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.
Project 2 Narrative Malignant tumors of the central nervous system are the third leading cause of cancer-related deaths in adolescents and adults and the leading cause of cancer death in children with a mean survival time of 15 months and a mortality rate exceeding 95%. Despite the promise of convection-enhanced delivery in which a chemotherapeutic drug is directly infused in the brain, this method has demonstrated only minor improvements in patient survival due to inability to infuse drug to the primary tumor and infiltrative cells. This project will optimize and evaluate a novel catheter and control system which will enable the first opportunity to effectively treat malignant brain tumors by broadly delivering drug over the tumor and infiltrative cells through unique features of arborization, photothermal activation, and image guidance.
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