Targeting the Cubilin Receptor through the Vitamin B₁₂ 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.

Re(I) carbonyl complexes: Multimodal platforms for inorganic chemical biology

“…Imaging (L)Re(CO) n remains possible thanks to the large bandwidth of their absorption band. Interestingly, though, Re(I) tricarbonyl complexes bearing a bis-quinoline ligand could be imaged in cells by fluorescence microscopy with excitation at 488 nm [50,51]. [42] pyta (R = Bn) Cl 355 538 0.33 [46] pyta (R = alkyl) Cl 332 522 0.1 [47] quinta Br N. E.…”

“…Similarly, Re(I) tricarbonyl complexes were appended to estrogen derivatives to target estrogen receptors [9,20] or to indoles to target indole-binding proteins [20]. Doyle et al conjugated luminescent Re(I) bisquinoline complexes to folic acid and to vitamin B12 to target folate receptor and cubilin receptor, respectively [50,97]. We also mentioned in this review the conjugation of Re(I) complexes to bombesin to target GPR receptor.…”

Underestimated Potential of Organometallic Rhenium Complexes as Anticancer Agents

“…Furthermore, all reported cytotoxic Re organometallic compounds are based on the Re(CO) 3 core, which is chemically robust and easily accessible, e.g. from [Re(CO) 3 29,34 Re(CO) 5 Cl/Re(CO) 5 Br 26-28, 31-33, 41, 42, 49 or Re 2 (CO) 10 24, 30, 40 in 1-3 step synthesis. The introduced ligands can be designed to incorporate other functional moieties such as targeting biomolecules.…”

“…The introduced ligands can be designed to incorporate other functional moieties such as targeting biomolecules. 28,29,34,35,39,41,44,46,47,50,51 However, the key property of the Re organometallic complexes is the possibility to prepare "hot" analogues that can be applied for radio-imaging as well as for therapy . Besides 186 Re and 188 Re isotopes, 99m Tc can often be used with the same set of ligands as the cold Re due to the similarity in the coordination chemistry of these group 7 congeners.…”

Vitamin B12–Metal Conjugates for Targeted Chemotherapy and Diagnosis: Current Status and Future Prospects

“…They reported on some fluorescent water-soluble vitamin B 12 -{Re I (CO) 3 } conjugates ( Figure 15) capable of probing cancer cells. [86,87] Again, the {Re I (CO) 3 } moiety was attached to the 5′-hydroxy position The targeted delivery of 25 to the cubilin receptor was successfully demonstrated; in fact, it was observed that it requires IF and exploits the IF-cubilin import mechanism. Confocal microscopy results showed internalization and accumulation of 25 bound to IF in the nuclear and cytosolic region of the cubilinoverexpressing human placental choriocarcinoma BeWo cells.…”