Biodegradable dendritic positron-emitting nanoprobes for the noninvasive imaging of angiogenesis

Adah Almutairi, Raffaella Rossin, Monica Shokeen, Aviv Hagooly, Ashwin Ananth, Benjamin Capoccia, Steve Guillaudeu, Dana Abendschein, Carolyn J. Anderson, Michael J. Welch, Jean M.J. Fréchet

Research output: Contribution to journalArticlepeer-review

195 Scopus citations

Abstract

A biodegradable positron-emitting dendritic nanoprobe targeted at αvβ3 integrin, a biological marker known to modulate angiogenesis, was developed for the noninvasive imaging of angiogenesis. The nanoprobe has a modular multivalent core-shell architecture consisting of a biodegradable heterobifunctional dendritic core chemoselectively functionalized with heterobifunctional polyethylene oxide (PEO) chains that form a protective shell, which imparts biological stealth and dictates the pharmacokinetics. Each of the 8 branches of the dendritic core was functionalized for labeling with radiohalogens. Placement of radioactive moieties at the core was designed to prevent in vivo dehalogenation, a potential problem for radiohalogens in imaging and therapy. Targeting peptides of cyclic arginine-glycine-aspartic acid (RGD) motifs were installed at the terminal ends of the PEO chains to enhance their accessibility to αvβ 3 integrin receptors. This nanoscale design enabled a 50-fold enhancement of the binding affinity to αvβ3 integrin receptors with respect to the monovalent RGD peptide alone, from 10.40 nM to 0.18 nM IC50. Cell-based assays of the 125I-labeled dendritic nanoprobes using αvβ3-positive cells showed a 6-fold increase in αvβ3 receptor-mediated endocytosis of the targeted nanoprobe compared with the nontargeted nanoprobe, whereas αvβ3-negative cells showed no enhancement of cell uptake over time. In vivo biodistribution studies of 76Br-labeled dendritic nanoprobes showed excellent bioavailability for the targeted and nontargeted nanoprobes. In vivo studies in a murine hindlimb ischemia model for angiogenesis revealed high specific accumulation of 76Br-labeled dendritic nanoprobes targeted at αvβ3 integrins in angiogenic muscles, allowing highly selective imaging of this critically important process.

Original languageEnglish
Pages (from-to)685-690
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number3
DOIs
StatePublished - Jan 20 2009

Keywords

  • Dendrimer
  • Molecular imaging

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