Optical Surgical Navigation Clinical Trials with IRDye Infrared Dyes

Recent blog posts have highlighted some of the most exciting clinical developments of IRDye® near-infrared fluorescent dyes as surgical aides. Beyond these examples, IRDye infrared dye products are being used in more than 20 clinical trials around the globe, many of which involve the deadliest and most common cancers.

Brain and Pancreatic Cancer

Glioblastoma and glioma brain and pancreatic adenocarcinoma tumors are particularly aggressive forms of cancer that are difficult to treat. IRDye dye-conjugated optical probes are currently being investigated as an alternative to traditional surgical treatments for these cancers.

Very recently in April 2018, Deling Li and colleagues announced the results their first-in-human study a novel 68Ga-IRDye 800CW-BBN positron emission tomography (PET) and near-infrared fluorescent (NIRF) dual modality optical probe in patients with glioblastoma multiforme (GBM) [1, 2]. The authors used preoperative PET and intraoperative fluorescence-guided surgery methods, demonstrating that the “novel dual model imaging technique is feasible for integrated pre- and intra-operative targeted imaging via the same molecular receptor improved intraoperative GBM visualization and maximum safe resection” [1]. GBM is the deadliest and most aggressive glioma type, and novel GBM therapies have the potential to impact many lives.

Learn More About Dual Imaging Modalities with IRDye Optical Probes.


Figure 1. Intraoperative images of glioblastoma multiforme resection with IRDye 800CW-BBN fluorescent dyes [1].

The Dartmouth-Hitchcock Medical Center is sponsoring an investigatory study utilizing IRDye 800CW for ABY-029 in patients with recurrent glioma to determine if proper tumor/background ratio is present for surgical resection [3]. This study is expected to conclude in September 2019. A similar study is being conducted by Eben Rosenthal (Stanford University) to evaluate the effectiveness of IRDye 800CW-panitumumab in glioma surgery for distinguishing tumor cells from other central nervous system tissue [5]. Rosenthal’s study is set to conclude in 2022. Rosenthal has also studied Cetuximab-IRDye 800CW intraoperatively in patients with malignant glioma [4].

Pancreatic cancer has one of the highest mortality rates of all cancers. G.M. van Dam at the University Medical Center Groningen is currently evaluating dosing of IRDye 800CW-bevacuzimab conjugates for pancreatic adenocarcinoma [7]. Similar studies set to conclude soon by Eben Rosenthal are also evaluating the intraoperative potential of IRDye conjugates in pancreatic cancer [6].

Breast and Colorectal Cancer

Breast and colon cancers are some of the most common cancers around the globe with millions of cases diagnosed each year. Two very recent clinical trials by G.M. van Dam at University Medical Center Groningen in collaboration with Martini Hospital Groningen and UMC Utrecht have evaluated the anti-vascular endothelial growth factor antibody-IRDye 800CW-bevacizumab conjugate in breast cancer study [8, 9]. van Dam’s studies are currently assessing dosing, uptake, quantification, and localization of the optical probe, as well as determining if the conjugate is appropriate for intraoperative breast cancer surgery [8, 9].

Learn More About Optical Probe Validation and Parameters.

Colorectal cancer is also a very common diagnosis around the world. Two recent clinical trials by W.B. Nagengast of the University Medical Center Groningen evaluated IRDye 800CW-bevacizumab for colorectal cancer diagnosis [10, 11]. Nagengast noted “there is a need for better visualization of polyps during surveillance endoscopy in patients with hereditary colon cancer syndromes like Familial Adenomatous Polyposis (FAP) and Lynch Syndrome (LS), to improve adenoma detection rate,” also stating that “optical molecular imaging of adenoma associated biomarkers is a promising technique to accommodate this need” [10]. In addition to detection, IRDye 800CW-bevacizumab is also being investigated as an aid for narrowing down specific colon cancer management surgeries and therapies [11].

Other Clinical Applications

While the focus of this blog post series has been on pre-clinical and clinical applications of IRDye conjugates for cancer, these are not the only applications. Currently, IRDye fluorophores are being evaluated in several trials for clinical use in non-cancer surgeries, like abdominal and urological. Ureters, the path for urine between the kidneys and bladder, and the urethra, often present difficulties in abdominal and urological surgery. By illuminating these pathways with fluorescent dyes, the anatomy is bright and clear, which may allow surgeons to more precisely navigate around them during surgery.

A study published in 2017 by T.G. Barnes et.al. in Techniques in Coloproctology demonstrated urethra illumination in cadavers with IRDye 800BK as a method for enhancing low rectal surgical navigation [15]. The authors concluding that “IRDye 800BK is a promising alternative to ICG [indocyanine green] in visualizing the urethra,” and that “Its greater depth of penetration may allow earlier detection of the urethra during surgery and prevent wrong plane surgery sooner” [15].


Figure 2: Intraoperative images of low rectal surgery demonstrating urethral fluorescence at various depths of incision. The first row of images shows how IRDye 800BK illuminates the urethra through layers of tissue to better guide further incisions [15].

LI-COR Biosciences is currently sponsoring a clinical trial being conducted at the University of Alabama-Birmingham evaluating the dose response and safety/toxicity of IRDye 800BK for ureter delineation, which is expected to conclude soon [12]. A similar study is being conducted at the University of Oxford, sponsored by the Oxford University Hospitals NHS Trust, and is evaluating the signal/background ratio of IRDye 800BK in the ureter [13]. This trial will likely conclude later this year.


Figure 3: Intraoperative laproscopic images showing ureter delineation with IRDye 800BK. In minimally invasive surgery (such as laproscopy) ureters may be difficult to see in white light without fluorescent illumination [16].

One final application of IRDye fluorescent dyes is in endometriosis surgery. G.M. van Dam at the University Medical Groningen is investigating the feasibility of IRDye 800CW-bevacizumab for endometriosis surgery [14]. van Dam noted that “incomplete resection of endometriosis lesions often results in recurrence of symptoms and the need for repeated surgery, with considerable associated morbidity” [14]. This is the first feasibility study for IRDye 800CW and endometriosis, and is expected to conclude in early 2019.

Conclusion

This blog series on optical surgery navigation has illuminated the potential of IRDye fluorescent dyes as surgical aids. From the deadliest cancers to routine, minimally-invasive gynecological surgeries, IRDye fluorophores present a valuable opportunity for visualizing, understanding, and ultimately treating various diseases.

Could your probe be our next clinical study? For questions regarding probe development services, contact LI-COR Custom Services.

More information about the studies mentioned can be found at ClinicalTrials.gov at the locations mentioned below or on our Optical Probe Development and Molecular Activity Measurement web pages.

IRDye fluorophores are only used for investigative purposes in clinical trials.

References

  1. Li, D., Zhang, J., Chi, C., Xiao, X., Wang, J., Lang, L., & Ali, I. (2018, April 3). First-In-Human Study of PET and Optical Dual-Modality Image-Guided Surgery in Glioblastoma Using 68Ga-IRDye800CW-BBN. Theranostics, 8(9), 2508-2520. doi:10.7150/thno.25599
  2. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT02901925, A Microdose Evaluation Study in Recurrent Glioma (ABY-029); 2016 December. Available from: https://clinicaltrials.gov/ct2/show/NCT02901925.
  3. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT02910804, IRDye800CW-BBN PET-NIRF Imaging Guiding Surgery in Patients With Glioblastoma; 2015 November. Available from: https://clinicaltrials.gov/ct2/show/NCT02910804.
  4. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT02855086, Cetuximab-IRDye 800CW in Detecting Tumors in Patients With Malignant Glioma Undergoing Surgery; 2016 October. Available from: https://clinicaltrials.gov/ct2/show/NCT02855086.
  5. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT03510208, Panitumumab-IRDye800 in Diagnosing Participants With Malignant Glioma Undergoing Surgery; 2018 May 14. Available from: https://clinicaltrials.gov/ct2/show/NCT03510208.
  6. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT02736578, Cetuximab-IRDye800CW and Intraoperative Imaging in Finding Pancreatic Cancer in Patients Undergoing Surgery; 2016 July. Available from: https://clinicaltrials.gov/ct2/show/NCT02736578.
  7. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT02743975, Near-Infrared Image Guided Surgery in Pancreatic Adenocarcinoma (PENGUIN); 2016 September. Available from: https://clinicaltrials.gov/ct2/show/NCT02743975.
  8. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT02583568, Fluorescence Guided Surgery in Breast Cancer (MARGIN); 2015 October. Available from: https:/clinicaltrials.gov/ct2/show/NCT02583568.
  9. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT01508572, VEGF-Targeted Fluorescent Tracer Imaging in Breast Cancer; 2011 October. Available from: https://clinicaltrials.gov/ct2/show/NCT01508572.
  10. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT02113202, Molecular Fluorescence Endoscopy in Patients With Familial Adenomatous Polyposis, Using Bevacizumab-IRDye800CW (FLUOFAP); 2014 March. Available from: https://clinicaltrials.gov/ct2/show/NCT02113202.
  11. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT01972373, Visualization of Rectal Cancer During Endoscopy, Using a Fluorescent Tracer (RAPIDO-TRACT);2013 October. Available from: https://clinicaltrials.gov/ct2/show/NCT01972373.
  12. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT03106038, Dose-Escalation Study of a Constrant Agent for Delineation of Urological Anatomy in Minimally Invasive Surgery; 2017 May 4. Available from: https://clinicaltrials.gov/ct2/show/NCT03106038.
  13. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT03387410, Ureter Identification with IRDye 800BK; 2018 April 6. Available from: https://clinicaltrials.gov/ct2/show/NCT03387410.
  14. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT02975219, Feasibility Study of Using Molecular Fluorescence Guided Surgery in Endometriosis (Endo-Light); 2017 May 1. Available from: https://clinicaltrials.gov/ct2/show/NCT02975219.
  15. Barnes, T. G., Volpi, D., Cunningham, C., Vonjovic, B., & Hompes, R. (2018, February 19). Improved Urethral Fluorescence During Low Rectal Surgery: A New Dye and a New Method. Techniques in Coloproctology, 22, 115-119. doi:10.1007/s1051-018-1757-6
  16. Al-Taher, M., van den Bos, J., Schols, R. M., Kubat, B., Bouvy, N. D., & Stassen, L. S. (2018, February 2). Evaluation of a Novel Dye for Near-Infrared Fluorescence Delineation of the Ureters During Laparoscopy. British Journal of Surgery BJS Open. doi:10.1002/bjs5.59

Use of IRDye Infrared Dye-Labeled Optical Probes for Intraoperative Tumor Visualization

A major challenge in cancer surgery is being certain that all the tumor has been removed, including the residual cancer cells not immediately identified with the naked eye after resection. Surgeons need intraoperative methods of imaging tumors to assist them in identifying healthy and diseased tissue. These methods need to be safe and effective. Near-infrared (NIR) fluorescent optical probes may provide a viable solution.

Near-infrared fluorescent optical probes have been used intraoperatively in clinical trials. These NIR dye-conjugated compounds offer several advantages for use in the operating room. NIR probes can be used safely, unlike other imaging modalities that require radiation (such as CT, PET, and SPECT).

IRDye® dye-conjugated optical probes have been shown to be sensitive and biomarker-specific and their fluorescent signal correlates with tumor location observed by other imaging methods and traditional pathology. Because fluorescence from NIR optical probes is invisible to the human eye, visualization of the surgical field of view with white light is unimpeded.

Fluorescence from tissue excised during surgery can be visualized while in the operating room and used to assess whether resection of the tumor is complete. Traditional pathologic examination can then be done for confirmation. Specialized NIR imaging equipment, such as the Pearl® Imaging System, has been used successfully to image tumor sections during an operation.
The following two studies involved the intraoperative use of near-infrared fluorescence optical probes.

IRDye 800CW Dye-Conjugated Probes Provide Verification of Tumor

In this study by van Driel, et al., investigators evaluated the Artemis imaging system, developed in collaboration with the Center for Translational Molecular Medicine. The goal of the study “was to evaluate the Artemis camera in two oncological procedures in which real-time NIR fluorescence could be of added value: (a) radical tumor resection; and (b) detection of sentinel lymph nodes. . .” [1]
For the evaluation of the Artemis imaging system, the investigators used ICG and two IRDye® 800CW infrared dye-conjugated nanobodies. “IRDye 800CW (LI-COR, Lincoln, NE, USA, λex=774 nm, λem=789 nm) was chosen because it is one of two novel fluorophores in the process of clinical translation.” [1] The study assessed the sensitivity and utility of the Artemis system for intraoperative detection of head-and-neck tumors and sentinel lymph nodes in xenograft mouse models. [1]

Fluorescent images were concurrently acquired with the Pearl® Impulse Small Animal Imager (LI-COR). [1] “The Pearl system is expected to be an order of magnitude more sensitive than the Artemis, and therefore, these images serve as a ground truth comparison.” [1]

IRDye 800CW Dye-Labeled Probes Target VEGF and HER2

Research performed by Terwisscha van Scheltinga, et al. used IRDye 800CW dye-labeled antibodies to investigate their use in targeting certain tumors for optical surgical navigation [2]. The group concluded that “NIR fluorescence-labeled antibodies targeting VEGF or HER2 can be used for highly specific and sensitive detection of tumor lesions in vivo. These preclinical findings encourage future clinical studies with NIR fluorescence–labeled tumor-specific antibodies for intraoperative-guided surgery in cancer patients.” [2]

In this preclinical mouse study, fluorescent optical imaging with IRDye 800CW NHS ester coupled to bevacizumab was compared to PET imaging with 89Zr (5 MBq)-labeled bevacizumab or trastuzimab along with a non-specific antibody control, 111In-IgG (1 MBq). [2]

The researchers of this study stated, “IRDye 800CW is a NIR fluorophore with optimal characteristics for clinical use, allowing binding to antibodies when used in its N-hydroxy-succinimide (NHS) ester form. A preclinical toxicity study with IRDye 800CW carboxylate showed no toxicity in doses of up to 20 mg/kg intravenously or intradermally.” [2] They concluded that “In a preclinical setting, NIR fluorescence–labeled antibodies targeting VEGF or HER2 allowed highly specific and sensitive detection of tumor lesions in vivo.” [2]

IRDye 800CW dye-conjugated optical probes are currently involved in over a dozen clinical trials for a wide range of different cancers. These studies demonstrate the use of IRDye probes for optical surgical navigation. Several studies have employed the use of dual-labeled probes showing the strength of combining near-infrared fluorescence with other imaging modalities.

Examples of optical probe applications are detailed on Optical Probe Development and Molecular Activity Measurement web pages.

Do you have questions about how IRDye infrared dye-labeled probes could be used in your research or need help conjugating your optical probe? If so, please contact LI-COR Custom Services.

References:

  1. van Driel, P.B.A.A., et al. Characterization and Evaluation of the Artemis Camera for Fluorescence-Guided Cancer Surgery Mol Imaging Biol (2015) 17:413Y423. doi: 10.1007/s11307-014-0799-z
  2. Terwisscha van Scheltinga, A.G.T., et al. Intraoperative Near-Infrared Fluorescence Tumor Imaging with Vascular Endothelial Growth Factor and Human Epidermal Growth Factor Receptor 2 Targeting Antibodies J Nucl Med 2011; 52:1778–1785. doi: 10.2967/jnumed.111.092833.

NEW! IRDye® Goat Anti-Mouse IgM Secondary Antibodies from LI-COR®!

IRDye Dye-labeled Goat anti-Mouse AntibodiesOur IRDye secondary antibody line is growing! We have recently added IRDye Goat anti-Mouse IgM (μ chain specific) secondaries labeled with:

  • IRDye 800CW (PN 926-32280)
  • IRDye 680RD (PN 926-68180) or
  • IRDye 680LT (PN 926-68080).

Just like all of the LI-COR IRDye secondary antibodies, these are highly cross-adsorbed secondary antibody conjugates suitable for a variety of applications (see the table below).

IRDye 800CW secondary antibodies are the antibodies of choice for a wide variety of applications in the 800 nm channel (see the list below). IRDye 800CW secondary antibodies can be used for 2-color detection when multiplexed with IRDye 680RD or IRDye 680LT secondary antibodies.

IRDye 680RD secondary antibodies are the antibodies of choice for In-Cell Western Assay and Western blot applications in the 700 nm channel. These antibodies can be used for 2-color detection when multiplexed with IRDye 800CW secondary antibodies. These antibodies are our most universal use 700 nm channel antibodies. Start using IRDye 680RD first over other 700 nm dyes. Dilution working range 1:10,000 – 1:40,000.

IRDye 680LT secondary antibodies have been proven the brightest signal for Western blot detection in the 700 nm channel and are comparable to Alexa Fluor 680 secondary antibodies. Choose IRDye 680LT secondary antibodies to get high signal and for specific uses of detection in the 700nm channel. These antibodies are not recommended when getting up and running on system. Once established near-infrared protocols are optimized with IRDye 680RD, IRDye 680LT can be used to optimize signals in the 700 channel. Dilution range 1:20,000 – 1:40,000. Note: optimization may be required with IRDye 680LT.

Application IRDye 800CW
Secondaries
IRDye 680RD
Secondaries
IRDye 680LT
Secondaries
Western Blot
In-Cell Western™ Assay Not Recommended
On-Cell Western Assay Not Recommended
Protein Array
Immunohistochemistry
Microscopy
2D Gel Detection
Tissue Section Imaging
Small Animal Imaging Not Recommended
Virus Titration Assay Not Known Not Known
FRET-based Assay Not Known Not Known


Note: Now, as of December 15, 2014, you can also get 0.1 mg sizes of all of our IRDye dye-labeled secondary antibodies. Check out our complete listing here and our new filtering tool!