Miles Miller

Single-cell imaging of nanomaterial behavior in the tumor microenvironment.

Therapeutic nanoparticles (NPs) have long been used to deliver cytotoxic chemotherapeutics and other drugs more safely and efficiently to patients.  Despite extensive testing and development, it still remains a challenge to understand and reliably predict how such nanomaterials actually behave in vivo, especially across patients or tumor regions, and heterogeneous NP clinical trial results often fail to show superior efficacy. To better understand the cellular-level mechanisms of NP behavior within tumors, here we use multicolor in vivo confocal fluorescence imaging (intravital microscopy) for integrated pharmacokinetic and pharmacodynamic (PK/PD) measurement at the single-cell level.  Using this strategy, we have identified new mechanisms of how NPs co-opt tumor associated macrophages as “drug depots” for enhanced drug delivery and efficacy. We use this mechanism to develop a companion diagnostic strategy based on magnetic resonance imaging (MRI) for identifying tumors with high macrophage levels and consequently high susceptibility to NP treatment. Ultimately, intravital imaging sheds light on how NP physicochemical properties and traditional pharmacokinetics translate into altered cellular uptake and spatial distribution among diverse immune, stromal, and tumor cell populations.