Development of Iodinated Indocyanine Green Analogs as a Strategy for Targeted Therapy of Liver Cancer
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Sierra C Marker1, Andres F Espinoza2, A Paden King3
1Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
Abstract:
Liver cancer is one of the leading causes of cancer-related deaths, with a significant increase in incidence worldwide. Novel therapies are needed to address this unmet clinical need. Indocyanine green (ICG) is a broadly used fluorescence-guided surgery (FGS) agent for liver tumor resection and has significant potential for conversion to a targeted therapy. Here, we report the design, synthesis, and investigation of a series of iodinated ICG analogs (I-ICG), which can be used to develop ICG-based targeted radiopharmaceutical therapy. We applied a CRISPR-based screen to identify the solute carrier transporter, OATP1B3, as a likely mechanism for ICG uptake. Our lead I-ICG compound specifically localizes to tumors in mice bearing liver cancer xenografts. This study introduces the chemistry needed to incorporate iodine onto the ICG scaffold and defines the impact of these modifications on key properties, including targeting liver cancer in vitro and in vivo.
Insights
Researchers developed novel iodinated indocyanine green (ICG) analogs for targeted liver cancer radiopharmaceutical therapy. These compounds show promise for improved tumor localization and treatment by targeting the OATP1B3 transporter.
Area of Science:
- Oncology
- Radiopharmaceutical Chemistry
- Molecular Imaging
Background:
- Liver cancer presents a significant global health challenge with increasing incidence.
- Existing treatments are limited, necessitating novel therapeutic strategies.
- Indocyanine green (ICG) is utilized in fluorescence-guided surgery but has potential for targeted therapy development.
Purpose of the Study:
- To design, synthesize, and investigate novel iodinated ICG analogs (I-ICG) for targeted liver cancer therapy.
- To explore the potential of ICG analogs as radiopharmaceuticals.
- To identify the mechanism of ICG uptake in liver cancer cells.
Main Methods:
- Synthesis of a series of iodinated indocyanine green (ICG) analogs.
- CRISPR-based screening to identify the solute carrier transporter OATP1B3 as an ICG uptake mechanism.
- In vitro and in vivo evaluation of lead I-ICG compound's tumor localization in liver cancer models.
Main Results:
- Successful synthesis of iodinated ICG analogs with potential for radiopharmaceutical applications.
- Identification of OATP1B3 transporter as a key mediator of ICG uptake.
- The lead I-ICG compound demonstrated specific tumor localization in mice with liver cancer xenografts.
Conclusions:
- The study introduces novel chemistry for iodinating ICG, creating potential targeted radiopharmaceuticals.
- OATP1B3 is identified as a crucial transporter for ICG uptake, enabling targeted delivery.
- The developed I-ICG compounds show promise for targeted liver cancer therapy and imaging.
