Convection-Enhanced Thermo-chemotherapy Catheter System (CETCS)

对流增强输送（CED）是一种立体定向引导的小口径导管， 通过颅骨和硬脑膜插入，有希望改善药物输送，允许局部输注 治疗药物直接进入脑实质并有效地绕过血脑屏障 （BBB）。我们构思了对流增强热化疗导管系统（CETCS）的想法， 这将广泛地将治疗递送到原发性肿瘤部位，如胶质母细胞瘤（GBM）和肿瘤浸润性 细胞（延伸~2厘米）具有高覆盖体积，从而减少复发的可能性。我们有 发明了一种新型的CETCS，其由导管外壳7组成，导管外壳7使光纤显微针分叉， 激光能量的同时局部输送和利用可溶性药剂对目标组织的治疗。微- 针头由光学透明的中空玻璃（直径约300微米）制成，可单独引导 由神经外科医生用遥控系统将其植入大脑中的目标位置，并用MRI进行可视化。 我们假设具有额外光热激活的分支导管将提供更广泛的 与目前使用的防回流导管相比，脑组织中的输注物的体积分布。在 在P01提案的项目2中，我们将提出三个具体目标。在目标1中，我们将优化和评估 使用共定位的同时光热激活的树枝状导管，用于广泛分布 脑组织中的输注物（幻影组织和脑组织）。我们将展示在广度上的显著增加 与市售产品相比，在具有光热活化的树状导管中的输注物分散（> 7倍） 导尿管在目标2中，我们将集成和评估远程控制系统CETCS，以使导管 基于反馈的光剂量和药物灌注的控制 实时核磁共振成像我们的目标是证明集成系统（CETCS）可以实现更大的输注 药物靶体积覆盖率（> 20%肿瘤+ 2 cm肿瘤边缘覆盖率），与 用固定导管实现。在目标3中，我们将通过CETCS评估药物分布和疗效，用于治疗 自发性犬GBM。我们的目标是显示CETCS可以广泛地饱和肿瘤和边缘（> 20%）， QUAD-CTX+Gd-alb（项目1中生成的药物偶联物）治疗自发性 GBM。其次，我们的目标是证明肿瘤消退（总直径减少> 50%），并且 改善这些患者的Karnofsky行为量表评分（与基线相比）。这种新方法 将使用两种创新的CETCS对脑肿瘤进行局部区域治疗 在我们的P01项目1中产生的分子靶向抗癌剂。此外，它将用于交付 工程化的干细胞在项目4中产生，以便透化BBB。我们设想我们的CETCS 将大大改善局部区域的药物输送，从而在GBM患者中获得更好的结果。

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.