Indocyanine green-loaded injectable alginate hydrogel as a marker for precision cancer surgery

Abstract

Background: Accurate identification of tumor sites and boundaries is of paramount importance during minimally invasive surgery. Although laparoscopic resection is being increasingly and widely performed for early gastric and colorectal cancers, the detection of tumors located inside the stomach and intestine is difficult owing to the lack of tactile sensation. Here, we propose the application of an indocyanine green (ICG)-loaded alginate hydrogel system as a fluorescence surgical marker for precise laparoscopic operations.Methods: A physical complex of ICG and human serum albumin (HSA) was mixed with sodium alginate to form an injectable hydrogel system. Calcium carbonate and D-gluconic acid (GA) were added to the gel to control its strength and gelation time, respectively. The optimal conditions for the preparation of injectable hydrogels were determined by analyzing the fluorescence spectra and sol-gel transition time of the prepared samples at various concentrations and compositions. Next, the aqueous solutions of ICG, ICG-HSA, and ICG-HSA-loaded alginate were subcutaneously injected into nude mice (three mice per group), and nearinfrared (NIR) fluorescence images of the mice (λ ex. =780 nm, λ em. =845 nm) were obtained at different points in time for 8 days. Then, fluorescence intensities at the injection sites, target-to-background ratio, and areas of ICG fluorescence were analyzed. Finally, the potential utility of ICG-HSA-loaded alginate hydrogel as a surgical marker was evaluated in a porcine model. The ICG-HSA-loaded alginate solution was injected into three sites in the submucosal space of the porcine stomach via a catheter. A fluorescent laparoscopic system was installed on the abdomen of the pig 3 days post-injection, and the fluorescence signal generated from the fluorescence surgical marker located inside the stomach was evaluated using the fluorescence laparoscope system (λ ex. =785 nm, λ em. =805 nm). Results:The optimal concentration of ICG-HSA complex was determined to be 30 μM, and maximum fluorescence intensity of the complex was obtained at a 1:1 mole ratio of HSA to ICG. The subcutaneous injection of ICG or ICG-HSA solution in mice resulted in the rapid spread of the fluorescence signal around the injection site in 3 h, and a weak fluorescence was detected at the injection site 24 h post-injection. In contrast, the fluorescence detection time was effectively prolonged up to 96 h post-injection in the case of ICG-HSA-loaded alginate gel, while diffusion of the injected ICG from the injection site was effectively prevented. In the laparoscopic operation, injection sites of the hydrogel in porcine stomach could be accurately detected in real time even after 3 days.Conclusions: This alginate hydrogel system may be potentially useful as an effective surgical marker in terms of accuracy and persistence for laparoscopic operation.

Dynamic contrast-enhanced near-infrared spectroscopy using indocyanine green on moderate and severe traumatic brain injury: a prospective observational study

“…ICG is a contrast dye with absorption and fluorescence properties in the NIR spectral range, and is commonly used in clinical practice (e.g., neuro-oncology; theranostic nanomedicine) (19)(20)(21)(22). The ICG photon absorption is related to the dye concentration and to the nature of the solvent in which it is dissolved (23).…”

Radionuclide 131I-labeled albumin-indocyanine green nanoparticles for synergistic combined radio-photothermal therapy of anaplastic thyroid cancer

“…As a natural drug carrier, HSA had the characteristics of low immunogenicity, good biocompatibility, good biodegradability, and long circulation in vivo . As a low-toxic and safe clinical dye, ICG had a high affinity for proteins ( 19 ) and could non-covalently bind to HSA ( 20 ). 131 I therapy (RAI) was the mainstay of standard treatment for DTC ( 34 ).…”

“…ICG had a high affinity for protein ( 19 ). ICG non-covalently bound to HSA has higher fluorescence efficiency and stability than free ICG ( 20 ). HSA-ICG nanoparticles (NPs) could be further loaded with a variety of functional drugs, such as chemotherapeutic drugs, metal ions, radionuclides, and other two-dimensional materials, thus being successfully used for multimodal tumor imaging and treatment ( 21 ).…”

Lanthanide-based metal–organic frameworks solidified by gelatin-methacryloyl hydrogels for improving the accuracy of localization and excision of small pulmonary nodules

“…Nevertheless, as a small-molecule fluorescent dye, ICG is unstable, and is easily quenched under protracted laser excitation [ 10 ]. Furthermore, rapid diffusion of the ICG solution into the surrounding pulmonary parenchyma and visceral pleura may decrease the accuracy of localization [ 11 ]. Moreover, ICG is difficult to observe in CT images prior to surgery when it is necessary to confirm the localization site, although it can be observed immediately after injection.…”