Engineered modular recombinant transporters: application of new platform for targeted radiotherapeutic agents to alpha-particle emitting 211 At

Int J Radiat Oncol Biol Phys. 2008 Sep 1;72(1):193-200. doi: 10.1016/j.ijrobp.2008.05.055.


Purpose: To generate and evaluate a modular recombinant transporter (MRT) for targeting 211 At to cancer cells overexpressing the epidermal growth factor receptor (EGFR).

Methods and materials: The MRT was produced with four functional modules: (1) human epidermal growth factor as the internalizable ligand, (2) the optimized nuclear localization sequence of simian vacuolating virus 40 (SV40) large T-antigen, (3) a translocation domain of diphtheria toxin as an endosomolytic module, and (4) the Escherichia coli hemoglobin-like protein (HMP) as a carrier module. MRT was labeled using N-succinimidyl 3-[211 At]astato-5-guanidinomethylbenzoate (SAGMB), its 125 I analogue SGMIB, or with 131 I using Iodogen. Binding, internalization, and clonogenic assays were performed with EGFR-expressing A431, D247 MG, and U87MG.wtEGFR human cancer cell lines.

Results: The affinity of SGMIB-MRT binding to A431 cells, determined by Scatchard analysis, was 22 nM, comparable to that measured before labeling. The binding of SGMIB-MRT and its internalization by A431 cancer cells was 96% and 99% EGFR specific, respectively. Paired label assays demonstrated that compared with Iodogen-labeled MRT, SGMIB-MRT and SAGMB-MRT exhibited more than threefold greater peak levels and durations of intracellular retention of activity. SAGMB-MRT was 10-20 times more cytotoxic than [211 At]astatide for all three cell lines.

Conclusion: The results of this study have demonstrated the initial proof of principle for the MRT approach for designing targeted alpha-particle emitting radiotherapeutic agents. The high cytotoxicity of SAGMB-MRT for cancer cells overexpressing EGFR suggests that this 211 At-labeled conjugate has promise for the treatment of malignancies, such as glioma, which overexpress this receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alpha Particles / therapeutic use
  • Antigens, Polyomavirus Transforming / metabolism
  • Astatine / pharmacokinetics
  • Astatine / therapeutic use*
  • Benzoates / pharmacokinetics
  • Benzoates / therapeutic use
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / radiotherapy
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Nucleus / radiation effects*
  • Confidence Intervals
  • Dihydropteridine Reductase / pharmacokinetics
  • Diphtheria Toxin / pharmacokinetics
  • Drug Carriers / pharmacokinetics
  • Drug Carriers / therapeutic use*
  • Endosomes / metabolism
  • Epidermal Growth Factor / metabolism
  • ErbB Receptors / metabolism*
  • Escherichia coli Proteins / pharmacokinetics
  • Glioblastoma / metabolism
  • Glioblastoma / radiotherapy
  • Guanidine / analogs & derivatives
  • Guanidine / pharmacokinetics
  • Guanidine / therapeutic use
  • Guanidines / pharmacokinetics
  • Guanidines / therapeutic use
  • Hemeproteins / pharmacokinetics
  • Humans
  • NADH, NADPH Oxidoreductases / pharmacokinetics
  • Radioimmunotherapy / methods


  • Antigens, Polyomavirus Transforming
  • Benzoates
  • Diphtheria Toxin
  • Drug Carriers
  • Escherichia coli Proteins
  • Guanidines
  • Hemeproteins
  • N-succinimidyl 3-astato-5-guanidinomethylbenzoate
  • N-succinimidyl 4-guanidinomethyl-3-iodobenzoate
  • Epidermal Growth Factor
  • Dihydropteridine Reductase
  • hmp protein, E coli
  • NADH, NADPH Oxidoreductases
  • ErbB Receptors
  • Guanidine
  • Astatine