Abstract
Purpose
Noninvasive and real-time detection of tumor sites is highly important for precision cancer surgery. In this study, we developed indocyanine green (ICG)-loaded microspheres as near-infrared (NIR) fluorescence markers for the noninvasive and long-term localization of tumor sites.
Methods
Microspheres were prepared using a water-in-oil-in-water method to encapsulate ICGs into small and multiple separated pores inside the microspheres. Microspheres containing different amounts of Poloxamer 188 were evaluated both in vitro and in vivo.
Results
Encapsulation of ICG and the human serum albumin (HSA) complex in the microspheres showed 25-fold higher fluorescence signals than ICG alone. The addition of 1% poloxamer 188 (P-188) to the oil phase resulted in the highest fluorescence signal from the microspheres. When ICG-HSA-loaded microspheres with 1% P-188 were subcutaneously injected into SKH-1 hairless mice, strong fluorescence signals from the injection sites were detected for up to 30 d without a significant reduction in the NIR fluorescence intensity.
Conclusion
Biocompatible ICG dye-loaded microspheres have great potential as long-term fluorescent markers for imaging-guided precision surgery.
![](https://cdn.statically.io/img/media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs40005-024-00685-8/MediaObjects/40005_2024_685_Fig1_HTML.png)
![](https://cdn.statically.io/img/media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs40005-024-00685-8/MediaObjects/40005_2024_685_Fig2_HTML.jpg)
![](https://cdn.statically.io/img/media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs40005-024-00685-8/MediaObjects/40005_2024_685_Fig3_HTML.png)
![](https://cdn.statically.io/img/media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs40005-024-00685-8/MediaObjects/40005_2024_685_Fig4_HTML.png)
![](https://cdn.statically.io/img/media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs40005-024-00685-8/MediaObjects/40005_2024_685_Fig5_HTML.jpg)
Similar content being viewed by others
Data availability
All data generated or analysed during this study are included in this published article and its supplementary information file.
References
An F, Yang Z, Zheng M, Mei T, Deng G et al (2020) Rationally assembled albumin/indocyanine green nanocomplex for enhanced tumor imaging to guide photothermal therapy. J Nanobiotechnology 18:49
Cassinotti E, Al-Taher M, Antoniou SA, Arezzo A, Baldari L et al (2023) European Association for Endoscopic Surgery (EAES) consensus on indocyanine green (ICG) fluorescence-guided surgery. Surg Endosc 37:1629–1648
Cheng X, Henick BS, Cheng K (2024) Anticancer therapy targeting cancer-derived extracellular vesicles. ACS Nano 18:6748–6765
Choi Y, Kim SY, Kim SH, Park TG, Moon HT et al (2002) In vivo biocompatibility studies of poly(D, L-lactide)/poly(ethylene glycol)-poly(L-lactide) microspheres containing all-trans-retinoic acid. J Biomater Sci Polym Ed 13:301–322
Cui W, Bei J, Wang S, Zhi G, Zhao Y et al (2005) Preparation and evaluation of poly(L-lactide-co-glycolide) (PLGA) microbubbles as a contrast agent for myocardial contrast echocardiography. J Biomed Mater Res B Appl Biomater 73:171–178
Garbarino GM, Laracca GG, Lucarini A, Piccolino G, Mercantini P et al (2022) Laparoscopic versus open surgery for gastric cancer in western countries: a systematic review and meta-analysis of short- and long-term outcomes. J Clin Med 11:3590
Gnant M (2022) Breast surgery after neoadjuvant therapy. Curr Opin Oncol 34:643–646
Hartmann S, Reimer T, Gerber B, Stubert J, Stengel B et al (2018) Wire localization of clip-marked axillary lymph nodes in breast cancer patients treated with primary systemic therapy. Eur J Surg Oncol 44:1307–1311
Jang HJ, Song MG, Park CR, Youn HW, Lee YS et al (2023) Imaging of indocyanine green-human serum albumin (ICG-HSA) complex in secreted protein acidic and rich in cysteine (SPARC)-expressing glioblastoma. Int J Mol Sci 24:850
Kim HJ, Kim HY, Lee EY, Choi BK, Jang HC et al (2020) A quenched annexin V-fluorophore for the real-time fluorescence imaging of apoptotic processes in vitro and in vivo. Adv Sci 7:2002988
Kosaka N, Ogawa M, Choyke PL, Kobayashi H (2009) Clinical implications of near-infrared fluorescence imaging in cancer. Future Oncol 5(9):1501–1511
Lee SS, Kim HJ, Sohn DK, Eom JB, Seo YS et al (2020) Indocyanine green-loaded injectable alginate hydrogel as a marker for precision cancer surgery. Quant Imaging Med Surg 10:779–788
Madhi H, Lee JS, Choi YE, Li Y, Kim MH et al (2022) FOXM1 inhibition enhances the therapeutic outcome of lung cancer immunotherapy by modulating PD-L1 expression and cell proliferation. Adv Sci 9:e2202702
Miliotou AN, Papadopoulou LC (2018) CAR T-cell therapy: a new era in cancer immunotherapy. Curr Pharm Biotechnol 19:5–18
Mylonaki I, Allémann E, Delie F, Jordan O (2018) Imaging the porous structure in the core of degrading PLGA microparticles: the effect of molecular weight. J Control Release 286:231–239
NtziachristosV BC, Weissleder R (2003) Fluorescence imaging with near-infrared light: new technological advances that enable in vivo molecular imaging. Eur Radiol 13:195–208
Pang Q, Duan L, Jiang Y, Liu H (2021) Oncologic and long-term outcomes of enhanced recovery after surgery in cancer surgeries—a systematic review. World J Surg Oncol 19:191
Philip R, Penzkofer A, Bäumler W, Szeimies RM, Abels C (1996) Absorption and fluorescence spectroscopic investigation of indocyanine green. J Photochem Photobio A 96:137–148
Philpotts LE, Lee CH (2002) Clip migration after 11-gauge vacuum-assisted stereotactic biopsy: case report. Radiology 222:794–796
Raj A, Babu A, Kothandan VK, Park IK, Hwang SR (2023) Development of nano-immunotherapy for cancer treatment: achievements and scopes. J Pharm Investig 53:827–844
Reinhart MB, Huntington CR, Blair LJ, Heniford BT, Augenstein VA (2016) Indocyanine green: historical context, current applications, and future considerations. Surg Innov 23:166–175
Rhew K, Chae YJ, Chang JE (2022) Progress and recent trends in photodynamic therapy with nanoparticles. J Pharm Investig 52:587–599
Saxena V, Sadoqi M, Shao J (2003) Degradation kinetics of indocyanine green in aqueous solution. J Pharm Sci 92:2090–2097
Song G, Petschauer JS, Madden AJ, Zamboni WC (2014) Nanoparticles and the mononuclear phagocyte system: pharmacokinetics and applications for inflammatory diseases. Curr Rheumatol Rev 10:22–34
Zandstra J, Hiemstra C, Petersen AH, Zuidema J, Beuge MM et al (2014) Microsphere size influences the foreign body reaction. Eur Cell Mater 28:335–347
Acknowledgements
This work was supported by the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety) (Project Number: RS-2020-KD000107) and a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2022R1A2C3011436).
Funding
Funding was provided by Korea Medical Device Development Fund (Grant No. RS-2020-KD000107), National Research Foundation of Korea (Grant No. 2022R1A2C3011436).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All authors (HJ Kim and Y Choi) declare that they have no conflict of interest.
Research involving in human and animal rights
All animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee of the National Cancer Center Research Institute (IACUC approval no. NCC-21-638).
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Kim, HJ., Choi, Y. Indocyanine green-loaded microspheres as a near-infrared fluorescence marker for long-term localization of tumor sites. J. Pharm. Investig. (2024). https://doi.org/10.1007/s40005-024-00685-8
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s40005-024-00685-8