Biodegradable dendritic positron-emitting nanoprobes for the noninvasive imaging of angiogenesis.
A biodegradable positron-emitting dendritic nanoprobe targeted at alpha(v)beta(3) 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 alpha(v)beta(3) integrin receptors. This nanoscale design enabled a 50-fold enhancement of the binding affinity to alpha(v)beta(3) integrin receptors with respect to the monovalent RGD peptide alone, from 10.40 nM to 0.18 nM IC(50). Cell-based assays of the (125)I-labeled dendritic nanoprobes using alpha(v)beta(3)-positive cells showed a 6-fold increase in alpha(v)beta(3) receptor-mediated endocytosis of the targeted nanoprobe compared with the nontargeted nanoprobe, whereas alpha(v)beta(3)-negative cells showed no enhancement of cell uptake over time. In vivo biodistribution studies of (76)Br-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 (76)Br-labeled dendritic nanoprobes targeted at alpha(v)beta(3) integrins in angiogenic muscles, allowing highly selective imaging of this critically important process.
Almutairi
Adah
A
College of Chemistry, University of California, Berkeley, CA 94720-1460, USA.
Rossin
Raffaella
R
Shokeen
Monica
M
Hagooly
Aviv
A
Ananth
Ashwin
A
Capoccia
Benjamin
B
Guillaudeu
Steve
S
Abendschein
Dana
D
Anderson
Carolyn J
CJ
Welch
Michael J
MJ
Fréchet
Jean M J
JM
D000818:Animals; D050091:Dendrimers; D006614:Hindlimb / Q000098:blood supply; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D007511:Ischemia / Q000000981:diagnostic imaging / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D036103:Nanotechnology; D018919:Neovascularization, Physiologic; D009842:Oligopeptides / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D049268:Positron-Emission Tomography / Q000379:methods*; D014018:Tissue Distribution
D050091:Dendrimers; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid