Development of a Macromolecular Dual-Modality MR-Optical Imaging for Sentinel Lymph Node Mapping

Abstract

Objective-To evaluate the effectiveness of a dual magnetic resonance-near infrared fluorescence optical imaging agent, poly(L-glutamic acid)-DTPA-Gd-NIR813, for both preoperative and intraoperative visualization and characterization of sentinel lymph nodes (SLN) in mice.Materials and Methods-Poly(L-glutamic acid) was conjugated with DTPA-Gd and NIR813 dye to obtain PG-DTPA-Gd-NIR813. To confirm drainage into the SLNs, this agent was injected subcutaneously into the front paw of nude mice followed by isosulfan blue (n = 6). Furthermore, PG-DTPA-Gd-NIR813 was injected subcutaneously at doses of 0.002 mmol Gd/kg (4.8 nmol eq. NIR813) and 0.02 mmol Gd/kg (48 nmol eq. NIR813) (n = 3/dose). To differentiate metastatic from non-metastatic lymph nodes, nude mice bearing human oral squamous cell carcinoma (DM14) were injected intralingually with 0.02 mmol Gd/kg PG-DTPA-Gd-NIR813 (n=3). Pre-and post-contrast images were taken using 4.7T Bruker MRI scanner and Xenogen optical imaging system. The status of lymph nodes resected under the guidance of optical imaging was confirmed by histologic examinations.Results-PG-DTPA-Gd-NIR813 co-localized with isosulfan blue, indicating drainage to the SLN. After subcutaneous injection, axiliary and branchial lymph nodes were clearly visualized with both T1-weighted MR and optical imaging within 3 min of contrast injection, even at the lowest dose tested (0.002 mmol Gd/kg). After intralingual injection in tumor-bearing mice, MR imaging identified 4 of the 6 superficial cervical lymph nodes, whereas NIRF optical imaging identified all 6 cervical nodes. The pattern of contrast enhancement of SLN visualized in MR images showed a characteristic ring-shaped appearance with a central filling defect, possibly resulting from nodal infiltration of metastatic lesions. Histopathologic examination of the SLNs resected under NIRF imaging guidance revealed micrometastases in all 6 SLNs identified by NIRF imaging.

Are nanotheranostics and nanodiagnostics-guided drug delivery stepping stones towards precision medicine?

“…In addition, this probe provided both high sensitivity and anatomical data by a single administration (Koyama et al, 2007). Melancon et al introduced a 46± 6 nm macromolecule consisting of biodegradable poly(L-glutamic acid) conjugated to Gd and NIR813 fluorescent dye (Melancon et al, 2007). The researchers found their system to co-localize with isosulfan blue when injected together subcutaneously to healthy mice while the surrounding tissue was left signal-free.…”

Sentinel lymph node biopsy in renal malignancy: The past, present and future

“…First introduced in 2003 in mice models, it was initially studied in breast cancer, with Melancon et al [47] successfully demonstrating that NIRF provided a superior alternative pre-operative ultrasound [59] . An alternative solution would be the introduction of mathematical algorithms such as the Partin table and Briganti nomograms used in prostate malignancy.…”

“…A study of 2020 patients undergoing SLNB for prostate cancer cited a false a negative rate of 6.2%, whilst a study in 2011 of SLNB in penile malignancy cited an even higher rate of 15% [44,45] . In both cases, figures are controversial and highly variable, and measures such as pre SLNB CT to exclude macrometastases, a potential cause of false negatives, have been implemented [8,44,46,47] . More importantly, SLNB has overcome these problems to become part of the accepted management for both penile and pelvic cancers.…”

Nanoparticles for multimodal in vivo imaging in nanomedicine

“…For example, NIRF-guided sentinel lymph-node mapping techniques could be a promising way in the near future to evaluate lymphatic metastasis in humans. 61,62 In the previous section, we reviewed four imaging modalities (MRI, CT, PET/SPECT, and optical imaging) widely applied in both research and clinical fields. They have both strengths and weaknesses for in vivo imaging.…”