Highly Controlled Janus Organic‐Inorganic Nanocomposite as a Versatile Photoacoustic Platform

Stimuli-responsive nanomaterials are increasingly important in a variety of applications such as biosensing, molecular imaging, drug delivery and tissue engineering. For cancer detection, a paramount challenge still exists in search of methods that can illuminate tumors universally regardless of their genotypes and phenotypes. Here we capitalized on the acidic, angiogenic tumor microenvironment to achieve broad detection of tumor tissues in a wide variety of mouse cancer models. This was accomplished using ultra-pH sensitive fluorescent nanoprobes that have tunable, exponential fluorescence activation upon encountering subtle, physiologically relevant pH transitions. These nanoprobes were silent in the circulation, then dramatically activated (>300 fold) in response to neovasculature or to the low extracellular pH in tumors. Thus, we have established non-toxic, fluorescent nanoreporters that can non-linearly amplify tumor microenvironmental signals, permitting identification of tumor tissue independently of histological type or driver mutation, and detection of acute treatment responses much more rapidly than conventional imaging approaches.

Optical imaging has played a pivotal role in biology and medicine, but it faces challenges of relatively low tissue penetration and poor signal-to-background ratio due to light scattering and tissue autofluorescence. To overcome these issues, second near-infrared fluorescence, self-luminescence, and photoacoustic imaging have recently emerged, which utilize an optical region with reduced light-tissue interactions, eliminate real-time light excitation, and detect acoustic signals with negligible attenuation, respectively. Because there are only a few endogenous molecules absorbing or emitting above the visible region, development of contrast agents is essential for those deep-tissue optical imaging modalities. Organic semiconducting agents with π-conjugated frameworks can be synthesized to meet different optical imaging requirements due to their easy chemical modification and legible structure-property relation. Herein, the deep-tissue optical imaging applications of organic semiconducting agents including small-molecule agents and nanoparticle derivatives are summarized. In particular, the molecular engineering and nanoformulation approaches to further improve the tissue penetration and detection sensitivity of these optical imaging modalities are highlighted. Finally, current challenges and potential opportunities in this emerging subfield of biomedical imaging are discussed.