TM1-IR680 peptide for assessment of surgical margin and lymph node metastasis in murine orthotopic model of oral cancer

Abstract

Treatment outcome after surgical removal in oral carcinoma is poor due to inadequate methodologies available for marking surgical margins. Even though some methodologies for intraoperative margin assessment are under clinical and preclinical trials for other solid tumours, a promising modality for oral cancer surgery is not developed. Fluorescent-based optical imaging using Near Infrared (NIR) dyes tagged to tumour specific target will be an optimal tool for this purpose. One such target, Gastrin Releasing Peptide Receptor (GRPR) was selected for the study, and its binding peptide, TM1-IR680, was tested for its efficacy for surgical margin prediction in murine orthotopic model of oral cancer, derived from primary samples. Here, for the first time in a preclinical analysis, we show that the size and margin of oral cancer can be predicted, as revealed by 3D-imaging. Interestingly, the peptide was sensitive enough to detect lymph nodes that harboured dispersed tumour cells before colonization, which was impossible to identify by conventional histopathology. We recommend the use of TM1-NIR dyes alone or in combination with other technologies to improve the clinical outcome of oral cancer surgery.

Gastrin releasing peptide receptor targeted nano-graphene oxide for near-infrared fluorescence imaging of oral squamous cell carcinoma

“…Other researchers have also shown that other tumors overexpress GRPR on their cell surface, including head/neck 14 . GRPR was further used as a biomarker for surgical margin prediction in a murine orthotopic model of oral cancer and a strong expression of GRPR was observed uniformly in primary OSCC sections as compared to respective adjacent non-malignant region 15 . Bombesin (BBN) peptide has shown high binding affinity and specificity to target the GRPR; efforts have been focused on developing radiolabeled or fluorescent dye labeled BBN analogues for tumor imaging and therapy 14 , 16 – 19 .…”

A Novel Bimodal Imaging Agent Targeting HER2 Molecule of Breast Cancer

“…On the other hand, the dual-modality imaging of optical and ultrasound would provide a complementary mode for tumor molecular diagnosis. Several studies reported that modified NIR fluorescence by conjugating various molecules showed excellent accuracy in the intraoperative detection of tumor margins [ 30 , 31 ]. NIR fluorescence is also a good tracer in visualizing the lymphatics and lymph nodes [ 32 – 34 ] and has been explored for intraoperative image-guiding modality [ 34 , 35 ] with diverse degrees of success.…”

Cyanine Conjugate‐Based Biomedical Imaging Probes

“…Based on the sequence of bombesin, peptide TM1 was designed and coupled to IR680RD; the resultant conjugate 15 was able to predict the tumor size and metastatic lymph nodes in murine orthotopic model of oral cancer (Figure 4b). [28] More often analogues of endogenous ligands are used for the pursuit of improved pharmacokinetics and safety profile, simplified synthesis, conjugation process, and so forth (Figure 4a). For instance, based on endogenous -(2,9)-oligosialic acid sugar epitope and mannose, -(2,9)-trisialic acid and 2amino-2-deoxymannose were conjugated with cyanine fluorophores for targeted imaging of sia-binding immunoglobulinlike lectins on PC-12 cells (16) and mannose receptors on tumorassociated macrophages (17), respectively.…”

“…Two small molecular antagonist L-733060 (26) and Z-360 (27) were directly coupled with the same cyanine scaffold, LS-288, for targeted imaging of tumor xenografts expressing neurokinin-1 receptor (NK1R) and cholecystokinin 2 receptor (CCK2R), respectively (Figure 6b). [39] cFLFLFK, a peptide antagonist that binds to human neutrophils via formyl peptide receptor 1, was conjugated with Cy3 (28) to visualize tuberculosis granuloma. [40] It is also acceptable to modify these agents for all kinds of purposes as long as their binding affinities do not get significantly hampered.…”