Novel locally nebulized indocyanine green for simultaneous identification of tumor margin and intersegmental plane.

BACKGROUND: Segmentectomy, recommended for early-stage lung cancer or compromised lung function, demands precise tumor detection and intersegmental plane identification. While indocyanine green (ICG) commonly aids in these aspects using near-infrared imaging, its separate administrations through different routes and times can lead to complications and patient anxiety. This study aims to develop a lung-specific delivery method by nebulizing low-dose ICG to targeted lung segments, allowing simultaneous detection of lung tumors and intersegmental planes across diverse animal models. METHODS: To optimizing the dose of ICG for lung tumor and interlobar fissure detection, different doses of ICG (0.25, 0.1, and 0.05 mg/kg) were nebulized to rabbit lung tumor models. The distribution of locally nebulized ICG in targeted segments was studied to evaluate the feasibility of detecting lung tumor and intersegmental planes in canine lung pseudotumor models. RESULTS: Near-infrared fluorescence imaging demonstrated clear visualization of lung tumor margin and interlobar fissure using local nebulization of 0.1 mg/kg ICG for only 4 min during surgery in the rabbit models. In the canine model, the local nebulization of 0.05 mg/kg of ICG into the target segment enabled clear visualization of pseudotumor and intersegmental planes for 30 min. CONCLUSIONS: This innovative approach achieves a reduction in ICG dose and prolonged the visualization time of the intersegmental plane and effectively eliminates the need for the hurried marking of tumors and intersegmental planes. The authors anticipate that lung-specific delivery of ICG will prove valuable for image-guided limited resection of lung tumors in clinical practice.

Simultaneous Visualization of Lung Tumor and Intersegmental Plane during Pulmonary Segmentectomy by Intravenous Injection of Indocyanine Green.

Segmentectomy is a targeted surgical approach tailored for patients with compromised health and early-stage lung cancer. The key to successful segmentectomy lies in precisely identifying the tumor and intersegmental planes to ensure adequate resection margins. In this study, we aimed to enhance this process by simultaneously visualizing the tumor and intersegmental planes through the intravenous injection of indocyanine green (ICG) at different time points and doses. Lung tumors were detected by intravenous injection of ICG at a dose of 2 mg/kg 12 h before surgery in a rabbit model. Following the dissection of the pulmonary artery, vein, and bronchi of the target segment, 0.6 mg/kg of ICG was injected intravenously to detect the intersegmental plan. Fluorescent images of the lung tumors and segments were acquired, and the fluorescent signal was quantified using the signal-to-background ratio (SBR). Finally, a pilot study of this method was conducted in three patients with lung cancer. In a preclinical study, the SBR of the tumor (4.4 ± 0.1) and nontargeted segments (10.5 ± 0.8) were significantly higher than that of the targeted segment (1.6 ± 0.2) (targeted segment vs. nontarget segment, p < 0.0001; target segment vs. tumor, p < 0.01). Consistent with preclinical results, lung tumors and the intersegmental plane were successfully detected in patients with lung cancer. Consequently, adequate resection margins were identified during the surgery, and segmentectomy was successfully performed in patients with lung cancer. This study is the first to use intravenous ICG injections at different time points and doses to simultaneously detect lung cancer and intersegmental planes, thereby achieving segmentectomy for lung cancer.

An injectable fluorescent and iodinated hydrogel for preoperative localization and dual image-guided surgery of pulmonary nodules.

The widespread use of video-assisted thoracoscopic surgery (VATS) has triggered the rapid expansion in the field of computed tomography (CT)-guided preoperative localization and near-infrared (NIR) fluorescence image-guided surgery. However, its broader application has been hindered by the absence of ideal imaging contrasts that are biocompatible, minimally invasive, highly resolvable, and perfectly localized within the diseased tissue. To achieve this goal, we synthesize a dextran-based fluorescent and iodinated hydrogel, which can be injected into the tissue and imaged with both CT and NIR fluorescence modalities. By finely tuning the physical parameters such as gelation time and composition of iodinated oil (X-ray contrast agent) and indocyanine green (ICG, NIR fluorescence dye), we optimize the hydrogel for prolonged localization at the injected site without losing the dual-imaging capability. We validate the effectiveness of the developed injectable dual-imaging platform by performing image-guided resection of pulmonary nodules on tumor-bearing rabbits, which are preoperatively localized with the hydrogel. The injectable dual-imaging marker, therefore, can emerge as a powerful tool for surgical guidance.

Detection of metastatic lymph node and sentinel lymph node mapping ​using mannose receptor targeting in in vivo mouse footpad tumor models and rabbit uterine cancer models.

BACKGROUND: This study aimed to evaluate the effectiveness of neo-mannosyl human serum albumin-indocyanine green (MSA-ICG) for detecting metastatic lymph node (LN) and mapping sentinel lymph node (SLN) using mouse footpad uterine tumor models. Additionally, the authors assessed the feasibility of MSA-ICG in SLN mapping in rabbit uterine cancer models. MATERIALS AND METHODS: The authors compared the LN targeting ability of MSA-ICG with ICG. Six mouse footpad tumor models and two normal mice were each assigned to MSA-ICG and ICG, respectively. After the assigned tracers were injected, fluorescence images were taken, and the authors compared the signal-to-background ratio (SBR) of the tracers. A SLN biopsy was performed to confirm LN metastasis status and CD206 expression level. Finally, an intraoperative SLN biopsy was performed in rabbit uterine cancer models using MSA-ICG. RESULTS: The authors detected 14 groin LNs out of 16 in the MSA-ICG and ICG groups. The SBR of the MSA-ICG group was significantly higher than that of the ICG group. The metastatic LN subgroup of MSA-ICG showed a significantly higher SBR than that of ICG. CD206 was expressed at a high level in metastatic LN, and the signal intensity difference increased as the CD206 expression level increased. SLN mapping was successfully performed in two of the three rabbit uterine cancer models. CONCLUSIONS: MSA-ICG was able to distinguish metastatic LN for an extended period due to its specific tumor-associated macrophage-targeting property. Therefore, it may be a more distinguishable tracer for identifying metastatic LNs and SLNs during uterine cancer surgery. Further research is needed to confirm these results.

Precise and safe pulmonary segmentectomy enabled by visualizing cancer margins with dual-channel near-infrared fluorescence.

BACKGROUND: Segmentectomy is a type of limited resection surgery indicated for patients with very early-stage lung cancer or compromised function because it can improve quality of life with minimal removal of normal tissue. For segmentectomy, an accurate detection of the tumor with simultaneous identification of the lung intersegment plane is critical. However, it is not easy to identify both during surgery. Here, the authors report dual-channel image-guided lung cancer surgery using renally clearable and physiochemically stable targeted fluorophores to visualize the tumor and intersegmental plane distinctly with different colors; cRGD-ZW800 (800 nm channel) targets tumors specifically, and ZW700 (700 nm channel) simultaneously helps discriminate segmental planes. METHODS: The near-infrared (NIR) fluorophores with 700 nm and with 800 nm channels were developed and evaluated the feasibility of dual-channel fluorescence imaging of lung tumors and intersegmental lines simultaneously in mouse, rabbit, and canine animal models. Expression levels of integrin αvß3, which is targeted by cRGD-ZW800-PEG, were retrospectively studied in the lung tissue of 61 patients who underwent lung cancer surgery. RESULTS: cRGD-ZW800-PEG has clinically useful optical properties and outperforms the FDA-approved NIR fluorophore indocyanine green and serum unstable cRGD-ZW800-1 in multiple animal models of lung cancer. Combined with the blood-pooling agent ZW700-1C, cRGD-ZW800-PEG permits dual-channel NIR fluorescence imaging for intraoperative identification of lung segment lines and tumor margins with different colors simultaneously and accurately. CONCLUSION: This dual-channel image-guided surgery enables complete tumor resection with adequate negative margins that can reduce the recurrence rate and increase the survival rate of lung cancer patients.