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Synthesis and in vitro evaluation of an 111In-labeled ST-peptide enterotoxin (ST) analogue for specific targeting of guanylin receptors on human colonic cancers.

AbstractBACKGROUND:
Human colonic cancer cells are known to express guanylate cyclase C (GC-C) receptors for guanylin and uroguanylin. E. coli ST is a peptide with high metabolic stability that specifically binds to GC-C receptors. An in vitro evaluation of a new synthetic indium-111 labeled ST conjugate for specific targeting of human colonic cancers that express GC-C receptors was performed.
MATERIALS AND METHODS:
A DOTA conjugated ST analogue DOTA-NCS-6-Ahx-Phe19-ST[1-19] (DOTA-NCS-ST) was synthesized and labeled with indium-111. The non-radioactive indium analogue (In-DOTA-NCS-ST) was also prepared in macroscopic quantities. 111In-DOTA-NCS-ST was produced as a single species (>80% RCP) and purified by HPLC. Human colon cancer CaCO-2 and T-84 cells were used to evaluate the in vitro IC50 values for GC-C receptor binding and determine the cell uptake and retention of radioactivity.
RESULTS:
The DOTA-NCS-ST and In-DOTA-NCS-ST conjugates exhibit high in vitro binding affinity for GC-C receptors with IC50 values <10 nM. The in vitro cell binding studies with the 111In-DOTA-NCS-ST conjugate demonstrated that 111In-label ST internalizes in human colon cancer cells and exhibits long-term retention.
CONCLUSION:
The combination of radiolabeling efficacy and specific in vitro cell uptake and retention suggests that the DOTA-NCS-ST construct holds potential for the development of diagnostic or therapeutic radiopharmaceuticals labeled with trivalent radiometals for specific targeting of human colonic cancers.
AuthorsH Gali, G L Sieckman, T J Hoffman, G E Kiefer, D T Chin, L R Forte, W A Volkert
JournalAnticancer research (Anticancer Res) 2001 Jul-Aug Vol. 21 Issue 4A Pg. 2785-92 ISSN: 0250-7005 [Print] Greece
PMID11724355 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Bacterial Toxins
  • Enterotoxins
  • Escherichia coli Proteins
  • Heterocyclic Compounds, 1-Ring
  • In-DOTA-NSC-ST
  • Indium Radioisotopes
  • Radiopharmaceuticals
  • Receptors, Cell Surface
  • Receptors, Peptide
  • heat stable toxin (E coli)
  • Guanylate Cyclase
  • Receptors, Enterotoxin
  • Receptors, Guanylate Cyclase-Coupled
Topics
  • Amino Acid Sequence
  • Bacterial Toxins (chemistry, metabolism)
  • Colonic Neoplasms (diagnostic imaging, metabolism)
  • Enterotoxins (chemistry, metabolism)
  • Escherichia coli Proteins
  • Guanylate Cyclase
  • Heterocyclic Compounds, 1-Ring (chemical synthesis, metabolism)
  • Humans
  • Indium Radioisotopes (chemistry)
  • Molecular Sequence Data
  • Radionuclide Imaging
  • Radiopharmaceuticals (chemical synthesis, metabolism)
  • Receptors, Cell Surface (metabolism)
  • Receptors, Enterotoxin
  • Receptors, Guanylate Cyclase-Coupled
  • Receptors, Peptide
  • Substrate Specificity
  • Tumor Cells, Cultured

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