Modular nanoparticulate platforms facilitate structures amenable to multiple usages and disease states. The present focus involves molecular imaging with attention to potential developments in delivery of therapeutics using the devices described. The diseases chosen for proof-of-principle of targeted, imageable nanoparticle platforms include atherosclerosis and breast cancer; molecular imaging is performed via magnetic resonance imaging and non-destructive evaluation ultrasound. The ultimate purpose for this work was to demonstrate proof-of-principle of 1. nanoparticle-based targeted contrast for MRI as a screening technique for heart disease for the general population and 2. early ex vivo detection of breast cancer and prediction of therapeutic response using targeted nanoparticles and ultrasound.
Herein, the feasibility of delivery of ultrasmall superparamagnetic particulate iron oxide (USPIO)-mediated negative contrast to atherosclerotic plaques was probed by biochemical affinity in vivo. An array of targeting reagents was surveyed to yield the most appropriate reagent for binding to vulnerable plaques. This work focused upon Annexin V conjugated USPIOs via interaction with phosphatidylserine. Biofunctional Annexin V USPIOs partitioned rapidly and deeply into plaques, primarily into plaque-localized apoptotic macrophages, which indicated lesion vulnerability. The doses of targeted USPIOs needed to generate specific contrast using MRI were minute in comparison to non-targeting studies (2000-fold lower). Distinct plaque morphologies were differentiable using targeted USPIOs.
Using characterization mode ultrasound (CMUS) and C-Scan systems, targeted USPIOs along with continuum and nano-mechanics were used to probe cells and tissue that overexpressed the Her-2/neu growth receptor. Studies showed that USPIOs could be successfully bound to their targets (via microscopy and flow cytometry) and that CMUS successfully differentiated between cells targeted with USPIOs and controls. Furthermore, tissue biopsy sections were sensitively and specifically identified using the other ultrasound mode, C-Scan, and targeted USPIOs. Thus, malignancy information was reconstructed by quantification of the molecular expression of Her-2/neu using anti-Her-2/neu conjugated USPIOs. The mechanical properties of tissues were thereby correlated with their malignancy and Her-2/neu status.
The work provides proof-of-principle for the platform nature of USPIOs. The modularity of the USPIO platform enabled precise and quantitative molecular information to be collected for two disparate disease states using two different imaging modalities.