Tumor‐Associated Immune‐Cell‐Mediated Tumor‐Targeting Mechanism with NIR‐II Fluorescence Imaging

Abstract

The strategy of structure‐inherent tumor targeting (SITT) with cyanine‐based fluorophores is receiving more attention because no chemical conjugation of targeting moieties is required. However, the targeting mechanism behind SITT has not yet been well explained. Here, it is demonstrated that heptamethine‐cyanine‐based fluorophores possess not only targetability of tumor microenvironments without the need for additional targeting ligands but also second near‐infrared spectral window (NIR‐II) imaging capabilities, i.e., minimum scattering and ultralow autofluorescence. The new SITT mechanism suggests that bone‐marrow‐derived and/or tissue‐resident/tumor‐associated immune cells can be a principal target for cancer detection due to their abundance in tumoral tissues. Among the tested, SH1 provides ubiquitous tumor targetability and a high tumor‐to‐background ratio (TBR) ranging from 9.5 to 47 in pancreatic, breast, and lung cancer mouse models upon a single bolus intravenous injection. Furthermore, SH1 can be used to detect small cancerous tissues smaller than 2 mm in diameter in orthotopic lung cancer models. Thus, SH1 could be a promising cancer‐targeting agent and have a bright future for intraoperative optical imaging and image‐guided cancer surgery.

Recent Advances in Near‐Infrared‐II Fluorescence Imaging for Deep‐Tissue Molecular Analysis and Cancer Diagnosis

“…[33] Tumor-targeting cyanine-based fluorophores, SH1 900-1250 11% using IR-E1050 and IR26 as references Targeted imaging of various tumors in vivo. [34] AIEgen DTPA-TBZ 1200 11.1% using IR-26 as a reference Multimodal bioimaging for cancer diagnosis. [35] PFTQ-PEG-Gd NPs 1056 0.38% using IR-1061 as a reference Multimodal bioimaging-guided PTT.…”

Topical pH Sensing NIR Fluorophores for Intraoperative Imaging and Surgery of Disseminated Ovarian Cancer

“…[ 53 ] Together, this result suggests that PH08 shows a higher affinity to OATPs than PH03 with its inherent targeting potency which arises from the chemical structure of compound, representing SIT. [ 40 , 41 , 42 , 43 , 44 ]…”

“…[53] Together, this result suggests that PH08 shows a higher affinity to OATPs than PH03 with its inherent targeting potency which arises from the chemical structure of compound, representing SIT. [40][41][42][43][44] We further determined the possible contribution of other membrane transporters including organic cation transporters (OCTs) and organic carnitine (zwitterion) transporters (OCTNs), which are known to play critical roles in the transcellular movement of a wide variety of xenobiotics, including small organic cationic molecules, [55] and may play roles in the uptake of PH08. To this end, ID8 ovarian cancer cells were treated with inhibitors for OATPs, OCTs, or OCTNs.…”

“…This novel NIR fluorophore exhibits rapid signal increases in acidic TME by reducing intramolecular quenching. [ 38 , 39 ] In addition, to resolve the historical issue of lack of targeting mechanisms of fluorophores, we introduced inherent cancer‐targeting within the compounds' chemical structure, the “Structure Inherent Targeting (SIT)” strategy, [ 40 , 41 , 42 , 43 , 44 ] for FGS. By introducing different surface charges and lipophilicity to the backbone of the polymethine structure using various alkyl groups, PH08 showed endogenous affinity to organic anion transporter peptides (OATPs) and enters cancer cells primarily via OATPs and retains in the mitochondria and lysosomes, supporting a long retention time.…”

NIR-I Dye-Based Probe: A New Window for Bimodal Tumor Theranostics

“…Generally, it can be further divided into first near-infrared (NIR-I, 650–950 nm) and second near-infrared (NIR-II, 1,000–1700 nm) fluorescence imaging ( Qi et al, 2018 ; Kubicek-Sutherland et al, 2020 ; Moreno et al, 2020 ; Shinn et al, 2021 ). Although possessing a better signal-to-noise ratio and depth-to-resolution ratio, NIR-II fluorophores still show deficiencies in stability, quantum yield, and biocompatibility ( Bhavane et al, 2018 ; Kenry et al, 2018 ; Qian et al, 2021 ; Kang et al, 2022 ). Hence, FI which we have mentioned in this review refers to NIR-I fluorescence imaging.…”