hypothesis works, we plan to then apply this same method of generating new analogues to other anticancer agents or drugs with poor brain bioavailibility. The specific aims of this project will be: 1. Establish the primary cell culture of system of Bovine brain microvessel endothelial cells (BMECs) for high-throughput screening of anticancer drugs. 2. To characterize active, functional transporter systems (i.e., MCT, OAT, and NaDC) present in the brain that may be utilized as alternative pathways of delivery of therapeutic agents. 3. To determine the mechanistic pathway of a new taxane analogue synthesized by chemical modification by assessing the transcellular permeability properties. 4. To determine uptake and permeability properties of other novel anticancer drugs in the brain to assess whether chemical modifications will enhance their brain availability.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 血脑屏障（BBB）有效防止微管稳定药物容易进入中枢神经系统（CNS）。 这些稳定药物和抗癌药物渗透到BBB的主要限制因素是通过过表达P-糖蛋白（P-GP）重新进入循环中的活性外排。 这项研究的重点是克服新的紫杉烷类似物的P-gp介导的外排和其他可用于治疗脑肿瘤以及可能用于治疗诸如阿尔茨海默氏病的神经退行性疾病的微管（MT）稳定剂。 我们假设可以通过改变和/或删除转运蛋白识别元素的官能团来准备紫杉烷类似物来避免MDR转运蛋白。 此外，我们假设通过将已知的向量与BBB内皮细胞中的载体联系起来产生的类似物将借助这些传输系统传递到大脑。 我们以前的研究表明，对紫杉醇进行小型化学修饰以产生新的类似物的可行性，以降低对P-gp的亲和力，但保留药理学活性。成功证明我们的假设有效后，我们计划采用这种相同的方法来为其他抗癌药或脑生物利用度较差的药物产生新的类似物。 该项目的具体目的是： 1。建立牛脑微血管内皮细胞（BMEC）的原发性细胞培养，以对抗癌药的高通量筛查。 2。表征大脑中存在的主动功能转运蛋白系统（即MCT，OAT和NADC），可以用作治疗剂的替代途径。 3。确定通过评估跨细胞渗透性特性，通过化学修饰合成的新紫杉烷类似物的机械途径。 4。确定大脑中其他新型抗癌药物的摄取和渗透率，以评估化学修饰是否会增强其大脑的可用性。