ICG-based NIR imaging has exhibited significant potential in intraoperative surgery. However, there are two fundamental challenges in medical imaging that remain unresolved. Firstly, the nonspecific uptake of intravenously administered diagnostic or therapeutic agents by normal tissues and organs, and secondly, the incomplete elimination of unbound targeted agents from the body. These issues pose substantial difficulties in image-guided cancer surgery due to high background signals and consequently low Target-to-Background Ratios (TBR). A critical solution lies in the design of a targeted contrast agent that exhibits swift clearance from background tissues and eventually from the entire body post-complete targeting. This is pivotal for the success of image-guided interventions.

Various molecular platforms, including small molecule dyes, polymers, and organic and inorganic nanoparticles, have been explored for developing targeted agents for NIR-I/II fluorescence imaging. This underscores the high potential and impact of NIR fluorescence in theranostic imaging. The “Structure-Inherent Targeting” strategy is another approach that combines tissue-specific targeting components and imaging domains into a single molecule. This design allows the unbound contrast agent to be quickly cleared from the body after tissue-specific targeting, reducing background signal and enhancing the signal emitted from the targeted tissue in real-time.

The effectiveness of these compounds in terms of targetability, biodistribution, and clearance hinges on their physicochemical properties. This strategic approach holds promise in addressing the unmet clinical need in image-guided cancer surgery. Notably, the physiological filtration and clearance pathways of these compounds align closely with the Choi criteria. Hydrophobic compounds larger than 5.5 nm in hydrodynamic diameter (HD) are observed in the liver, while charge-balanced agents with smaller HD can be cleared through renal filtration.

Recently, we have pioneered a novel pharmacophore design approach termed “structure-inherent targeting,” wherein tissue-specific targeting is inherently engineered into the non-resonant structure of a near-infrared fluorophore. This innovative strategy results in the creation of the most compact possible optical contrast agent for applications in bioimaging and nanomedicine (Nat Med. 2015). The biodistribution and targeting profiles of these compounds are intricately dependent on their unique physicochemical descriptors and cellular receptors, affording several significant benefits: selective binding to the target tissue/organ, visualization of cancer with specificity and selectivity, and the provision of therapeutic options such as image-guided surgery or photon-induced therapy. Our comprehensive study addresses two fundamental challenges confronting bioimaging and nanomedicine, laying the groundwork for the development of additional targeted agents with optimized optical and in vivo performance.

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Figure 1. Structure-inherent targeting concept used for the design of tissue-specific imaging and theranostics.

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