Long-term safety of combined intracerebral delivery of free gadolinium and targeted chemotherapeutic agent PRX321.
OBJECTIVES: While convection enhanced delivery (CED) is an effective delivery method that bypasses the blood-brain barrier, its utility is limited by infusate leakage due to catheter misplacement. Therefore, it is critical to evaluate drug distribution during CED infusion. Gadolinium conjugated to diethylenetriamine penta-acetic acid (Gd-DTPA) is a common, readily available MRI contrast agent, which may be able to predict and actively monitor drug distribution. In this study, we assess the long-term safety and toxicity of intracerebrally infused Gd-DTPA along with an experimental targeted agent PRX321. METHODS: Fifty-four immunocompetent rats were implanted with intracerebral cannulas linked to subcutaneously placed osmotic pumps. After pump implantation, the rats were randomized into six groups of nine rats each in order to assess the toxicities of six different concentrations of human serum albumin (HSA) with and without Gd-DTPA and PRX321. The rats were monitored clinically for 6 weeks before they were autopsied and assessed for histological toxicity to their central nervous system (CNS). RESULTS: There was one unexplained death in a group infusing low concentration HSA, Gd-DTPA and PRX321. Upon microscopic examination of the CNS in that animal, no unexpected histological toxicity was found. Additionally, there were no signs of clinical or histological toxicity in any of the remaining rats, which all survived until the end of the 6 week observation period. DISCUSSION: Free Gd-DTPA can be safely infused via CED in a pre-clinical animal model. Future studies should include its use in predicting and actively monitoring CED drug infusions in early phase human clinical trials.
Ding, D; Kanaly, CW; Cummings, TJ; Herndon, JE; Raghavan, R; Sampson, JH
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