Fluorescence-guided Surgery with a Fluorophore-conjugated Antibody to Carcinoembryonic Antigen (CEA), that Highlights the Tumor, Improves Surgical Resection and Increases Survival in Orthotopic Mouse Models of Human Pancreatic Cancer

Metildi, Cristina; Kaushal, Sharmeela; Pu, Minya; Messer, K.; Luiken, George A.; Moossa, A. R.; Hoffman, Robert M.; Bouvet, Michael

doi:10.1245/s10434-014-3495-y

Cited by 78 publications

(49 citation statements)

References 43 publications

(36 reference statements)

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“…Cure rates with FGS compared to BLS improved from 4.5 to 40 %, respectively, and 1-year postoperative survival rates increased from 0 % with BLS to 28 % with FGS. 18 …”

Section: Discussionmentioning

confidence: 99%

Advantages of Fluorescence-Guided Laparoscopic Surgery of Pancreatic Cancer Labeled with Fluorescent Anti–Carcinoembryonic Antigen Antibodies in an Orthotopic Mouse Model

Metildi

Kaushal

Luiken

et al. 2014

Journal of the American College of Surgeons

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Background Our laboratory has previously developed fluorescence-guided (FGS) of pancreatic and other cancers in orthotopic mouse models. Laparoscopic surgery is being used more extensively in surgical oncology. The present report describes the efficacy of laparoscopic FGS of pancreatic cancer in an orthotopic mouse model. Study Design Mouse models of human pancreatic cancer were established with fragments of the BxPC-3 RFP human pancreatic cancer using surgical orthotopic implantation (SOI). Mice were randomized to bright light laparoscopic surgery (BLLS) or to fluorescence guided laparoscopic surgery (FGLS). FGLS was performed with an LED light source through a 495-nm emission filter in order to remove the primary tumors and any additional separate sub-millimeter deposits within the pancreas, the latter of which was not possible with BLLS. Tumors were labeled with anti-CEA-Alexa 488 antibodies 24 hours before surgery with intravenous injection. Perioperative fluorescence images were obtained to evaluate tumor size. Mice were followed postoperatively to assess for recurrence and at termination to evaluate tumor burden. Results At termination, the FGLS group had less pancreatic tumor volume than the BLLS group (5.75 mm2 vs 28.43 mm2, respectively; p=0.012) and lower tumor weight (21.1 mg vs 174.4 mg, respectively; p=0.033). FGLS compared to BLLS also decreased local recurrence (50% vs 80%, respectively; p=0.048) and distant recurrence (70% vs 95%, respectively; p=0.046). More mice in the FGLS than the BLLS group were free of tumor at termination (25% vs 5%, respectively). The median disease free survival (DFS) was lengthened from 2 weeks with BLLS (95% CI [1.635, 2.365]) to 7 weeks with FGLS (95% CI [5.955, 8.045]) (p=0.001). Conclusions FGLS is more effective than BLLS, and therefore has important potential for surgical oncology.

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“…Cure rates with FGS compared to BLS improved from 4.5 to 40 %, respectively, and 1-year postoperative survival rates increased from 0 % with BLS to 28 % with FGS. 18 …”

Section: Discussionmentioning

confidence: 99%

Advantages of Fluorescence-Guided Laparoscopic Surgery of Pancreatic Cancer Labeled with Fluorescent Anti–Carcinoembryonic Antigen Antibodies in an Orthotopic Mouse Model

Metildi

Kaushal

Luiken

et al. 2014

Journal of the American College of Surgeons

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“…The cumulative effects of PEGylation were to increase dye-conjugated anti-CEA antibody half-life, favorably alter the biodistribution, and significantly increase tumor to background contrast. PEGylated dyes conjugated to tumor-specific antibodies should have an important impact in the development of fluorescence guided surgery of cancer, 1,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] as these dyes offer the possibility of high fidelity-targeted tumor and metastases labeling.…”

Section: Tissue Biodistributionmentioning

confidence: 99%

Specific tumor labeling enhanced by polyethylene glycol linkage of near infrared dyes conjugated to a chimeric anti-carcinoembryonic antigen antibody in a nude mouse model of human pancreatic cancer

et al. 2014

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Abstract. Labeling of metastatic tumors can aid in their staging and resection of cancer. Near infrared (NIR) dyes have been used in the clinic for tumor labeling. However, there can be a nonspecific uptake of dye by the liver, lungs, and lymph nodes, which hinders detection of metastasis. In order to overcome these problems, we have used two NIR dyes (DyLight 650 and 750) conjugated to a chimeric anti-carcinoembryonic antigen antibody to evaluate how polyethylene glycol linkage (PEGylation) can improve specific tumor labeling in a nude mouse model of human pancreatic cancer. The conjugated PEGylated and non-PEGylated DyLight 650 and 750 dyes were injected intravenously into non-tumor-bearing nude mice. Serum samples were collected at various time points in order to determine serum concentrations and elimination kinetics. Conjugated PEGylated dyes had significantly higher serum dye concentrations than non-PEGylated dyes (p ¼ 0.005 for the 650 dyes and p < 0.001 for the 750 dyes). Human pancreatic tumors subcutaneously implanted into nude mice were labeled with antibody-dye conjugates and serially imaged. Labeling with conjugated PEGylated dyes resulted in significantly brighter tumors compared to the non-PEGylated dyes (p < 0.001 for the 650 dyes; p ¼ 0.01 for 750 dyes). PEGylation of the NIR dyes also decreased their accumulation in lymph nodes, liver, and lung. These results demonstrate enhanced selective tumor labeling by PEGylation of dyes conjugated to a tumor-specific antibody, suggesting their future clinical use in fluorescence-guided surgery.

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“…One such tumor biomarker that is being developed is anti-carcinoembryonic antigen (CEA) antibodies to target and label human colorectal cancer in nude mouse models (3–6). Mouse and chimeric (mouse/human) antibodies against CEA have been conjugated with fluorescent dye and are capable of enhancing visualization of submillimeter tumor deposits (5) and successful FGS (7, 8). This technique has been applied to human clinical trials to localize squamous cell carcinoma of the head and neck using a cetuximab-IRDye800CW conjugate (9).…”

Section: Introductionmentioning

confidence: 99%

Near-infrared–conjugated humanized anti-carcinoembryonic antigen antibody targets colon cancer in an orthotopic nude-mouse model

DeLong

Murakami

Yazaki

et al. 2017

Journal of Surgical Research

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Introduction The success of a curative surgery for cancer is dependent on the complete removal of all cancer cells. Tumor visualization by the surgeon can be enhanced through fluorescent-antibody targeting. To further develop such technology, we selected humanized anti-carcinoembryonic antigen (CEA) conjugated to a near-infrared (NIR) dye to target orthotopically implanted human colon cancer in nude mice. Materials & Methods The HT-29 human colon cancer cell line was grown in culture and subcutaneously injected subcutaneously in mice. After 3 weeks of growth, tumors were resected and cut into 2 mm3 fragments that were sutured to the cecum of 5 additional nude mice for orthotopic implantation. The tumors were allowed to grow for 4 weeks at which point 3 had successful orthotopic tumor growth and were selected for injection of the humanized anti-CEA antibody conjugated to the NIR dye IRDye800CW (anti-CEA-IRDye800CW). The antibody-dye conjugate (75 μg) was administered via tail vein injection. Images were obtained with the Pearl Trilogy Small Animal Imaging System (LI-COR, Lincoln, NE) with both 700 nm and 800 nm channels and evaluated using Image Studio. Results Laparotomy was performed 24 hours after labeling the tumors. When imaged through the 800 nm channel, the tumors were observed to be strongly labeled with anti-CEA-IRDye800. At 48 hours laparotomy was repeated which again demonstrated strong labeling of the tumors through the 800 nm channel, but with a lower absolute intensity (in relative units), than at 24 hours for each of the 3 mice imaged. Conclusion Humanized anti-CEA-IRDye800CW can rapidly and effectively label CEA-expressing human colon cancer in an orthotopic nude mouse model. Given the ability of this technology to target and label tumors with great specificity, the anti-CEA-IRDye800CW is currently being developed for clinical use in fluorescence-guided surgery.

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Fluorescence-guided Surgery with a Fluorophore-conjugated Antibody to Carcinoembryonic Antigen (CEA), that Highlights the Tumor, Improves Surgical Resection and Increases Survival in Orthotopic Mouse Models of Human Pancreatic Cancer

Cited by 78 publications

References 43 publications

Advantages of Fluorescence-Guided Laparoscopic Surgery of Pancreatic Cancer Labeled with Fluorescent Anti–Carcinoembryonic Antigen Antibodies in an Orthotopic Mouse Model

Advantages of Fluorescence-Guided Laparoscopic Surgery of Pancreatic Cancer Labeled with Fluorescent Anti–Carcinoembryonic Antigen Antibodies in an Orthotopic Mouse Model

Specific tumor labeling enhanced by polyethylene glycol linkage of near infrared dyes conjugated to a chimeric anti-carcinoembryonic antigen antibody in a nude mouse model of human pancreatic cancer

Near-infrared–conjugated humanized anti-carcinoembryonic antigen antibody targets colon cancer in an orthotopic nude-mouse model

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