Porphyrin Nanodroplets: Sub-micrometer Ultrasound and Photoacoustic Contrast Imaging Agents

Robert J Paproski, Alexander Forbrich, Elizabeth Huynh, Juan Chen, John D Lewis, Gang Zheng, Roger J Zemp
Ultrasound offers signifi cant potential as a molecular imaging modality when imaging microbubble agents owing to single-bubble sensitivity. However, these agents are typically too large to escape the vascular system. Photoacoustic imaging is a novel hybrid imaging modality offering optical contrast in deep tissues with scalable ultrasonic spatial resolution. Multi-spectral photoacoustic imaging offers signifi cant potential for molecular imaging. In this paper a novel class of all-organic nanoscale porphyrin nanodroplet agents suitable for multi-modality ultrasound and photoacoustic molecular imaging is demonstrated. These agents build on strengths of previous nan-odroplet and porphysome agents and combine their strengths. Lovell et al. previously created liposomes termed " por-physomes " which contained a porphyrin called pyropheo-phorbide as one of the acyl chains on the most abundant phospholipid. [ 1 ] Pyropheophorbide allowed the porphysomes to have signifi cant optical absorption at near-infrared wave-lengths which is useful for in vivo photoacoustic imaging, fl uorescence imaging, and photodynamic-and photothermal-therapies. Compared to inorganic nanoparticles with strong A novel class of all-organic nanoscale porphyrin nanodroplet agents is presented which is suitable for multimodality ultrasound and photoacoustic molecular imaging. Previous multimodality photoacoustic-ultrasound agents are either not organic, or not yet demonstrated to exhibit enhanced accumulation in leaky tumor vasculature, perhaps because of large diameters. In the current study, porphyrin nanodroplets are created with a mean diameter of 185 nm which is small enough to exhibit the enhanced permeability and retention effect. Porphyrin within the nanodroplet shell has strong optical absorption at 705 nm with an estimated molar extinction coeffi cient >5 × 10 9 m −1 cm −1 , allowing both ultrasound and photoacoustic contrast in the same nanoparticle using all organic materials. The potential of nanodroplets is that they may be phase-changed into microbubbles using high pressure ultrasound, providing ultrasound contrast with single-bubble sensitivity. Multispectral photoacoustic imaging allows visualization of nanodroplets when injected intratumorally in an HT1080 tumor in the chorioallantoic membrane of a chicken embryo. Intravital microscopy imaging of Hep3-GFP and HT1080-GFP tumors in chicken embryos determines that nanodroplets accumulated throughout or at the periphery of tumors, suggesting that porphyrin nanodroplets may be useful for enhancing the visualization of tumors with ultrasound and/or photoacoustic imaging.

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