The advancement of targeted drug delivery faces significant challenges for clinical translation, such as issues related to poor solubility, non-specific distribution, and limited bioavailability of cancer theranostics. Notably, promising developments in near-infrared (NIR) imaging, particularly those centered around Indocyanine Green (ICG), hold the potential for intraoperative tumor targeting. However, the field of medical imaging grapples with two persistent challenges: 1) non-targeted uptake and 2) incomplete elimination of imaging agents. In response to these issues, we focus on the creation of targeted NIR-I/II fluorescence agents possessing optimized physicochemical properties. These innovative compounds encompass zwitterionic organic nanocarriers, such as the noteworthy Harvard Dots (H-Dots). Importantly, these agents can be administered systemically, circumventing non-specific tissue uptake and achieving exclusive elimination through the urinary system. H-dots not only enable the precise determination of surgical margins through NIR image-guided procedures but also serve as effective carriers for targeted anticancer drug delivery. Their unique characteristics result in reduced uptake by the immune system, heightened selectivity for tumors, and enhanced tumor suppression compared to conventional free drugs. Consequently, these H-Dots represent a highly promising theranostic nanoplatform. This research paves the way for the creation of renal-clearable, tissue-specific NIR contrast agents, holding great promise for future advancements in image-guided cancer surgery and, ultimately, improved patient outcomes.
While ICG-based NIR imaging has shown great potential in intraoperative surgery, there are two fundamental and unsolved problems facing medical imaging: 1) nonspecific uptake of intravenously administered diagnostic and/or therapeutic agents by normal tissues and organs and 2) incomplete elimination of unbound targeted agents from the body. These problems make image-guided cancer surgery extremely difficult because the background signal is high, and therefore the TBR is low. Designing a targeted contrast agent that shows fast clearance from the background tissues and eventually from the body after complete targeting is the key to the success of image-guided interventions. “Structure-Inherent Targeting” is a strategy that combines tissue-specific targeting components and imaging domain into a single molecule for targeting and imaging specific tissues in real-time, where the compact structural design enables the unbound contrast agent to be easily cleared from the body after targeting.
Accurate mapping of gastrointestinal stromal tumors (GIST) during surgery is difficult, which contributes to the suboptimal diagnosis and recurrence of cancers. To overcome this limitation, we developed a near-infrared (NIR) fluorescent nanoprobe for real-time navigation of GIST using a targeted strategy against the CD117 ligand stem cell factor (SCF). A zwitterionic NIR fluorophore conjugated to SCF showed specific binding to a xenograft mouse model of CD117-positive GIST-T1 with minimal nonspecific tissue signals. This promising intraoperative imaging strategy could be further explored for early diagnosis and follow-up of GIST prognosis before and after surgical resection.
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