Synthesis of a nickel tetracarboranylphenylporphyrin for boron neutron-capture therapy: Biodistribution and toxicity in tumor-bearing mice

Abstract

BNCT using 'OB-enriched BPA as the neutron-capture agent is being investigated at Brookhaven National Laboratory for the post-operative treatment of human cerebral GBM (Coderre et al., 1996). This therapy is based on the selective accumulation of 1°B carriers such as BPA in tumors and the subsequent production of microscopically localized high linearenergy-transfer radiation from capture of thermalized neutrons by 1°B in the I0B(n,a)'Li reaction. For BNCT of malignant brain tumors, it is crucial that there be robust uptake of boron in tumor relative to normal tissues within the neutronirradiated target volume. Fairchild and Bond (1985) estimated that major advances in BNCT should be possible if ratios of 1°B concentrations in tumor (B1J to those in normal tissue were at least 5. In BNCT of a brain tumor, the dose to normal endothelium is most critical (Slatkin, 1991) and is proportional to two-thirds of the brain parenchymal boron concentration (Bbr) plus one-third of the blood boron concentration (Bbl) (Kitao, 1975). Thus, a major improvement in BNCT would require that B,,/(0.67Bhr + 0.33Bbl) > 5 or Bru/Bbl > 3.33(&,/ Bbl) + 1.67. Therefore, to protect non-edematous zones of the brain using an agent for closed-skull BNCT that respects the blood-brain barrier, Bb, should be close to 0 so that Btu/Bbl > 1.67. However, to protect edematous zones of the brain around a GBM tumor where Bbr/Bbl is nearly 1, Blu/Bbl > 5.We have synthesized a nickel tetraphenylporphyrin, NiTCP, that contains 4 carborane moieties, making the compound 22.3% boron (natural isotopic abundance) by weight. Its biodistribution and toxicity were studied in mice bearing an S.C. transplanted murine tumor. Two different total doses, 160 and 244 pg NiTCP/gbw, were given to tumor-bearing mice by a scries of i.p. injections. Boron concentrations were measured in various tissues removed at necropsy. Indicators of toxicity were sought by assessing changes in body weight and by hematological, chemical and enzymatic assays of the blood. MATERIAL AND METHODS ChemistryAll reagents and solvents were purchased from Aldrich (Milwaukee, WI). IH-NMR was run on a Bruker (Billerica, MA) AM-300 spectrometer, and optical absorption spectra were obtained with a Beckman (Fullerton, CA) DU-8 spectrophotometer. Mass spectra were recorded on a Kratos (Ramsey, NJ) MS 890 instrument equipped with a Sattlefield FAB gun using a nitrobenzyl alcohol matrix at the State University of New York, Stony Brook, by Drs. R.A. Rieger and C. Iden.NiTCP (Fig. l), a non-planar carboranyl tetraphenylporphyrin containing 8 methyl acetate groups, was synthesized by a procedure used for making analogous porphyrins without carborane groups (Miura et al., 1994). In a typical preparation of NiTCP, a method (Lindsey et al., 1987) was used to cyclize 3,4-diacetic acid pyrrole dimethylester (280 mg, 1.32 mmol) (Chiusoli et al., 1989) with 3-o-carboranylmethoxybenzaldehyde (364 mg, 1.32 mmol) (Miura etal., 1990)4 by stirring them in anhydrous dichloromethane (CH;?C12] (35 ml) for 20 min at room te...

In vivo studies of Gd‐DTPA‐monoclonal antibody and gd‐porphyrins: Potential magnetic resonance imaging contrast agents for melanoma

“…The amount of boron introduced into the tumor by Gd‐TCP was found to be 24 μg. This compares well with other values for related complexes (18), is sufficient for BNCT, and proves the potential application of the Gd‐TCP in the dual roles of MRI agent and boron delivery agent for BNCT.…”

Reactivation of precore mutant hepatitis B virus in chemotherapy-treated patients

“…Aside from their diagnostic use, porphyrin derivatives have also been developed as an agent for photodynamic therapy (6, 23), as a radiation sensitizer (24), and as an agent for neutron‐capture therapy (25, 26). This study revealed that the enhancement effect detected on the MR images was well correlated with the biodistribution of the HOP‐8P (Figs.…”

Tumour enhancement with newly developed Mn-metalloporphyrin (HOP-9P) in magnetic resonance imaging of mice

“…Aside from diagnostic usage, porphyrin derivatives have also been developed as an agent for photodynamic therapy (CalzavaraPinton et al, 1996;Hill et al, 1996;Kessel, 1992;Kostenich et al, 1997;Lapes et al, 1996;McIlroy et al, 1998;Nakajima et al, 1998;Shopova et al, 1994;Takemura et al, 1992;Woodburn et al, 1998), radiation sensitizer (Rowinsky 1999;Viala et al, 1999) and an agent for neutron capture therapy (Matsumura et al, 1999;Miura et al, 1996;Shibata et al, 1998). This study revealed that the enhancement effect of the tumour demonstrated on the MR images was well correlated with the biodistribution of the HOP-9P (Figure 2, Table 1).…”