A Spectral Fiedler Field-based Contrast Platform for Imaging of Nanoparticles in Colon Tumor

In efforts to improve solid tumor imaging, and enable image-guided drug delivery (IGDD), multiple types of clinical imaging modalities have been combined with nanoparticle platforms1,2. These have improved ability to understand tumor microenvironment and quantify tissue drug concentrations3–5. However, current IGDD plat- forms suffer from interference by target tissue movement, scattering and image blurring for targets that are farther away and low resolution. These combine to limit clinicians’ ability to define undertreated regions with nanopar- ticles6–11. To address these IGDD barriers, in this study we developed a spectral Fiedler field (SFF)-based compu- tational technology for enhancement of image sensitivity and spatial location of nanoparticles in solid tumors. The proposed SFF methodology utilize graph and matrix theories to assess changes in surface topology from baseline. To do so, the deviations from reference geometry (i.e. subtle contrast changes vs. baseline) are transformed as quantifiable-flooded contour plots following nanoparticle injection. This innovative feature of SFF precisely measures the mismatch in tumor contrast in solid tumors over-time. We investigated this approach in murine colon cancer model utilizing ultrasound (US) imageable liposome as model nanoparticles. Ultrasound-imageable liposome are synthesized by encapsulation of phase-change contrast agents, consisting of nanodroplets of liquid perfluorocarbons (PFCs), emulsion12 (and other particles)13. The relatively small size of liposomes (100–300 nm) enables passive accumulation within tumors via the enhanced permeability and reten- tion (EPR) effect14. However, the encapsulated PFC emulsions in liposomes is incompressible in a liquid state, and produce poor oscillation, backscatter, and image sensitivity in the ultrasound field15–17. Also, when stabilized by a lipid shell, the Laplace pressure, which is the pressure difference between the inside and the outside of an ultrasound (US) contrast agent (perfluoropentane, PFP) changes with the boiling temperature18. Thus, their poor resolution in the liquid state, and dynamic changes in the contrast with temperature can be an excellent model system for understanding the feasibility of SFF imaging approaches of nanoparticles in solid tumors. Our in vivo data suggest that the innovative SFF topological imaging approach has high sensitivity of detection for clinical applications.