Directional Fourier spatial frequency analysis was used on standard histological sections to identify salient directional bias in the spatial frequencies of stromal and epithelial patterns within tumor tissue. This directional bias is shown to be correlated to the pathway of reduced fluorescent tracer transport. Optical images of tumor specimens contain a complex distribution of randomly oriented aperiodic features used for neoplastic grading that varies with tumor type, size, and morphology. The internal organization of these patterns in frequency space is shown to provide a precise fingerprint of the extracellular matrix complexity, which is well known to be related to the movement of drugs and nanoparticles into the parenchyma, thereby identifying the characteristic spatial frequencies of regions that inhibit drug transport. The innovative computational methodology and tissue validation techniques presented here provide a tool for future investigation of drug and particle transport in tumor tissues, and could potentially be used a priori to identify barriers to transport, and to analyze real-time monitoring of transport with respect to therapeutic intervention.
The optical spatial frequencies of tumor interstitial fluid (TIF) are investigated. As a concentrated colloidal suspension of interacting native nanoparticles, the TIF can develop internal ordering under shear stress that may hinder delivery of antitumor agents within tumors. A systematic method is presented to characterize the TIF nanometer-scale microstructure in a model suspension of superparamagnetic iron-oxide nanoparticles and reconstituted high-density lipoprotein by Fourier spatial frequency (FSF) analysis so as to differentiate between jammed and fluid structural features in static transmission electron microscope images. The FSF method addresses one obstacle faced in achieving quantitative dosimetry to neoplastic tissue, that of detecting these nanoscale barriers to transport, such as would occur in the extravascular space immediately surrounding target cells.