Abstract 5145: Demystification of obstacles encountered using convection enhanced delivery in preclinical models of diffuse intrinsic pontine glioma
Authors: Gittens Jamila S. , Yadavilli Sridevi , Lin Michael , Panditharatna Eshini , Magge Suresh N. , Packer Roger J. , Nazarian Javad 
Published: July 2017

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a pediatric brain tumor that arises in the pons of the brainstem. The vital location of the tumor and the presence of the impermeable blood brain barrier (BBB) make treatments ineffective and leads to a high mortality rate of DIPG patients. Convection enhanced delivery (CED) is a promising drug delivery method because of its ability to bypass the BBB that is currently being investigated to deliver therapeutic agents directly to brain tumors. Nonetheless, clinical trials investigating the use of CED to treat patients have not shown prolonged patient survival. Previous studies have determined poor distribution in clinical studies due to reflux or back flow. Additionally, by analyzing the H&E and Ki67 stained brain sections of a DIPG patient that underwent CED, we determined that areas of radiation-induced necrosis within the tumor were a possible reason for treatment failure. In this study, we intend to optimize CED in orthotopic murine model of DIPG. Specifically, we have tested the ideal volume and rate of injection, as well as using the combined approach of using CED and radiation. Ideal injection rate was established by assessing infusion profiles in agarose brain phantoms using various needles, which resulted in the injection rate of 0.3ul/min producing the least back flow. Next, the ideal injection rate and volumes were tested in vivo by injecting non-tumor bearing mice with trypan blue. To assess the infusion rate, brain sections were analyzed at necropsy to determine distributions of the injected dye. To investigate accumulation of CED-mediated payload in necrotic sites, tumor bearing mice were exposed to radiation and then injected with the fluorescent dye, DiI. Formalin fixed brain sections were stained with DAPI and fluorescent images were taken. The results of this study indicate that a rate of 0.5ul/min results in a significantly larger distribution area compared to the 0.3ul/min injection rate (50.71 ± 4.84 compared to 30.47 ± 1.18, p=0.0462). Fluorescent images of brain sections of mice injected with DiI indicated the accumulation of dye in areas where there were no live cells, supporting the assumption that drug injections may be retreating to necrotic pockets and thus preventing equal distribution of the drug in the tumor. Ongoing studies include investigating the survival benefits of using CED to deliver therapeutic agents in tumor-bearing mice. Understanding the obstacles of convection enhanced delivery in murine models can help establish better treatment regimens and devices for patients and provide better preclinical models for drug testing.
Citation Format: Jamila S. Gittens, Sridevi Yadavilli, Michael Lin, Eshini Panditharatna, Suresh N. Magge, Roger J. Packer, Javad Nazarian. Demystification of obstacles encountered using convection enhanced delivery in preclinical models of diffuse intrinsic pontine glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5145. doi:10.1158/1538-7445.AM2017-5145