In vitro and in vivo evaluation of radiolabeled methyl N-[5-(3'-halobenzoyl)-1H-benzimidazol-2-yl]carbamate for cancer radiotherapy.
The role of theranostics in cancer management is growing so is the selection of vectors used to deliver these modalities to cancer cells. We describe biological evaluation of a novel theranostic agent targeted to microtubules. Methyl N-[5-(3'-[131 I]iodobenzoyl)-1H-benzimidazol-2-yl]carbamate (1) and methyl N-[5-(3'-[125 I]iodobenzoyl)-1H-benzimidazol-2-yl]carbamate (2) were synthesized from a common precursor 3'-stannylated derivative (4). Antiproliferative effects and radiotoxicity of 131 I-labeled β-particle emitting 1 were examined in vitro in human neuroblastoma and glioblastoma cells lines. The therapeutic potential of 1 was also examined in a subcutaneous mouse model of human glioblastoma U-87 MG. Compound 1 at the extracellular radioactive concentration of 0.35 MBq/mL, easily achievable in vivo, kills >90% of neuroblastoma cells and >60% glioblastoma cells as measured in a clonogenic assay. D10 doses established for 1 indicate that as few as 3,000 decays are sufficient to kill 90% of BE(2)-C cells. Even U-87 MG cells, the least sensitive of the tested cell lines, require <20,000 decays of intracellular 131 I to reduce number of clonogenic cells by 90%. Biodistribution studies of 2 delivered either intratumorally or intraperitoneally show a similar tissue distribution for both routes of the drug administration. The whole body clearance half-lives were on average 6 hr. Intratumor administration of 1 produces significant tumor growth delay. After a single dose of 8.4 ± 0.3 MBq of compound 1, the tumor doubling times were 3.2 ± 0.1 and 7.9 ± 0.6 days in control and treated mice, respectively. Methyl N-[5-(3'-radiohalobenzoyl)-1H-benzimidazol-2-yl]carbamates have properties compatible with a theranostic approach to cancer management.
['Kortylewicz|Zbigniew P|ZP|', 'Coulter|Don W|DW|', 'Baranowska-Kortylewicz|Janina|J|0000-0002-2254-0791']
D000818:Animals D001932:Brain Neoplasms D002219:Carbamates D045744:Cell Line, Tumor D049109:Cell Proliferation D002470:Cell Survival D005909:Glioblastoma D006801:Humans D007274:Injections, Intraperitoneal D007457:Iodine Radioisotopes D051379:Mice D000068936:Theranostic Nanomedicine D014018:Tissue Distribution D016896:Treatment Outcome D023041:Xenograft Model Antitumor Assays
theranostics microtubules β-particles benzimidazole carbamates cancer therapy