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Lipid-stabilized nanoemulsions containing a volatile liquid perfluorocarbon core have been studied as ultrasound contrast agents owing to their ability to transform into high-contrast microbubbles when subjected to high intensity focused ultrasound (HIFU). However, while there have been several studies on the effect of acoustic parameters on contrast, the effect of the droplet's stabilizing shell has not been studied as extensively. Inspired by previous studies showing lateral phase separation in microbubbles and vesicles, nanodroplets were formulated with a perfluorohexane core and a shell composed of varying amounts of saturated (DPPC) phospholipids, unsaturated (DOPC) phospholipids, and cholesterol, which were fractionated to obtain nanodroplets of mean diameter 300-400 nm and were stable over one week. When the DOPC content was increased to 40 mol%, ultrasound contrast increased by about one order of magnitude over DPPC-only droplets. Based on fluorescence microscopy results of lateral lipid phase separation on the droplet surface, the various combinations of DPPC, DOPC, and cholesterol were assigned to three regimes on the ternary phase diagram: solid-liquid ordered (low contrast), liquid ordered-liquid disordered (medium contrast), and solid-liquid disordered (high contrast). These regimes were confirmed by TEM analysis of nanoscale droplets. Droplets containing mixed lipid monolayers were also found to produce a significantly greater yield than single-component droplets. The discovery of the dependence of acoustic response on lipid phase separation will help to understand the formulation, behavior, and vaporization mechanism of acoustically-responsive nanoemulsions.

A grand challenge for medicine is to develop tools to selectively image and treat diseased cells. Rare earth doped upconverting nanoparticles (UCNPs) have been extensively studied for imaging applications because of their ability to absorb near infrared radiation (NIR) and emit visible light, but these particles cannot induce therapy alone. Recently, we developed methods to couple the UCNPs to visible and NIR-absorbing gold nanostructures through nucleic acid interactions. Here, we show that gold-UCNP clusters with optimized plasmon resonance and particle compositions provide both in vitro imaging contrast and combination cell killing through simultaneous photothermal (PTT) and photodynamic (PDT) therapy. PDT was induced by embedding singlet oxygen photosensitizers in silica shells on the UCNPs. Upon photoexcitation with 980 nm light, the NIR absorbing gold-UCNP clusters both increased the local temperature and generated singlet oxygen, increasing cell killing relative to either modality alone. The multifunctional polyethylene glycol (PEG) coated gold-NaYF 4 :Yb/Er clusters exhibited high biocompatibility without irradiation but synergistic cell killing of MCF-7 cancer cells under light excitation. Finally, we also demonstrate that an optimal gold plasmon resonance is critical for minimizing absorbance overlap with the photosensitizers.