Convection-Enhanced Thermo-chemotherapy Catheter System (CETCS)

对流增强输送(CED)，一种立体定向引导的小口径导管 植入头骨和硬脑膜，有望改善药物输送，允许局部输注 治疗药物直接进入脑实质，有效绕过血脑屏障 (Bbb)。我们设想了一种对流增强型热化疗导管系统(CETCS)， 它将广泛地向原发肿瘤部位提供治疗，如胶质母细胞瘤(GBM)和肿瘤浸润性 细胞(延伸~2厘米)覆盖体积大，从而降低复发的可能性。我们有 发明了一种由导管外壳7个树枝状光纤微针组成的新型CETCS，它允许 同时，局部输送激光能量，并使用可溶性试剂治疗目标组织。微型-- 针由光学透明的中空玻璃(直径约300m)制成，可单独引导 由神经外科医生用远程控制系统进入大脑中的目标位置，并通过核磁共振成像进行可视化。 我们假设附加光热激活的树枝状导管将提供更广泛的 脑组织中输液的体积分布与目前使用的防止返流导管的比较。在……里面 在我们P01提案的这个项目2中，我们将解决三个具体目标。在目标1中，我们将进行优化和评估 一种使用共同定位、同时光热激活的树枝状导管，用于广泛分布 注入脑组织(幻影和移植组织)。我们将展示在广度上的显著增长 使用光热激活的树枝状导管中输液分散性的比较(&gt；7倍) 导管。在目标2中，我们将集成和评估远程控制系统CETCS，以启用导管 定位和微针分枝，基于反馈的光量和药物灌流控制 来自实时核磁共振。我们的目标是证明集成系统(CETCS)可以实现更大的输液 用药物覆盖靶体积(&gt；20%肿瘤+2 cm肿瘤边缘覆盖)，与覆盖相比 通过固定的导尿管实现。在目标3中，我们将使用CETCS评估药物分布和疗效 自发性的犬类GBM。我们的目标是证明CETCS可以广泛地饱和肿瘤和边缘(&gt；20% 4-CTX+Gd-Alb(一种在项目1中产生的药物结合物)治疗自发性犬病 GBM。其次，我们的目标是证明肿瘤消退(总积直径减少50%)和 这些患者的Karnofsky绩效量表评分(与基线相比)有所改善。这一新方法 使用CETCS对脑肿瘤进行局部治疗的测试将使用两种类型的创新 我们P01项目1中产生的分子靶向抗癌药物。此外，它将被用来交付 在项目4中产生了工程干细胞，以使血脑屏障通透性。我们设想我们的CETCS 将极大地改善药物的区域递送，从而为GBM患者带来更好的结果。

Convection-enhanced delivery (CED), a modality in which a stereotactic-guided small-caliber catheter is inserted through the skull and dura, has promisingly improved drug delivery permitting local infusion of therapeutic drugs directly into the brain parenchyma and effectively circumventing the blood-brain barrier (BBB). We conceived the idea of a Convection-Enhanced Thermo-chemotherapy Catheter System (CETCS), which will deliver therapies broadly to the primary tumor site, like glioblastoma (GBM) and tumor infiltrative cells (extending ~2 cm) with high coverage volume, thereby diminishing the likelihood of recurrence. We have invented a novel CETCS consisting of a catheter housing 7 arborizing fiber optic micro-needles that allows simultaneous, localized delivery of laser energy and therapy with soluble agents to targeted tissue. The micro- needles are made of optically transparent hollow glass (~300 m in diameter), which can be individually guided by a neurosurgeon with a remote control system into the target position in the brain and visualized with MRI. We hypothesize that the arborizing catheter with additional photothermal activation will provide more broad volumetric distribution of infusates in brain tissue compared to a currently used reflux-preventing catheter. In this Project 2 of our P01 proposal, we will address three Specific Aims. In Aim 1, we will optimize and evaluate an arborizing catheter using co-localized, simultaneous photothermal activation for broad distribution of infusates in brain tissue (phantoms and explanted tissue). We will demonstrate significant increase in breadth of infusate dispersion in arborizing catheters with photothermal activation (> 7- fold) compared to a commercial catheter. In Aim 2, we will Integrate and evaluate a remote control system, CETCS, to enable catheter positioning and microneedle arborization, and control of light dosage and drug perfusion based on feedback from real-time MRI. We aim to demonstrate the integrated system (CETCS) can achieve greater infusion coverage of target volume with drug (> 20% tumor + 2 cm tumor margin coverage), compared to the coverage achieved with a fixed catheter. In Aim 3, we will evaluate drug distribution and efficacy by CETCS for treating spontaneous canine GBMs. We aim to show CETCS can broadly saturate tumor and margins (> 20% coverage) with QUAD-CTX+Gd-alb (a drug conjugate generated in Project 1) in canines with spontaneous GBM. Secondly, we aim to demonstrate tumor regression (> 50% decrease in sum product diameters) and improved Karnofsky Performance Scale scores (compared to base-line) in these patients. This novel approach to loco-regional delivery of treatment to brain tumors using CETCS will be tested using two types of innovative molecularly targeted anti-cancer agents generated in Project 1 of our P01. Moreover, it will be used to deliver engineered stem cells generated in Project 4 in order to permeabilize the BBB. We envision that our CETCS will greatly improve loco-regional deliveries of drugs resulting in better outcomes in patients with GBM.