TARGETED DRUG DELIVERY OF ANTICANCER AGENTS ACROSS THE BLOOD-BRAIN BARRIER

跨越血脑屏障的抗癌药物的靶向给药

• 批准号: 8359805
• 负责人: ANTONIE H RICE
• 金额: $ 11.95万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359805
• 关键词: Affinity; Alzheimer' s Disease; Antineoplastic Agents; Arkansas; Biomedical Research; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Capillary Permeability; Cell Culture Techniques; Chemicals; Computer Simulation; Detection; Development; Drug Delivery Systems; Funding; Grant; HIV; Hereditary Disease; High Dose Chemotherapy; In Situ; In Vitro; Intra-Arterial Injections; Knowledge; Lead; Modeling; Modification; National Center for Research Resources; Neuraxis; Other Genetics; P-Glycoprotein; Paclitaxel; Pathway interactions; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacy (field); Plasma; Principal Investigator; Property; Research; Research Infrastructure; Resources; Site; Source; Structure-Activity Relationship; System; Therapeutic; United States National Institutes of Health; analog; analytical method; base; combinatorial chemistry; cost; driving force; drug modification; nervous system disorder; response; uptake; vector

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The inadequate delivery of chemotherapeutics to the desired site of action in the brain results in a poor response to drug treatment for many neurological disorders (i.e., Alzheimer's disease, brain tumors, HIV, and other genetic disorders). The bloodbrain barrier (BBB) regulates the influx and efflux of a wide variety of substances and remains the major obstacle of delivery of pharmaceutics into the central nervous system (CNS). The development of BBB targeting strategies is a very active field of research and includes manipulation of the drug, modification of capillary permeability of the BBB, or attempts to increase the driving force for transport by increasing plasma concentrations of the drug (i.e., high-dose chemotherapy, intra-arterial injection). We have been successful in demonstrating that chemical modification of a highly lipophilic non-permeable p-glycoprotein (P-gp) substrate (i.e., paclitaxel [Taxol¿]) can be achieved, resulting in increased permeability through the BBB, and that targeting active drug transporter vector systems is viable. Our long-term objectives are to (1) demonstrate that through the utilization of combinatorial chemistry we can successfully synthesize new pharmacologically active derivatives of anticancer moieties with enhanced permeability, (2) characterize active transporters at the BBB with known vectors that may be useful in explaining the mechanistic pathways of the analogues, and (3) demonstrate an in vitro/in situ correlation of the mechanistic pathways of a derivative's enhanced permeability. Knowledge of these mechanisms should lead to strategies that may be employed to enhance therapeutic delivery of pharmaceuticals to the brain. The specific aims of this project will be: 1. Devise a computational model to study structureactivity relationships of P-gp substrates. 2. Synthesize derivatives based on the predictive parameters from computational modeling. 3. Determine uptake and permeability properties of new analogues utilizing an in vitro cell culture model of the BBB and develop an analytical method of detection of new analogues. 4. Determine the mechanism of transport to explain enhanced uptake and permeability of compounds with reduced P-gp affinity.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 在大脑中，化学疗法向所需的作用部位的递送不足，导致许多神经系统疾病的药物治疗反应不佳（即阿尔茨海默氏病，脑肿瘤，HIV和其他遗传疾病）。血脑屏障（BBB）调节了多种物质的影响和外流，并且仍然是药物输送到中枢神经系统（CNS）的主要障碍。 BBB靶向策略的发展是一个非常积极的研究领域，包括操纵药物，修饰BBB的毛细血管渗透性，或试图通过增加药物血浆浓度（即高剂量化学疗法，内部内部注射）来增加运输的驱动力。我们已经成功地证明了可以实现高度亲脂性不可渗透的P-糖蛋白（P-GP）底物（即紫杉醇[紫杉醇]）的化学修饰，从而可实现通过BBB的渗透性增加，并且靶向活性药物转运器矢量系统的靶向可行。我们的长期目标是（1）证明，通过使用组合化学的利用，我们可以成功地合成具有增强的渗透性的抗癌部分的新药物活性衍生物，（2）表征BBB的活性转运蛋白，以已知的矢量来表征可在bbb中的活性转运剂，这些载体可在可能的机械途径中，以说明该途径的机械途径，并在（corral of the Ateriation fortro）中进行（3）的机械途径（3），并在（3）中（3）中的机械途径（3）衍生物的增强渗透性。 这些机制的知识应导致可能采用的策略，以增强药物向大脑的热递送。 该项目的具体目的是： 1。设计一个计算模型来研究P-gp底物的结构活动关系。 2。基于计算建模的预测参数合成衍生物。 3。确定利用BBB的体外细胞培养模型的新类似物的摄取和渗透率，并开发出一种检测新类似物的分析方法。 4.确定传输机制，以解释具有降低的P-gp亲和力的化合物的增强摄取和渗透性。