Abstract 3789: Development of an animal model for microdialysis sampling of pons and cerebral cortex in rhesus macaques

Abstract

Abstract Background: We developed a nonhuman primate model using rhesus macaques (Macaca mulatta) to compare drug exposure in cortical brain, pontine tissue, and cerebrospinal fluid (CSF) during systemic administration of chemotherapeutic agents by microdialysis (MD), a continuous in vivo extracellular sampling technique. Pediatric diffuse intrinsic pontine gliomas are aggressive brainstem tumors that respond minimally to chemotherapy. We hypothesize that, because of its role in maintaining basic life-sustaining functions, the protective features of the pons, including the blood brain barrier and the blood-cerebrospinal fluid barrier, may further limit antitumor agents from entering the pons compared to cortical brain tissue. Methods: The coordinates and surgical approach for probe placement were determined using 3T MRI (Philips Healthcare, Best Netherlands) and OsiriX imaging software (v 3.9.4) in 4 adult male rhesus macaques (Macaca mulatta). Custom MD cannulas and probes (CMA, Solna, Sweden) were stereotactically implanted in the brain. The pontine MD cannula (34 mm) was implanted superior to the pons, and the MD probe (34 mm shaft plus 8 mm membrane) was then lowered through the cannula, into the pons. The cortical MD cannula (10 mm) was implanted in frontal cortex and a MD probe (10 mm shaft plus 8 mm membrane) was lowered through the cannula. The MD probe inlet/outlet capillaries were connected to a MD infusion pump (CMA 106, flow rate 0.3 µL/min). Retrodialysis was performed to assess in vivo recovery. A systemic intravenous (IV) drug infusion of temozolomide was then administered over 1hr. Single continuous MD samples were collected from both the pons and cortex over 4 hours with concurrent serial plasma and CSF samples (via a subarachnoid or lumbar catheter). Post-surgical MRI verification of MD probe placement was obtained in 2 of 4 animals. Verification of probe placement was obtained via gross pathology and histology in all 4 animals. Results: MRI-determined coordinates and surgical approach for MD probe placement and sample collection in the pons and cerebral cortex was successful in 3 of 4 animals. Surgical monitoring for heart and respiration rates, ETCO2 and SPO2 remained normal in all animals during probe placement and sample collection. Conclusions: MRI-determined coordinates and surgical methodologies resulted in accurate placement of a MD probe in the pons and cerebral cortex of a rhesus macaque allowing for MD sampling from these sites, in conjunction with CSF and plasma sampling, following systemic drug administration. This new animal model allows for the determination of differences in penetration of chemotherapeutic agents in pons, cerebrum, and CSF following systemic drug administration. Additionally, this model provides the foundation for a subcutaneous, semi-permanent, closed system for CNS MD probe placement and continuous sampling in rhesus macaques. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3789. doi:1538-7445.AM2012-3789