Introduction: Diffuse intrinsic pontine gliomas (DIPG) are fatal, high-grade tumors arising in the pons of children. Convection-enhanced delivery (CED) is a method for direct delivery of agents into tumor using a hydrostatic pressure gradient, bypassing the blood brain barrier. By using an osmotic pump filled with chemotherapeutic agents, CED can achieve effective long-term continuous administration. Our objective is to optimize the technique for placement of the CED cannula carrying an osmotic pump into the tumor of preclinical DIPG mouse models.
Methods: An osmotic pump with a capacity to infuse 100µl over 4 weeks was used. Two cohorts of mice were selected. The first cohort assessed the feasibility of implantation into the pons of non-tumor bearing mice. The second cohort was stereotactically transplanted with murine DIPG cells and allowed to develop pontine tumors before cannula implantation. A cannula was stereotactically implanted into the pons in both cohorts and connected to a subcutaneously placed osmotic pump loaded with Evans blue dye (EBD) and DII. EBD/DII signal was evaluated to assess delivery to targeted site and distribution.
Results: We have established a methodology for surgical implantation of a cannula attached to an osmotic pump into mouse pons, and assessed the distribution of EBD/DII in healthy as well as tumor bearing murine models of DIPG. We first show that CED cannula installation does not affect the overall survival of the mouse. Necropsy studies indicated the exact delivery site by comparing fluorescent signal with histological profiles.
Conclusions: We conclude that surgical implantation of a cannula into the pons of healthy or DIPG murine models is feasible and provides an opportunity for targeted drug testing. We show that precise pontine delivery of cargo (dye) has optimal distribution within the pons, tissue integrity is not compromised, and more importantly, does not result in lower overall survival.
Patient Care: Finding therapeutics that cross the blood brain barrier (BBB) is a major obstacle in effective treatment of children with diffuse intrinsic pontine gliomas (DIPG). This research shows successful implantation of osmotic pump with cannula into the mouse pons in tumor bearing mice, thus bypassing the BBB. This DIPG mouse model receiving CED using an osmotic pump can be used to study tumor response to direct, long-term, continuous administration of therapeutic agents. This technique will serve as a platform for rapid assessment of tumor response to therapeutic agents. An effective agent can then be translated in clinical setting through upcoming clinical trials.
Additionally, patient biopsy tissue can be obtained at Children’s National Hospital that can be tested for genetic profiles and specific mutations. This tissue can be used for implantation into mouse xenografts. Using CED, therapeutic agents can be tested that directly target these patients’ specific mutations. In this way, the ideal therapeutic agent can be identified for each individual patient. Patients can be offered personalized therapy based on their individual genetic mutations of their tumor.
Learning Objectives: 1. Osmotic pump cannula installation into pons itself is not associated with any observed side effects and does not affect the overall survival of the mouse
2. An osmotic pump cannula can be stereotactically placed into a mouse pontine tumor in a DIPG allograft
3. This DIPG mouse model receiving CED using an osmotic pump can be used to study tumor response to direct, long-term, continuous administration of therapeutic agents.