Multimodality Imaging of Integrin α(v)β(3) Expression

Abstract

Over the last decade, integrin α(v)β(3) has been studied with every single molecular imaging modality. Since no single modality is perfect and sufficient to obtain all the necessary information for a particular question, combination of certain molecular imaging modalities can offer synergistic advantages over any modality alone. This review will focus on multimodality imaging of integrin α(v)β(3) expression, where the contrast agent used can be detected by two or more imaging modalities, such as combinations of PET and optical, SPECT and fluorescence, PET and MRI, SPECT and MRI, and lastly, MRI and fluorescence. Most of these agents are based on certain type(s) of nanoparticles. Contrast agents that can be detected by more than two imaging modalities are expected to emerge in the future and a PET/MRI/fluorescence agent will likely find the most future biomedical/clinical applications. Big strides have been made over the last decade for imaging integrin α(v)β(3) expression and several PET/SPECT probes have been tested in human studies. For dualmodality and multimodality imaging applications, a number of proof-of-principle studies have been reported which opened up many new avenues for future research. The next decade will likely witness further growth and continued prosperity of molecular imaging studies focusing on integrin α(v)β(3), which can eventually impact patient management.

Keywords: cancer; integrin αvβ3; molecular imaging; multimodality imaging; nanoparticle.

Figure 1

Dualmodality imaging of integrin α_vβ₃ on tumor vasculature with PET and fluorescence. A. A schematic structure of the dualmodality PET/NIRF probe. B. Fluorescence (after injection of QD-RGD) and coronal PET (after injection of ⁶⁴Cu-DOTA-QD-RGD) images of integrin α_vβ₃-positive U87MG tumor-bearing mice. Arrowheads indicate the tumors. C. Excellent overlay between CD31 and QD fluorescence, as well as between murine β₃ and QD fluorescence, confirmed that DOTA-QD-RGD mainly targeted integrin α_vβ₃ on the tumor vasculature. Adapted from .

Figure 2

Dualmodality imaging of integrin α_vβ₃ with SPECT and fluorescence. A. A RGD peptide is conjugated to both Cy5.5 and a chelating agent for radiolabeling with ^99mTc. B. After intravenous administration of the probe, localization of the Cy5.5 fluorescence (red) was observed in the infarct and peri-infarct zones in live animals at 2 weeks post-myocardial infarction (MI). A whole mouse slice also demonstrated myocardial uptake of the probe (square). C. Ex vivo images of the explanted hearts in control and post-MI animals after probe injection. Intense uptake was seen in 2-week post-MI animal. Adapted from .

Figure 3

An IO nanoparticle-based dualmodality PET/MR agent. A. A schematic illustration of the dualmodality probe. The DOTA chelator enables PET imaging after ⁶⁴Cu-labeling. B. Coronal PET and T2-weighted MR images of tumor-bearing mice at 4 h after injection of ⁶⁴Cu-labeled RGD-PASP-IO, PASP-IO, and RGD-PASP-IO mixed with unconjugated RGD peptides (denoted as “Block”). Prussian blue staining of the U87MG tumor (integrin α_vβ₃-positive) tissue slices after scanning is also shown, where blue spots indicate the presence of IO nanoparticles. Adapted from .

Figure 4

Various approaches have been undertaken to construct dualmodality MR/fluorescence agents for imaging of integrin α_vβ₃ expression. A. An agent that contains a RGD peptide, Gd-DTPA, and a fluorescent dye. B. A PAMAM dendrimer that contains a RGD peptide, Gd-DTPA, and a fluorescent dye. C. PEGylated paramagnetic and fluorescent liposomes containing RGD peptides as the targeting ligand. D. A QD encapsulated in a paramagnetic micelle with multiple covalently linked RGD peptides. E. A SPIO nanoparticle conjugated with both a fluorescent dye and RGD peptides.