Use of CereportTM (RMP-7) to Increase Delivery of Carboplatin to Gliomas: Insight and Parameters for Intracarotid Infusion Via a Single-Lumen Cannula

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Abstract
CereportTM (RMP-7) is a selective bradykinin B receptor ago2 nist that increases the permeability of the blood-brain tumor barrier (BBTB) to increase delivery of chemotherapeutic agents to brain tumors. Two experiments were performed in a rat glioma model to evaluate and refine intra-arterial dosing parameters using Cereport. The first experiment investigated whether desensitization or tachyphylaxis to the effects of Cereport on vascular permeability can be avoided during the course of super-selective, intracarotid drug administration. Super-selective administration may be used when two different arterial branches supply a single tumor in order to ensure that enough of the drug reaches the entire tumor. In this instance, the chemotherapeutic drug is infused separately and sequentially into each branch. This procedure necessitates an infusion duration that is sufficiently long to raise concerns that tachyphylaxis to B2 receptor stimulation might occur during the Cereport infusion. To study this possibility, relative concentrations, timing, and duration of Cereport were selected to mimic those encountered during super-selective drug administration.Cereport increased the uptake of carboplatin into gliomas to a similar extent as that achieved under more conventional intra-arterial procedures, suggesting that significant tachyphylaxis was not induced. A second experiment tested several alternative dosing paradigms to determine whether a single-lumen cannula could be employed when using Cereport to enhance delivery of carboplatin into a cerebral artery. Mixing carboplatin and Cereport prior to intracarotid infusion through a single-lumen cannula did not reduce the ability of Cereport to increase the permeability of the BBTB. Equivalent effects in carboplatin uptake into a tumor were also seen when the two drugs were co-infused and their infusions sequentially alternated. Finally, Cereport pretreatment did not offer any advantage, indicating very rapid effects of Cereport on the BBTB. Collectively, these data (1) establish a range of dosing paradigms wherein Cereport significantly increases delivery of chemotherapeutic drugs via a single-lumen, arterial cannula, (2) define some of the parameters required to do so successfully, and (3) further elucidate the pharmacodynamic effects of bradykinin B2 receptor-mediated changes in permeability of the BBTB.