Optical Imaging of Chemotherapy for Brain Tumors

描述（由申请人提供）：尽管在病理机制的理解方面取得了巨大进展，但恶性脑肿瘤的结局仍然暗淡。在某种程度上，失败可归因于无法将有效和足够浓度的化疗药物递送至肿瘤部位。脑组织独特的解剖学、生理学和功能特性对药物递送提出了巨大的挑战。已经开发了多种化疗药物制剂以更好地靶向肿瘤组织，这些制剂包括：常规脂质体、空间稳定（Stealth）脂质体、免疫脂质体、可编程融合载体、纳米颗粒和磁性纳米颗粒等。为了获得最佳益处，这些智能药物制剂必须局部注射，然而，由于缺乏真实的时间测量组织药物浓度的方法，动脉内（IA）药物递送到大脑的动力学尚不清楚。我们的总体目标是改善脂质体制剂化疗药物的IA递送，通过实时组织非侵入性光学方法监测药物浓度。我们提出的光学技术也允许同时评估血脑屏障通透性。我们将确定脂质体的性质，并确定其IA递送的最佳方法。我们将开发计算模型，帮助将这项临床前研究转化为人类脑肿瘤的新疗法。IA注射避开了脂质体和纳米颗粒通过高容量/高亲和力清除机制快速清除的非常重要的问题-主要是在网状内皮系统中，该网状内皮系统自20世纪70年代后期以来一直阻止有效的基于脂质体的治疗剂的开发。改善的IA递送意味着广泛的方法，这些方法通过全身给药已经变得无效，现在可以用于治疗恶性脑肿瘤。常规全身给药后效用有限的整个范围的脂质体组合物（或生物物理/生物制药性质）可通过改进的IA注射来使用。使用米托蒽醌作为原型化疗药物，我们的目标是利用光学工具，以更好地了解IA药物递送的超快和复杂的动力学，使用更好的注射技术和智能配方的组合，以改善区域药物递送，并证明在实验兔脑肿瘤模型中的生存率增加。该多中心（哥伦比亚大学、波士顿大学和布法罗大学）申请的双重目标是鉴定向脑/脑肿瘤递送药物的改进方法，并且同时开发能够跟踪组织浓度、血流和毛细血管渗透性参数的集成光学系统和破坏血脑屏障的更安全技术.虽然该项目的重点是化疗药物，但它将产生的技术和药代动力学见解将超越脑癌治疗的应用。 公共卫生相关性：该项目的总体目标是改善化疗药物脂质体制剂的动脉内（IA）递送，通过实时组织非侵入性光学方法监测药物浓度。我们提出的光学技术也允许同时评估血脑屏障通透性。我们将确定脂质体的性质，并确定其IA递送的最佳方法。此外，我们将开发计算模型，帮助将这项临床前研究转化为人类脑肿瘤的新疗法。

DESCRIPTION (provided by applicant): Despite enormous advances in understanding of the pathological mechanisms, the outcome of malignant brain tumors remains bleak. In part, the failure can be attributed to the inability to deliver effective and sufficient concentrations of chemotherapeutic drugs to the tumor site. The unique anatomical, physiological, and functional characteristics of brain tissue pose enormous challenges to drug delivery. A variety of formulations of chemotherapeutic drugs have been developed to better target tumor tissues, these include: conventional liposome, sterically-stabilized (Stealth) liposomes, immunoliposomes, programmable fusogenic vehicles, nanoparticles, and magnetic nanoparticles, amongst others. For optimum benefit these smart drug formulation have to be injected locally, however the kinetics of intraarterial (IA) drug delivery to the brain is ill-understood as yet due to the lack of a method to measure tissue drug concentrations in real time. Our overall goal is to improve IA delivery of liposomal formulations chemotherapeutic drugs, guided by real-time, tissue noninvasive optical methods for monitoring drug concentrations. Optical techniques we propose also permit simultaneous assessment of blood brain barrier permeability. We will identify the properties of liposomes and determine the optimum method for their IA delivery. We will develop computational models that will help translate this preclinical research to novel treatments of human brain tumors. IA injections side-step the very significant problem of rapid clearance of liposomes and nanoparticles, by the high- capacity/high affinity clearance mechanisms - mainly in the reticuloendothelial system that has prevented the development of effective liposome-based therapeutics since the late 1970's. Improved IA delivery means that a wide range of approaches, which have been rendered ineffective by systemic administration - may now be brought to bear for the treatment of malignant brain tumors. An entire range of liposomes compositions (or biophysical/biopharmaceutical properties) that were of limited utility after conventional systemic administration might be employable by improved IA injections. Using mitoxantrone as the prototype chemotherapeutic drug, our goal is to utilize optical tools to better understand the ultra-fast and complex kinetic of IA drug delivery, to use a combination of better injection techniques and smart formulations to improve regional drug delivery, and to demonstrate increased survival in experimental a rabbit brain tumor model. The twin objectives of this multi- center (Columbia University, Boston University and University of Buffalo) application are to identify improved methods of drug delivery to the brain/brain tumors, and in parallel, to develop of an integrated optical system capable of tracking tissue concentrations, blood flow, and capillary permeability parameters and safer techniques to disrupt the blood brain barrier. While this project focuses on chemotherapeutic drugs, the technologies and pharmacokinetic insights it will generate will have applications beyond treatment of brain cancers. PUBLIC HEALTH RELEVANCE: The overall goal of this project is to improve intraarterial (IA) delivery of liposomal formulations of chemotherapeutic drugs, guided by real-time, tissue noninvasive optical methods for monitoring drug concentrations. Optical techniques we propose also permit simultaneous assessment of blood brain barrier permeability. We will identify the properties of liposomes and determine the optimum method for their IA delivery. Furthermore, we will develop computational models that will help translate this preclinical research to novel treatments of human brain tumors.