1. Department of Pharmacology, Harold C. Simmons Comprehensive Cancer Center;
2. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA
Nanoparticulate imaging probes have become an increasingly important arsenal in the visualization of molecular markers for early diagnosis and post-therapy assessment of diseases. Surface functionalization of these nanoparticles has led to the development of a variety of targeted nanoprobes for various imaging modalities (e.g. PET, MRI, optical). Despite these advances, detailed understanding of the nanoparticle targeting kinetics, particularly at the early time points immediately after injection, is still lacking. In this study, we report the combination of a T2*-weighted time-resolved-MRI (TR-MRI) method with ultra-sensitive superparamagnetic polymeric micelle (SPPM) nanoprobes to quantify the targeting kinetics of cyclic (RGDfK) (cRGD)-encoded SPPM to angiogenic endothelium in subcutaneous human tumor xenograft models in mice. TR-MRI analyses of the αvβ3-targeted and non-targeted SPPMs allowed for the subtraction of blood volume and extravascular signal components from the cRGD-SPPM data, resulting in a specific measurement of the accumulation kinetics of nanoprobes in lung, breast and brain cancer preclinical models. In all three models, αvβ3-specific accumulation of SPPM nanoprobes was observed in the first 5 mins after intravenous injection (first order rate constants were in the range of 0.22-0.24 min-1). Similar αvβ3-targeting kinetics was observed for cRGD-SPPM nanoprobes in different tumor xenograft models, consistent with the targeting of mouse angiogenic endothelium despite tumor inoculation from different human cancer cell lines. Results from this study offer new opportunities in the quantitative characterization of the targeting kinetics of cancer-specific nanoparticles to their intended biological targets in an intact animal, which provides fundamental insights on molecular recognition processes in vivo for further development of these nanoprobes.
Keywords: Cancer molecular imaging, αvβ3, time-resolved magnetic resonance imaging, nanoparticle targeting kinetics