Optical Imaging of Chemotherapy for Brain Tumors

描述(申请人提供)：尽管在病理机制的理解方面取得了巨大的进步，但恶性脑瘤的结果仍然黯淡。在一定程度上，失败可以归因于无法将有效和足够浓度的化疗药物输送到肿瘤部位。脑组织独特的解剖、生理和功能特性给药物输送带来了巨大的挑战。为了更好地靶向肿瘤组织，已经开发了各种化疗药物配方，其中包括：传统脂质体、空间稳定(隐形)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。为了达到最佳效果，这些智能药物制剂必须局部注射，然而，由于缺乏实时测量组织药物浓度的方法，动脉内(IA)药物向脑内传递的动力学尚不清楚。我们的总体目标是在实时、组织非侵入性光学方法的指导下，改善脂质体制剂化疗药物的IA递送，以监测药物浓度。我们提出的光学技术还可以同时评估血脑屏障的通透性。我们将鉴定脂质体的性质并确定其IA的最佳给药方法。我们将开发计算模型，帮助将这一临床前研究转化为人类脑瘤的新疗法。IA注射通过高容量/高亲和力的清除机制绕过了脂质体和纳米粒快速清除的重大问题-主要是在网状内皮系统中，自20世纪70年代末S以来，该系统阻碍了基于脂质体的有效疗法的发展。IA传递的改进意味着广泛的方法，这些方法已经被全身给药弄得无效-现在可能被用于治疗恶性脑肿瘤。在常规全身给药后效用有限的一系列脂质体组合物(或生物物理/生物药学特性)可通过改进的IA注射使用。使用米托蒽醌作为化疗药物的原型，我们的目标是利用光学工具更好地了解IA药物传递的超快和复杂的动力学，使用更好的注射技术和智能处方的组合来改善局部药物传递，并在实验性的兔脑肿瘤模型中证明提高存活率。这一多中心(哥伦比亚大学、波士顿大学和布法罗大学)应用的双重目标是确定改进的脑肿瘤药物输送方法，同时开发能够跟踪组织浓度、血流和毛细血管通透性参数的集成光学系统，以及破坏血脑屏障的更安全的技术。虽然这个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应用于治疗脑癌以外的领域。

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.