Folic Acid-Conjugated Europium Complexes as Luminescent Probes for Selective Targeting of Cancer Cells

Abstract

We report the synthesis of three optical probes (Eu(3+)⊂1, Eu(3+)⊂2, and Eu(3+)⊂3) having a luminescent Eu complex (signaling unit) bonded in different positions to folic acid (FA), the folate receptor (FR) targeting unit. The structures of the two regioisomers Eu(3+)⊂1 and Eu(3+)⊂2 were assigned by mass spectrometric experiments. The optical properties and stability of these probes were assessed in phosphate-buffered saline, cell culture medium, rat serum, and cellular lysate, and results indicated that they are chemically and photophysically stable. Cytotoxicity was studied with ovarian cancer cells having high (SKOV-3), intermediate (OVCAR-3), low (IGROV-1), or null (A2780) expression of FRs. The internalized probe, evaluated in SKOV-3, IGROV-1, and A2780 cells, was in the order Eu(3+)⊂2 > Eu(3+)⊂1 > Eu(3+)⊂3. No internalization was observed for A2780 cells. Such results, together with those obtained in competition experiments of FA versus Eu(3+)⊂2 and FA or Eu(3+)⊂2 versus (3)H-FA, indicate that internalization is receptor-mediated and that Eu(3+)⊂2 shows high selectivity and specificity for FR.

Effects of X-shaped reduction-sensitive amphiphilic block copolymer on drug delivery

“…27 MTT assay was performed to elucidate the cytotoxicity of the synthesized X-shaped copolymer and the micellar suspension DTX/XNMs. First, A2780 cells were seeded at approximately 5,000 cells/well in 96-well plates and cultured for 24 hours.…”

Accessing Structurally Diverse Near‐Infrared Cyanine Dyes for Folate Receptor‐Targeted Cancer Cell Staining

“…Values in the low nanomolar range are in accordance with those reportedf or other folate probes( for example, values between 7.0 nm and 64 nm have been reported by Kelderhouse et al using similare xperimental conditions on KB cells). [45] (20,21,22)o rl Ex = 740 nm (23,24). Quantum yields wered etermined using ICG (f f = 0.13 in DMSO) [41] as standard.…”

“…Examples are the FR‐targeted radiotracer 99m Tc‐EC20 or the fluorescent markers Folate‐FITC (FITC=fluorescein isothiocyanate) and OTL0038 (a pteroyl‐linked, folate receptor targeted indotricarbocyanine dye), which have been used for the intraoperative labeling of various carcinomas in humans and are in advanced clinical trials . Further examples for optical FR‐targeted probes include silica nanoparticles, europium complexes, and cyanine dyes …”

“…[8][9][10] Folate-conjugated molecules have proven useful as targeted drugs [6,[11][12][13] or for selectivel abeling of cancerc ells and tissues.E xamples are the FR-targeted radiotracer 99m Tc-EC20 [14][15][16] or the fluorescent markers Folate-FITC (FITC = fluorescein isothiocyanate) and OTL0038 (a pteroyl-linked, folate receptor targeted indotricarbocyanine dye), [17] which have been used for the intraoperativel abeling of variousc arcinomas in humans and are in advanced clinical trials. [18,19] Further examples for opticalF R-targeted probes include silica nanoparticles, [20] europium complexes, [21] and cyanine dyes. [22][23][24] The chemicals tructure of the fluorophore in targeted indotricarbocyanine probes can dictate both in vitro and in vivo performance.…”

Targeting Integrin αV β3 with Theranostic RGD-Camptothecin Conjugates Bearing a Disulfide Linker: Biological Evaluation Reveals a Complex Scenario

“…Moreover, the high manufacturing costs and their possible immunogenicity are well‐known drawbacks of ADCs . For these reasons, vitamins such as folic acid,, biotin,, peptides, and other small ligands, that showed high affinity for tumor‐overexpressed antigens have been linked to different anticancer agents to form the so‐called small molecule‐drug conjugates (SMDCs). The tripeptide sequence Arg‐Gly‐Asp (RGD) in endogenous ligands has been found to efficiently bind to several integrins (including α V β 3 , α V β 5 , α 5 β 1 and α IIb β 3 ), divalent cation‐dependent heterodimeric membrane glycoproteins formed by non‐covalently associated α‐ and β‐subunits.…”