In vitro and in vivo evaluation of radiolabeled methyl N-[5-(3′-halobenzoyl)-1H-benzimidazol-2-yl]carbamate for cancer radiotherapy

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Abstract

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′-[131I]iodobenzoyl)-1H-benzimidazol-2-yl]carbamate (1) and methyl N-[5-(3′-[125I]iodobenzoyl)-1H-benzimidazol-2-yl]carbamate (2) were synthesized from a common precursor 3′-stannylated derivative (4). Antiproliferative effects and radiotoxicity of 131I-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 131I 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.

Original languageEnglish (US)
JournalDrug Development Research
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Carbamates
Radiotherapy
Glioblastoma
Neoplasms
Neuroblastoma
Drug Administration Routes
Cell Line
Tissue Distribution
Microtubules
Cell Count
In Vitro Techniques
Growth
Theranostic Nanomedicine

Keywords

  • benzimidazole carbamates
  • cancer therapy
  • microtubules
  • theranostics
  • β-particles

ASJC Scopus subject areas

  • Drug Discovery

Cite this

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title = "In vitro and in vivo evaluation of radiolabeled methyl N-[5-(3′-halobenzoyl)-1H-benzimidazol-2-yl]carbamate for cancer radiotherapy",
abstract = "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′-[131I]iodobenzoyl)-1H-benzimidazol-2-yl]carbamate (1) and methyl N-[5-(3′-[125I]iodobenzoyl)-1H-benzimidazol-2-yl]carbamate (2) were synthesized from a common precursor 3′-stannylated derivative (4). Antiproliferative effects and radiotoxicity of 131I-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 131I 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.",
keywords = "benzimidazole carbamates, cancer therapy, microtubules, theranostics, β-particles",
author = "Kortylewicz, {Zbigniew P.} and Coulter, {Don W.} and Janina Baranowska-Kortylewicz",
year = "2019",
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T1 - In vitro and in vivo evaluation of radiolabeled methyl N-[5-(3′-halobenzoyl)-1H-benzimidazol-2-yl]carbamate for cancer radiotherapy

AU - Kortylewicz, Zbigniew P.

AU - Coulter, Don W.

AU - Baranowska-Kortylewicz, Janina

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N2 - 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′-[131I]iodobenzoyl)-1H-benzimidazol-2-yl]carbamate (1) and methyl N-[5-(3′-[125I]iodobenzoyl)-1H-benzimidazol-2-yl]carbamate (2) were synthesized from a common precursor 3′-stannylated derivative (4). Antiproliferative effects and radiotoxicity of 131I-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 131I 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.

AB - 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′-[131I]iodobenzoyl)-1H-benzimidazol-2-yl]carbamate (1) and methyl N-[5-(3′-[125I]iodobenzoyl)-1H-benzimidazol-2-yl]carbamate (2) were synthesized from a common precursor 3′-stannylated derivative (4). Antiproliferative effects and radiotoxicity of 131I-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 131I 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.

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