Cereport® (RMP-7) increases carboplatin levels in brain tumors after pretreatment with dexamethasone

Abstract

Accumulating evidence suggests that dexamethasone might decrease permeability of the blood-brain tumor barrier, further limiting the delivery of agents into brain tumors. The bradykinin B2 receptor agonist, Cereport (RMP-7), selectively increases permeability of the vasculature supplying brain tumors in both animal models and humans. The present study was conducted to characterize the effects of dexamethasone on the blood-brain tumor barrier and its potential interaction with Cereport's ability to enhance penetration of radiolabeled carboplatin. Dexamethasone (1.5 mg/kg/day, twice a day) was given to RG2 glioma-bearing rats via oral gavage for 3 consecutive days. After treatment, animals received a 15-min intracarotid infusion of Cereport (4.5 micrograms/kg) and a bolus of [14C]carboplatin. The levels of [14C]carboplatin (nCi/g) in the tumor and nontumor regions were determined at 1, 14, or 24 h after the last dose of dexamethasone. Dexamethasone, alone, significantly decreased the levels of radiolabeled carboplatin permeating the tumor (19%), although there were no significant differences between any of the time points examined. Cereport administration significantly increased levels of carboplatin in the tumor, independent of whether or not dexamethasone was given (46% with and 49% without). Although the relative effects of Cereport on tumor carboplatin levels were not affected by dexamethasone, the absolute levels achieved with Cereport were modestly reduced (44 nCi/g versus 55.5 nCi/g of [14C]carboplatin, with and without dexamethasone, respectively). Thus, while the data support the use of Cereport as adjunctive therapy in the treatment of glioma patients, they also warn that the use of dexamethasone may reduce delivery of chemotherapeutic agents to brain tumors, even when special pharmacologic measures are employed to enhance delivery.

Recent progress in tight junction modulation for improving bioavailability

“…Because of its hydrophilic properties, it would benefit from combination with labradimil [56]. Therefore, this combination was tested to create a better pharmacokinetic profile and reduce the side effects of carboplatin (Table 1).…”

Brain Delivery of Drug and MRI Contrast Agent: Detection and Quantitative Determination of Brain Deposition of CPT-Glu Using LC–MS/MS and Gd-DTPA Using Magnetic Resonance Imaging

“…There are a few non-invasive strategies to improve brain delivery of drugs, which include the use of high osmotic mannitol 23-25 and bradykinin receptor agonists such as Cereport ™ . 26 One potential drawback of using a high concentration of mannitol to disrupt the BBB is associated with a long recovery period that increases the risk of infection, neurotoxicity, and inflammation in the brain. 24 Although bradykinin agonists resulted in shorter recovery times, the clinical utility of these analogs was ineffective.…”

Effective treatment of glioblastoma requires crossing the blood–brain barrier and targeting tumors including cancer stem cells: The promise of nanomedicine

“…Strategies have been proposed for CNS drug delivery involving mechanical or chemical disruptions of the BBB by MRI-guided focused ultrasound [41], convection enhanced diffusion [42], microdialysis catheter [43], hyperosmotic agents [44], hydrophilic surfactants such as polysorbate 80 [45,46], or chemical modulators of blood vessels [47]. Clearly, a general disruption of the BBB to allow therapeutic agents to enter the brain would compromise the normal protective role of the BBB.…”