Enhanced Intraarterial Delivery of Chemotherapeutic Drugs to the Brain

描述（由申请人提供）：原发性和继发性脑肿瘤是美国普通人群发病率和死亡率的主要原因。近年来，通过靶向特定分子或跨血脑屏障的转运机制将药物递送到大脑已经做出了巨大的努力。通过直接动脉内注射选择性地将化疗药物递送到脑的尝试尚未发现广泛的临床接受，因为组织药物浓度的控制不足，并且缺乏在临床前研究中严格研究动脉内药物的快速动力学的方法。在过去的十年中，血管内手术取得了相当大的进展。开发能够操纵血流并选择性地将药物输送到大脑特定区域的微导管，可以大大提高动脉内药物的安全性和有效性。该应用将表明，修改血流和团注特性可以显著增强药物向大脑的动脉内递送。我们试图调查的影响，操纵脑血流和团的配置上的动脉输送化疗药物的正常脑组织和肿瘤组织，以最大限度地提高区域沉积的药物。我们将进一步研究脂溶性在增强药物向大脑递送中的作用，特别是当局部血流短暂（30- 60秒）减少时。了解动脉内药物的动力学，其浓度在注射后迅速变化，需要高速原位测量。因此，对动脉内药物动力学的了解迄今仅限于少数研究。该应用程序使用最近开发的光学药代动力学（OP）技术来测量大脑中的局部药物浓度。OP在虚拟真实的时间（50 ms/测量）内跟踪组织药物浓度。我们将首次将OP测量应用于大脑。OP测量是通过颅骨的内板进行的;因此，脑组织的完整性不会受到影响。总之，拟议的研究将改善药物输送到大脑的方法。它将提高动脉化疗药物的安全性和有效性。它将导致治疗脑癌的新协议。 公共卫生相关性：该研究采用了新的光学技术和动脉内给药的新技术，将大大推进动脉内药物动力学的理解。它将导致新的协议，为交付化疗药物治疗脑癌。

DESCRIPTION (provided by applicant): Primary and secondary brain tumors are a leading cause of morbidity and mortality in the general American population. In recent years an enormous effort has been made to deliver drugs to the brain by targeting specific molecules or transport mechanisms across the blood brain barrier. Attempts to selectively deliver chemotherapeutic drugs to the brain by direct intra-arterial injection have not found wide clinical acceptance because of inadequate control of tissue drug concentrations, and the lack of a method to rigorously investigate the fast kinetics of intra-arterial drugs in pre-clinical studies. During the last decade considerable advances have been made in endovascular surgery. The development of microcatheters that are capable of manipulating blood flow and selectively delivering drugs to specific regions of the brain, can greatly improve the safety and efficacy of intra-arterial drugs. The application will show that modifying the blood flow and bolus injection characteristics can dramatically enhance intra-arterial delivery of drugs to the brain. We seek to investigate the effects of manipulating cerebral blood flow and bolus configuration on intra-arterial delivery of chemotherapeutic drugs to normal brain and tumor tissues, so as to maximize regional deposition of the drugs. We will further investigate the role of lipid solubility in enhancing drug delivery to the brain, particularly when the regional blood flow is transiently (30- 60s) reduced. Understanding the kinetics of intra-arterial drugs whose concentrations change rapidly after injection, requires high-speed in-situ measurements. Thus, insight into intra-arterial drug kinetics has hitherto been limited to only a few studies. This application uses the recently developed Optical Pharmacokinetics (OP) technique to measure regional drug concentrations in the brain. OP tracks tissue drug concentrations in virtual real time (50 ms/measurement). We will apply the OP measurements for the first time to the brain. OP measurements are made through the inner table of the skull; therefore, the brain tissue integrity is not compromised. In summary, the proposed research will improve methods of drug delivery to the brain. It will enhance the safety and efficacy of intra-arterial chemotherapeutic drugs. It will lead to new protocols for the treatment of brain cancers. Public Health Relevance: The proposed research which uses novel optical technology and new techniques of intraarterial drug delivery, will considerably advance the understanding of intraarterial drug kinetics. It will lead to new protocols for delivery of chemotherapeutic drugs for treating brain cancers.