Design, synthesis, and evaluation of near infrared fluorescent multimeric RGD peptides for targeting tumors

Yunpeng Ye, Sharon Bloch, Baogang Xu, Samuel Achilefu

Research output: Contribution to journalArticlepeer-review

124 Scopus citations


Molecular interactions between RGD peptides and integrins are known to mediate many biological and pathological processes. This has led to an increased interest in the development of RGD compounds with high affinity and improved selectivity for integrin receptors. In this study, we synthesized and evaluated a series of multimeric RGD compounds constructed on a dicarboxylic acid-containing near-infrared (NIR) fluorescent dye (cypate) for tumor targeting. An array of NIR fluorescent RGD compounds was prepared efficiently, including one RGD monomer (cypate-(RGD)2-NH2), two RGD dimers (cypate-(RGD)2-NH2 and cypate-(RGD-NH 2)2), one trimer (cypate-(RGD)3-NH 2), two tetramers (cypate-(RGD)4-NH2 and cypate-[(RGD)2-NH2]2), one hexamer (cypate-[(RGD)3-NH2]2), and one octamer (cypate-[(RGD)4-NH2]2). The binding affinity of the multimeric RGD compounds for αvβ3 integrin receptor (ABIR) showed a remarkable increase relative to the monomer cypate-RGD-NH2. Generally, the divalent linear arrays of the multimeric RGD units bound the ABIR with slightly higher affinity than their monovalent analogues. These results suggest that the receptor binding affinity was not only dependent on the number of RGD moieties but also on the spatial alignments of the pendant peptides. Internalization of the compounds by ABIR-positive tumor cells (A549) was monitored by NIR fluorescence microscopy. The data showed that endocytosis of the octameric RGD derivative was significantly higher by comparison to other compounds in this study. In vivo noninvasive optical imaging and biodistribution data showed that the compounds were retained in A549 tumor tissue. These results clearly demonstrated that an array of simple RGD tripeptides on a NIR fluorescent dye core can be recognized by ABIR. Optimization of the spatial alignment of the RGD moieties through careful molecular design and library construction could induce multivalent ligand-receptor interactions useful for in vivo tumor imaging and tumor-targeted therapy.

Original languageEnglish (US)
Pages (from-to)2268-2275
Number of pages8
JournalJournal of Medicinal Chemistry
Issue number7
StatePublished - Apr 6 2006
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


Dive into the research topics of 'Design, synthesis, and evaluation of near infrared fluorescent multimeric RGD peptides for targeting tumors'. Together they form a unique fingerprint.

Cite this