Indocyanine Green (ICG) is a highly versatile medical dye widely utilized in various diagnostic and therapeutic applications due to its strong near-infrared fluorescence properties. Since its clinical introduction in the 1950s, ICG has become an indispensable tool in fields such as cardiovascular diagnostics, ophthalmology, and oncology. This article explores the synthesis, key properties, and diverse applications of ICG, focusing on its role in enhancing modern medical practices.
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Mechanism of Action
ICG is a water-soluble tricarbocyanine dye that fluoresces under near-infrared light. Upon intravenous administration, it binds rapidly to plasma proteins and is primarily metabolized by the liver, from which it is excreted into the bile. This unique pathway of clearance makes ICG an ideal compound for hepatic and cardiovascular diagnostics. The fact that ICG does not undergo metabolic transformations within the body, combined with its high biocompatibility, has contributed to its widespread acceptance in clinical settings.
Fig.1 Mechanism of action for ICG[1].
ICG in Diagnostics
Cardiovascular and Hepatic Diagnostics
The most notable use of ICG lies in its ability to evaluate cardiac and liver functions. ICG clearance tests are widely employed for assessing hepatic function due to its exclusive uptake by hepatocytes and elimination through the biliary system. This allows for accurate assessments of liver reserve function, particularly in pre-operative evaluations for liver surgery or transplantation. In cardiovascular diagnostics, ICG is employed to measure cardiac output, providing clinicians with a non-invasive method to assess the efficiency of the heart's pumping capacity.
Ophthalmology and Retinal Imaging
In ophthalmology, ICG is used for choroidal angiography, allowing for visualization of the choroid and retinal vessels. Unlike traditional fluorescein angiography, ICG's near-infrared fluorescence penetrates deeper into tissues, providing better contrast and enabling the detection of conditions such as age-related macular degeneration and polypoidal choroidal vasculopathy.
Photodynamic and Photothermal Therapy
ICG in Cancer Treatment
One of the groundbreaking applications of ICG is in photodynamic therapy (PDT) for cancer treatment. ICG acts as a photosensitizer, absorbing near-infrared light to produce reactive oxygen species (ROS) that destroy cancerous cells. The key advantages of ICG-based PDT are its minimal side effects and its ability to target tumor tissues with high precision.
Recent advancements have focused on improving ICG's photodynamic efficacy. For instance, the development of ICG-loaded nanobubbles (NBs-O2) has significantly increased the photodynamic effect, achieving better tumor ablation outcomes. Clinical studies have demonstrated that ICG-NBs-O2 formulations exhibit superior tumor-targeting capabilities compared to free ICG, offering a promising solution for enhancing PDT outcomes in cancer therapies.
Fig.2 ICG-assembled free oxygen nanobubbles enhance near-infrared-induced photodynamic therapy[2].
ICG as a Dual-Modality Agent: Photothermal and Photodynamic Therapy
ICG's photothermal properties, alongside its photodynamic effects, make it a powerful agent in combined photothermal and photodynamic cancer therapies. When exposed to near-infrared light, ICG generates heat, leading to localized destruction of cancer cells through hyperthermia. This dual-action mechanism increases treatment efficacy and reduces damage to surrounding healthy tissues.
ICG as a Dual-Modality Agent: Photothermal and Photodynamic Therapy
ICG's photothermal properties, alongside its photodynamic effects, make it a powerful agent in combined photothermal and photodynamic cancer therapies[3]. When exposed to near-infrared light, ICG generates heat, leading to localized destruction of cancer cells through hyperthermia. This dual-action mechanism increases treatment efficacy and reduces damage to surrounding healthy tissues.
Advances in Nanotechnology for ICG Delivery
Nanoparticle Encapsulation
To overcome the limitations of ICG's instability in aqueous solutions, various nanoparticle systems have been developed. These systems enhance ICG's optical properties, improve its biodistribution, and prolong its retention in target tissues. For instance, polymeric nanoparticles and lipid-based nanocarriers have been used to encapsulate ICG, increasing its stability and enhancing its therapeutic potential in both imaging and therapy.
Targeted Delivery Systems
Surface modification of ICG-loaded nanoparticles with targeting ligands, such as hyaluronic acid or antibodies, has further enhanced its specificity towards cancer cells. Such targeted delivery systems reduce off-target effects and improve the selective accumulation of ICG in tumor tissues, improving the overall therapeutic index.
| Nanoparticle Type | Benefits |
|---|
| Lipid-based Nanoparticles | Improved biodistribution and stability |
| Polymeric Nanoparticles | Enhanced light absorption and release |
| Gold Nanoparticles | Synergistic photothermal effects |
| Micelles | Enhanced solubility and prolonged circulation time |
Clinical Applications
- Surgical Navigation - ICG has been increasingly employed in surgical navigation, providing real-time fluorescence-guided imaging during surgeries. In procedures such as sentinel lymph node mapping, tumor resection, and vascular imaging, ICG fluorescence significantly enhances the surgeon's ability to identify critical structures, thereby reducing surgical risks and improving patient outcomes.
- ICG in Tumor Resection - In oncology, ICG-guided surgery has demonstrated remarkable efficacy in ensuring complete tumor removal. The use of near-infrared imaging enables surgeons to delineate tumor margins more accurately, leading to higher rates of R0 resection, where no residual tumor remains post-surgery.
- Liver Function Tests - ICG clearance tests are widely used for assessing liver function pre-operatively, especially in liver transplantation and hepatectomy cases. Combined with other liver function markers, such as the Child-Turcotte-Pugh (CTP) score, ICG tests provide a comprehensive evaluation of liver reserve function, helping to determine the most appropriate surgical approaches and predict post-operative outcomes.
Overcoming Challenges in ICG Use
A. One of the main challenges with ICG is its poor stability in aqueous environments and its tendency to aggregate, which can reduce fluorescence efficiency. Recent innovations have addressed these challenges through various methods, including the development of deuterated ICG, nanoparticle encapsulation, and micellar formulations, all of which significantly enhance the stability and optical properties of ICG.
B. The introduction of deuterated ICG, where a hydrogen atom in the molecule is replaced with deuterium, has resulted in enhanced stability in aqueous solutions. This modification prevents rapid degradation and prolongs the dye's effectiveness, making it a valuable improvement for long-term diagnostic and therapeutic applications.
Conclusion
ICG continues to play a pivotal role in medical diagnostics and therapeutic interventions, particularly in oncology, ophthalmology, and surgical navigation. With the advancements in nanoparticle encapsulation, targeted delivery, and dual-modality therapies, ICG's potential has expanded beyond conventional diagnostics to become a key player in precision medicine.
References
- Cho SS, et al. (2019). "Indocyanine-Green for Fluorescence-Guided Surgery of Brain Tumors: Evidence, Techniques, and Practical Experience." Frontiers in Surgery, 6.
- Yang L, et al. (2021). "Indocyanine Green Assembled Free Oxygen-Nanobubbles towards Enhanced Near-infrared Induced Photodynamic Therapy." Nano Research, 15, 4285-4293.
- Xue P, et al. (2018). "Indocyanine Green-Conjugated Magnetic Prussian Blue Nanoparticles for Synchronous Photothermal/Photodynamic Tumor Therapy." Nano-Micro Letters, 10, 74.
