Permeability of the Blood-Brain Barrier to a Rhenacarborane

Abstract

The treatment of brain malignancies with boron neutron capture therapy depends on their ability to cross the blood-brain barrier (BBB). An especially promising class of boron-containing compounds is the rhenacarboranes that, if able to cross the BBB, could act as delivery vehicles as well as a source of boron. Here, we examined the ability of the 3-NO-3,3-2 -(2,2Ј-N 2 C 10 H 6 (Me){(CH 2 ) 7 131 I}-4,4Ј)-closo-3,1,2-ReC 2 B 9 H 11 (rhenacarborane) labeled with iodine-131 to be taken up into the bloodstream after subcutaneous administration and to cross the BBB. The 131 I-rhenacarborane was quickly absorbed from the injection site and reached a steady state in arterial serum of 2.59%/ml of the administered dose. Between 73 and 95% of the radioactivity in serum 6 h after administration represented intact 131 I-rhenacarborane. Its octanol/buffer partition coefficient was 1.74, showing it to be lipophilic. Tissue/serum ratios for brain, lung, and liver showed classic patterns for a lipidsoluble substance with high levels immediately achieved and rapid redistribution. For brain, a steady state of approximately 0.107% of the administered dose/gram-brain was rapidly reached, and 71% of the radioactivity in brain 6 h after subcutaneous administration represented intact 131 I-rhenacarborane. Steady-state values were 1.53 and 0.89% of the injected dose per gram for lung and liver, respectively. 131 I-Rhenacarborane was quickly effluxed from brain by a nonsaturable system after its injection into the lateral ventricle of the brain. In conclusion, these results show that a rhenacarborane was enzymatically resistant and able to cross the BBB by transmembrane diffusion and accumulate in brain in substantial amounts. This supports their use as therapeutic agents for targeting the central nervous system. Boron neutron capture therapy (BNCT) holds promise as a treatment for various malignancies of the central nervous system (CNS). For example, the method is currently used as an adjunct to surgery in the treatment of glioblastoma multiforme (Yamamoto et al., 2008). The effectiveness of BNCT relies on its ability to eradicate micrometastases in the brain that are otherwise undetectable by surgical methods (Pisarev et al., 2007). BNCT uses an isotope of boron to deliver targeted bursts of radiation to malignant cells. Upon uptake into the cells, boron-10 is externally irradiated with neutrons and becomes unstable, decaying to lithium and releasing a high-energy ␣ particle. A further advantage is that boron can form polyhedral clusters that allow for the delivery of multiple boron-10 atoms in a single molecule. The potency of treatment as well as the selectivity of neutron captures by the boron atom makes this option an encouraging alternative to other more toxic therapies.An especially promising class of boron compounds are the closo-3,1,2-ReC 2 B 9 rhenacarboranes, which consist of nidoicosahedral carborane cages 5 -bonded to the d-block transition element rhenium (Hawthorne, 1968;Blandford et al., 1998;Fischer et al., 200...

2,2′‐Bipyridine‐Modified Tamoxifen: A Versatile Vector for Molybdacarboranes

“…One advantage of half‐sandwich metallacarboranes is the incorporation of biologically relevant ligands in the coordination sphere of the metals, as in the present study, where [3‐(2,2′‐bipyridine‐κ 2 N , N ′)‐3‐(CO) 2 ‐ closo ‐3,1,2‐MoC 2 B 9 H 11 ] ( i ) was equipped with a vector molecule which was inspired by the well‐known tamoxifen. Further examples were reported by Causey et al., Hawkins et al., Pruitt et al . and Louie et al .…”

“…[4] One advantage of half-sandwich metallacarboranes is the incorporation of biologically relevant ligands in the coordination sphere of the metals, as in the present study, where [3-(2,2'bipyridine-k 2 N,N')-3-(CO) 2 -closo-3,1,2-MoC 2 B 9 H 11 ] (i) was equipped with a vector molecule which was inspired by the well-known tamoxifen. Further examples were reported by Causey et al, [10] Hawkins et al, [11] Pruitt et al [12] and Louie et al [13] who used stable and hydrophobic rhenacarboranes including the [Re(L)(CO) 2 ] fragment (L = 2,2'-bipyridine derivative or [NO] + ) as imaging agents.…”

Ameliorative Properties of Boronic Compounds in In Vitro and In Vivo Models of Alzheimer’s Disease

“…After 2 months of oral gavage (0.5 mg/kg), we found a significant decrease in Aβ plaque burden in several brain areas, such as the cortex, and the CA1, CA3, and DG regions of hippocampus ( Figure 3 ), suggesting that the TBSA crosses the blood brain barrier, permeates into the brain tissue, and inhibits amyloidogenic pathways, either by reducing Aβ production or preventing its aggregation. Although we did not measure the boron levels in the TBSA-treated mice brain tissue, previous studies have shown that boron compounds can cross the blood brain barrier and penetrate the brain tissue [ 32 ] and decrease inflammatory responses [ 33 ]. Combined with previous research showing efficacy of boron compounds in the brain [ 3 , 4 , 5 , 6 , 7 ], our findings of the efficacy of TBSA in the present study strongly suggest that TBSA is sufficiently permeable to brain tissue to reduce AD pathology.…”

Synthesis and functionalization of nitrosyl rhenacarboranes towards their use as drug delivery vehicles

“…A C C E P T E D ACCEPTED MANUSCRIPT 4 In preliminary studies with the 131 I-labeled prototypical rhenacarborane complex 3,3-κ 2 -(2,2'-N 2 C 10 H 6 (Me){(CH 2 ) 7 131 I}-4,4')-closo-3,1,2-ReC 2 B 9 H 11 ] (2), we have demonstrated the ability of a rhenacarborane to penetrate the BBB [9]. We determined rapid uptake and equilibrium phases with a steady state of ca.…”