Targeting the cubilin receptor through the vitamin B(12) uptake pathway: cytotoxicity and mechanistic insight through fluorescent Re(I) delivery.

Abstract

The intrinsic factor (IF) vitamin B(12) ileum anchored receptor, cubilin, mediates endocytotic uptake of the IF complex of vitamin B(12) to the blood serum. This receptor was targeted for the selective delivery and accumulation of a new bioprobe, a B(12) conjugate of rhenium 2, in the cubilin expressing placental choriocarcinoma BeWo cell line. Competitive uptake and cytotoxicity assays of 2 were investigated and interactions with nuclear DNA explored. In addition, the mechanism of internalization of 2 was confirmed to proceed in an IF-cubilin mediated fashion via siRNA transfection experiments. These studies show the great potential of cubilin as a new target for the delivery of B(12) based conjugates for cancer diagnostics and/or treatment.

• Authors: Nerissa Viola-Villegas, Amy E Rabideau, Mark Bartholomä, Jon Zubieta, Robert P Doyle
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 16 Pg. 5253-61 (Aug 27 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19627091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• B12-(BQBA(Re(CO)3))
• Coordination Complexes
• Fluorescent Dyes
• Molecular Probes
• Organometallic Compounds
• RNA, Small Interfering
• Receptors, Cell Surface
• intrinsic factor-cobalamin receptor
• Rhenium
• Intrinsic Factor
• Vitamin B 12

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology)
• CHO Cells
• Cell Line, Tumor
• Coordination Complexes (chemical synthesis, pharmacology)
• Cricetinae
• Cricetulus
• Female
• Fluorescent Dyes (chemical synthesis, pharmacology)
• Humans
• Intrinsic Factor (metabolism)
• Models, Molecular
• Molecular Probes (chemical synthesis, pharmacology)
• Organometallic Compounds (chemical synthesis, pharmacology)
• Pregnancy
• RNA, Small Interfering (genetics)
• Receptors, Cell Surface (genetics, metabolism)
• Rhenium
• Vitamin B 12 (analogs & derivatives, chemical synthesis, pharmacology)