Bimodal Nb-tracers for rapid and specific pre-and intra-operative cancer imaging

Activiteit: Talk or presentation at a conference

Description

Cancer surgery remains pivotal in the treatment of localized tumors and disseminated disease, often in combination with adjuvant therapies. However, the intra-operative identification of tumor margins depends fully on tactile and/or visual cues, which is insufficient. Misidentification of margins leads to under- or overtreatment, resulting in positive surgical margins (PSM) or damage to nearby structures. Unfortunately, PSM occur in 5-35% of the patients, depending on the tumor type and stage. The presence of PSM significantly increases the chance of local cancer recurrence and negatively impacts the disease-specific and overall survival rates.
Fluorescence image-guided surgery shows great potential for the intra-operative visualization of tumor margins. Compared to other techniques, fluorescence imaging provides real-time tumor margin visualization, without interfering in the surgical workflow. However, the tissue penetration of the fluorescent signal is limited and hinders the identification of deep or occult lesions. The combination of fluorescence imaging with pre-operative nuclear imaging and/or intra-operative gamma-probing can amend this disadvantage. The deep tissue penetration of gamma-rays supports tumor localization, and the fluorescent signal guides the specific tumor resection. Preferentially, both modalities are combined in a single-label, bimodal tracer to overcome kinetic variations. ,
In this study, we discuss two different strategies to design bimodal tracers based on Nanobodies (Nbs). Nbs have high target-specificity and exhibit an ideal biodistribution for imaging applications with high contrast images within hours after injection. The first approach to design bimodal Nb-tracers consists of labeling Nbs with a ‘Multifunctional Single Attachment Point’ (MSAP). This MSAP combines a Cy5-dye and a DTPA-chelator for Indium-111 functionalization in one structure, and thus allows single-label, bimodal tracer design. However, MSAP require a labor-intensive synthesis, and Indium-111 is not ideal for intra-operative gamma-probing. Thus, a second approach was explored, in which the Nb is site-specifically functionalized in two steps with both IRDye800CW, a dye emitting in near-infrared instead of far-red, and Technetium-99m, a clinically relevant radioisotope for intra-operative gamma-probing. Both approaches resulted in functional, bimodal tracers, which exhibited high specificity for their target and high in vivo and ex vivo target-to-background ratios within hours after injection.

1 Ryan K Orosco et al., “Positive Surgical Margins in the 10 Most Common Solid Cancers,” Scientific Reports 8, no. 1 (2018), https://doi.org/10.1038/s41598-018-23403-5.
2 Marlène C Hekman et al., “Tumor-Targeted Dual-Modality Imaging to Improve Intraoperative Visualization of Clear Cell Renal Cell Carcinoma: A First in Man Study.,” Theranostics 8, no. 8 (2018): 2161–70, https://doi.org/10.7150/thno.23335.
3 Ralph Weissleder and Vasilis Ntziachristos, “Shedding Light Onto Live Molecular Targets,” Nature Medicine 9, no. 1 (2003), https://doi.org/10.1038/NM0103-123.
Periode29 mei 20223 jun 2022
Evenementstitel22e GFPP-BPGM5: Joint meeting of the French and Belgian peptides and proteins societies
EvenementstypeConference
LocatieLeucate, France
Mate van erkenningInternational