Enhanced Intraarterial Delivery of Chemotherapeutic Drugs to the Brain

描述(申请人提供)：原发和继发性脑瘤是美国普通人群发病率和死亡率的主要原因。近年来，人们做出了巨大的努力，通过靶向特定的分子或跨血脑屏障的运输机制将药物输送到大脑。由于对组织药物浓度的控制不充分，以及在临床前研究中缺乏严格研究动脉内药物的快速动力学的方法，选择性地通过动脉内直接注射将化疗药物输送到脑内的尝试尚未被临床广泛接受。在过去的十年中，血管内外科取得了长足的进步。微导管的发展能够控制血流并选择性地将药物输送到大脑的特定区域，可以极大地提高动脉内药物的安全性和有效性。这项应用将表明，改变血流和团注特性可以显著提高药物在动脉内向大脑的输送。我们试图研究控制脑血流和团注结构对化疗药物经动脉输送到正常脑和肿瘤组织的影响，以最大限度地增加药物的区域沉积。我们将进一步研究脂类溶解性在促进药物向大脑输送方面的作用，特别是当局部血流量一过性(30-60秒)减少时。要了解动脉内药物在注射后浓度迅速变化的动力学，需要进行高速的现场测量。因此，到目前为止，对动脉内药物动力学的了解仅限于少数几项研究。这项应用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虚拟实时跟踪组织药物浓度(50毫秒/次测量)。我们将首次将OP测量应用于大脑。OP测量是通过头骨的内表进行的；因此，脑组织的完整性不会受到影响。总而言之，这项拟议的研究将改进向大脑输送药物的方法。这将提高动脉内化疗药物的安全性和有效性。这将导致治疗脑癌的新方案。 公共卫生相关性：拟议的研究使用新的光学技术和动脉内给药的新技术，将极大地促进对动脉内药物动力学的理解。这将导致治疗脑癌的化疗药物输送的新方案。

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.