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和死亡的主要原因。近年来，通过靶向特定分子或通过血脑屏障的运输机制将药物输送到大脑的研究取得了巨大的进展。由于对组织药物浓度的控制不足，以及在临床前研究中缺乏严格研究动脉内药物快速动力学的方法，通过直接动脉内注射有选择性地将化疗药物输送到大脑的尝试尚未得到广泛的临床接受。在过去的十年中，血管内手术取得了相当大的进展。微导管的发展能够控制血液流动并选择性地将药物输送到大脑的特定区域，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，改变血流量和大剂量注射特性可以显著增强动脉内药物向大脑的输送。我们试图研究调节脑血流量和脑丸配置对化疗药物动脉内输送到正常脑和肿瘤组织的影响，从而最大化药物的区域沉积。我们将进一步研究脂溶性在促进药物输送到大脑中的作用，特别是当局部血流量短暂减少（30- 60s）时。了解注射后浓度迅速变化的动脉内药物的动力学，需要高速的原位测量。因此，迄今为止，对动脉内药物动力学的了解仅限于少数研究。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区域药物浓度。OP以虚拟实时（50 ms/次测量）跟踪组织药物浓度。我们将首次将OP测量应用于大脑。OP测量通过颅骨内表进行；因此，脑组织的完整性没有受到损害。总之，拟议的研究将改进药物输送到大脑的方法。它将提高动脉内化疗药物的安全性和有效性。这将导致脑癌治疗的新方案。

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.