Novel near-infrared fluorescent integrin-targeted DFO analogue

Yunpeng Ye, Sharon Bloch, Baogang Xu, Samuel Achilefu

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Desferrioxamine (DFO), a siderophore initially isolated from Streptomyces pilosus, possesses extraordinary metal binding properties with wide biomedical applications that include chelation therapy, nuclear imaging, and antiproliferation. In this work, we prepared a novel multifunctional agent consisting of (i) a near-infrared (NIR) fluorescent probe-cypate; (ii) an integrin αvβ3 receptor (ABIR)-avid cyclic RGD peptide, and (iii) a DFO moiety, DFO-cypate-cyclo[RGDfK(∼)] (1, with ∼ representing the cypate conjugation site at the side chain of lysine; f is D-phenylalanine). Compound 1 and two control compounds, cypate- cyclo[RGDfK(∼)] (2) and cypate-DFO (3), were synthesized by modular assembly of the corresponding protected RGD peptide cyclo[R(Pbf)GD(OBut)fK] and DFO on the dicarboxylic acid-containing cypate scaffold in solution. The three compounds exhibited similar UV-vis and emission spectral properties. Metal binding analysis shows that DFO as well as 1 and 3 exhibited relatively high binding affinity with Fe(III), Al(III), and Ga(III). In contrast to Ga(III), the binding of Fe to 1 and 3 quenched the fluorescence emission of cypate significantly, suggesting an efficient metal-mediated approach to perturb the spectral properties of NIR fluorescent carbocyanine probes. In vitro, 1 showed a high ABIR binding affinity (10-7 M) comparable to that of 2 and the reference peptide cyclo(RGDfV), indicating that both DFO and cypate motifs did not interfere significantly with the molecular recognition of the cyclic RGD motif with ABIR. Fluorescence microscopy showed that internalization of 1 and 2 in ABIR-positive A549 cells at 1 h postincubation was higher than 3 and cypate alone, demonstrating that incorporating ABIR-targeting RGD motif could improve cellular internalization of DFO analogues. The ensemble of these findings demonstrate the use of multifunctional NIR fluorescent ABIR-targeting DFO analogues to modulate the spectral properties of the NIR fluorescent probe by the chelating properties of DFO and visualize intracellular delivery of DFO by receptor-specific peptides. These features provide a strategy to explore the potential of 1 in tumor imaging and treatment as well as some molecular recognition processes mediated by metal ions.

Original languageEnglish
Pages (from-to)225-234
Number of pages10
JournalBioconjugate Chemistry
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2008

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