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12 pages, 1481 KiB  
Article
Mucin4 (MUC4) Antibody Labeled with an NIR Dye Brightly Targets Pancreatic Cancer Liver Metastases and Peritoneal Carcinomatosis
by Sunidhi Jaiswal, Siamak Amirfakhri, Javier Bravo, Keita Kobayashi, Abhijit Aithal, Sumbal Talib, Kavita Mallya, Maneesh Jain, Aaron M. Mohs, Robert M. Hoffman, Surinder K. Batra and Michael Bouvet
Cancers 2025, 17(12), 2031; https://doi.org/10.3390/cancers17122031 - 18 Jun 2025
Viewed by 522
Abstract
Background/Objectives: Pancreatic cancer is the fourth leading cause of deaths related to cancer. It is a highly aggressive malignancy and often metastasizes quickly to other parts of the body and organs. The most effective cure is surgical resection, which also is limited by [...] Read more.
Background/Objectives: Pancreatic cancer is the fourth leading cause of deaths related to cancer. It is a highly aggressive malignancy and often metastasizes quickly to other parts of the body and organs. The most effective cure is surgical resection, which also is limited by tumor identification and clear tumor margin visualization. Previously, we used MUC4 antibodies labeled with IRDye800CW (anti-MUC4-IR800) to target primary human pancreatic cancer in orthotopic cell line mouse models. Methods: In the present study, we established a pancreatic cancer liver metastasis mouse model by implanting a tumor fragment in the liver and a peritoneal carcinomatosis mouse model by injecting pancreatic cancer cells interperitoneally. Once the tumors were established, anti-MUC4-IR800 was administered to the mice by tail vein injection. Laparotomy was performed and tumors were imaged under white-light and near-infrared (NIR) fluorescence with the Pearl Small Animal Imaging System. Results: NIR imaging after 72 h shows the bright targeting of pancreatic cancer metastasis in both mouse models with high tumor-to-background ratios. Conclusions: Anti-MUC4-IR800 was able to successfully target and brightly label metastatic pancreatic cancer as small as 1 mm. Future clinical applications of the results of the present study are discussed. Full article
(This article belongs to the Special Issue Enhancing Cancer Treatments through Fluorescence-Guided Surgery)
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24 pages, 1060 KiB  
Review
Near-Infrared Photoimmunotherapy in Brain Tumors—An Unexplored Frontier
by Haruka Yamaguchi, Masayasu Okada, Takuya Otani, Jotaro On, Satoshi Shibuma, Toru Takino, Jun Watanabe, Yoshihiro Tsukamoto, Ryosuke Ogura, Makoto Oishi, Takamasa Suzuki, Akihiro Ishikawa, Hideyuki Sakata and Manabu Natsumeda
Pharmaceuticals 2025, 18(5), 751; https://doi.org/10.3390/ph18050751 - 19 May 2025
Viewed by 997
Abstract
Near-infrared photoimmunotherapy (NIR-PIT) is a promising cancer treatment that uses near-infrared light to activate a conjugate of a monoclonal antibody (mAb) and a photoactivatable silica phthalocyanine dye (IRDye700DX: IR700). Unlike conventional photodynamic therapy (PDT), NIR-PIT selectively destroys targeted tumor cells while preserving the [...] Read more.
Near-infrared photoimmunotherapy (NIR-PIT) is a promising cancer treatment that uses near-infrared light to activate a conjugate of a monoclonal antibody (mAb) and a photoactivatable silica phthalocyanine dye (IRDye700DX: IR700). Unlike conventional photodynamic therapy (PDT), NIR-PIT selectively destroys targeted tumor cells while preserving the surrounding normal tissue and providing superior tissue penetration. Recently, NIR-PIT has been approved for the treatment of unresectable recurrent head and neck cancers in Japan. It induces highly selective cancer cell death; therefore, it is expected to be a new curative treatment option for various cancers, including brain tumors. In this review, we compare the principles of NIR-PIT and PDT and discuss the potential applications of NIR-PIT for brain tumors. We selected targetable proteins across various types of brain tumors and devised a strategy to effectively pass the mAb–IR700 conjugate through the blood–brain barrier (BBB), which is a significant challenge for NIR-PIT in treating brain tumors. Innovative approaches for delivering the mAb–IR700 conjugate across the BBB include exosomes, nanoparticle-based systems, and cell-penetrating peptides. Small-molecule compounds, such as affibodies, are anticipated to rapidly accumulate in tumors within intracranial models, and our preliminary experiments demonstrated rapid uptake. NIR-PIT also induces immunogenic cell death and activates the anti-tumor immune response. Overall, NIR-PIT is a promising approach for treating brain tumors. It has the potential to overcome the limitations of conventional therapies and offers new hope to patients with brain tumors. Full article
(This article belongs to the Special Issue Antibody-Based Imaging and Targeted Therapy in Cancer)
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16 pages, 7408 KiB  
Article
Treatment of Pancreatic Cancer Using Near-Infrared Photoimmunotherapy Targeting Cancer-Associated Fibroblasts in Combination with Anticancer Chemotherapeutic Drug
by Hiroki Yonemura, Masaki Kuwatani, Kohei Nakajima, Atsushi Masamune, Mikako Ogawa and Naoya Sakamoto
Cancers 2025, 17(9), 1584; https://doi.org/10.3390/cancers17091584 - 7 May 2025
Viewed by 778
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis, involves an overabundance of fibroblasts and extracellular matrix. Cancer-associated fibroblasts (CAFs) are critical for providing structural support by secreting soluble factors and extracellular matrix proteins into the stroma. We assessed the potential [...] Read more.
Background: Pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis, involves an overabundance of fibroblasts and extracellular matrix. Cancer-associated fibroblasts (CAFs) are critical for providing structural support by secreting soluble factors and extracellular matrix proteins into the stroma. We assessed the potential of near-infrared photoimmunotherapy (NIR-PIT) targeting CAFs in PDAC. Methods: PDAC cells (Capan-1 and SUIT-2) and CAFs (hPSC-5) were used. Anti-human fibroblast activation protein (FAP)/podoplanin (PDPN) antibodies were used to bind to CAFs and conjugates with the specific photosensitizer IRDye®700DX (IR700) to investigate the effects of NIR-PIT. Thereafter, BALB/c Slc-nu/nu mice were transplanted with Capan-1 and/or CAFs and treated with gemcitabine (GEM) with or without NIR-PIT. Results: The binding rate of anti-FAP antibody-AlexaFluor®488 conjugate to hPSC-5 cells was high, whereas that of the anti-PDPN antibody-conjugate was not. The incubation of anti-FAP antibody-IR700 conjugate (αFAP-IR700) with hPSC-5 cells for 3 h led to maximal fluorescence on the surface of hPSC-5 cells. When NIR-PIT with αFAP-IR700 was performed in the co-culture group of Capan-1 and hPSC-5 cells, the proliferative capacity of Capan-1 cells decreased to the same level as that when Capan-1 cells were cultured alone (p < 0.05). In vivo, compared with the GEM group, the NIR-PIT with the GEM group showed a significant reduction in the tumor volume (day 28: 79 vs. 382 mm3, p < 0.05). Tumor volumes in the NIR-PIT group were not reduced compared with those in the control group. Conclusions: Combining NIR-PIT with conventional chemotherapy to target CAFs may enhance the anticancer effects on PDAC. Full article
(This article belongs to the Special Issue Multimodal Treatment for Pancreatic Cancer)
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18 pages, 641 KiB  
Systematic Review
Identifying Molecular Probes for Fluorescence-Guided Surgery in Neuroblastoma: A Systematic Review
by Megan Hennessy, Jonathan J. Neville, Laura Privitera, Adam Sedgwick, John Anderson and Stefano Giuliani
Children 2025, 12(5), 550; https://doi.org/10.3390/children12050550 - 24 Apr 2025
Viewed by 709
Abstract
Background/Objectives: Targeted and non-targeted fluorescent molecular probes (FMPs) can be used intra-operatively to visualise tumour tissue. Multiple probes have been clinically approved for fluorescence-guided surgery (FGS) in adult oncology, and the translation of these technologies to paediatric neuroblastoma may provide novel strategies [...] Read more.
Background/Objectives: Targeted and non-targeted fluorescent molecular probes (FMPs) can be used intra-operatively to visualise tumour tissue. Multiple probes have been clinically approved for fluorescence-guided surgery (FGS) in adult oncology, and the translation of these technologies to paediatric neuroblastoma may provide novel strategies for optimising tumour resection whilst minimising morbidity. We aimed to identify clinically approved FMPs with potential utility for FGS in neuroblastoma. Methods: A systematic review of the literature was performed in accordance with the PRISMA guidelines (PROSPERO CRD42024541623). PubMed and Web of Science databases were searched to identify studies investigating clinically approved FGS probes and/or their targets in the context of neuroblastoma. Pre-clinical and clinical studies looking at human neuroblastoma were included. The primary outcomes were that the FGS probe was tested in patients with neuroblastoma, the probe selectively accumulated in neuroblastoma tissue, or that the target of the probe was selectively over-expressed in neuroblastoma tissue. Results: Forty-two studies were included. Four were clinical studies, and the remainder were pre-clinical studies using human neuroblastoma cell lines, human tumour tissue, or xenograft models using human neuroblastoma cells. The only FMP clinically evaluated in neuroblastoma is indocyanine green (ICG). FMP targets that have been investigated in neuroblastoma include poly-ADP ribose polymerase (PARP) (targeted by PARPiFL), endothelial growth factor receptor (EGFR) (targeted by Panitumumab-IRDye800CW, Cetuximab-IRDye800CW, Nimotuzumab-IRDye800CW and QRHKPRE-Cy5), vascular endothelial growth factor receptor (VEGFR) (targeted by Bevacizumab IRDye800CW), and proteases such as cathepsins and matrix metalloproteinases that activate the fluorescent signal of FMPs, such as LUM015 and AVB-620. Of the clinical studies included, all were found to have a high risk of bias. Conclusions: ICG is the only clinically approved fluorescent dye currently used for FGS in neuroblastoma; however, studies suggest that its ability to recognise neuroblastoma tissue is inconsistent. There are several clinically approved FMPs, or FMPs in clinical trials, that are used in adult oncology surgery that have targets expressed in neuroblastoma. Further research should validate these probes in neuroblastoma to enable their rapid translation into clinical practice. Full article
(This article belongs to the Section Pediatric Surgery)
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17 pages, 2437 KiB  
Review
Review of Clinically Assessed Molecular Fluorophores for Intraoperative Image Guided Surgery
by Yuan Ge and Donal F. O’Shea
Molecules 2024, 29(24), 5964; https://doi.org/10.3390/molecules29245964 - 18 Dec 2024
Cited by 1 | Viewed by 1334
Abstract
The term “fluorescence” was first proposed nearly two centuries ago, yet its application in clinical medicine has a relatively brief history coming to the fore in the past decade. Nowadays, as fluorescence is gradually expanding into more medical applications, fluorescence image-guided surgery has [...] Read more.
The term “fluorescence” was first proposed nearly two centuries ago, yet its application in clinical medicine has a relatively brief history coming to the fore in the past decade. Nowadays, as fluorescence is gradually expanding into more medical applications, fluorescence image-guided surgery has become the new arena for this technology. It allows surgical teams to real-time visualize target tissues or anatomies intraoperatively to increase the precision of resection or preserve vital structures during open or laparoscopic surgeries. In this review, we introduce the concept of near-infrared fluorescence guided surgery, discuss the recent and ongoing clinical trials of molecular fluorophores (indocyanine green, 5-aminolevulinic acid, methylene blue, IR-dye 800CW, pafolacianine) and their surgical goals, highlight key chemical and medical factors for imaging agent optimization, deliberate challenges and potential advantages, and propose a framework for integrating this technology into routine surgical care in the near future. The notable clinical achievements of these fluorophores over the past decade strongly indicates that the future of fluorescence in surgery is bright with many more patient benefits to come. Full article
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11 pages, 1827 KiB  
Article
Targeting Human Pancreatic Cancer with a Fluorophore-Conjugated Mucin 4 (MUC4) Antibody: Initial Characterization in Orthotopic Cell Line Mouse Models
by Sunidhi Jaiswal, Kristin E. Cox, Siamak Amirfakhri, Aylin Din Parast Saleh, Keita Kobayashi, Thinzar M. Lwin, Sumbal Talib, Abhijit Aithal, Kavita Mallya, Maneesh Jain, Aaron M. Mohs, Robert M. Hoffman, Surinder K. Batra and Michael Bouvet
J. Clin. Med. 2024, 13(20), 6211; https://doi.org/10.3390/jcm13206211 - 18 Oct 2024
Cited by 3 | Viewed by 1577
Abstract
Background/Objectives: Pancreatic cancer is the third leading cause of death related to cancer. The only possible cure presently is complete surgical resection; however, this is limited by difficulty in clearly defining tumor margins. Enhancement of the visualization of pancreatic ductal adenocarcinoma (PDAC) tumor [...] Read more.
Background/Objectives: Pancreatic cancer is the third leading cause of death related to cancer. The only possible cure presently is complete surgical resection; however, this is limited by difficulty in clearly defining tumor margins. Enhancement of the visualization of pancreatic ductal adenocarcinoma (PDAC) tumor margins using near-infrared dye-conjugated tumor-specific antibodies was pioneered by using anti-CEA, anti-CA19.9, and anti-MUC5AC in orthotopic mouse models of pancreatic cancer. Recently, an antibody to Mucin 4 (MUC4) conjugated to a fluorescent probe has shown promise in targeting colon tumors in orthotopic mouse models. Methods: In the present study, we targeted pancreatic cancer using an anti-MUC4 antibody conjugated to IRDye800 (anti-MUC4-IR800) in orthotopic mouse models. Two pancreatic cancer human cell lines were used, SW1990 and CD18/HPAF. Results: Anti-MUC4-IR800 targeted the two pancreatic cancer cell line tumors in orthotopic mouse models with high tumor-to-pancreas ratios and high tumor-to-liver ratios, with greater targeting seen in SW1990. Conclusions: The present results suggest anti-MUC4-IR800’s potential to be used in fluorescence-guided surgical resection of pancreatic cancer. Full article
(This article belongs to the Special Issue Advances in the Diagnosis and Treatment of Pancreatic Cancer)
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14 pages, 3122 KiB  
Article
Real-Time Fluorescence Monitoring System for Optimal Light Dosage in Cancer Photoimmunotherapy
by Hideki Tanaka, Yoshikatsu Koga, Mayumi Sugahara, Hirobumi Fuchigami, Akihiro Ishikawa, Toru Yamaguchi, Akiko Banba, Takeshi Shinozaki, Kazuto Matsuura, Ryuichi Hayashi, Shingo Sakashita, Masahiro Yasunaga and Tomonori Yano
Pharmaceuticals 2024, 17(9), 1246; https://doi.org/10.3390/ph17091246 - 22 Sep 2024
Cited by 2 | Viewed by 1514
Abstract
Background/Objectives: Near-infrared photoimmunotherapy (NIR-PIT) was recently approved for the treatment of unresectable locally advanced or recurrent head and neck cancers in Japan; however, only one clinical dose has been validated in clinical trials, potentially resulting in excessive or insufficient dosing. Moreover, IRDye700X [...] Read more.
Background/Objectives: Near-infrared photoimmunotherapy (NIR-PIT) was recently approved for the treatment of unresectable locally advanced or recurrent head and neck cancers in Japan; however, only one clinical dose has been validated in clinical trials, potentially resulting in excessive or insufficient dosing. Moreover, IRDye700X (IR700) fluorescence intensity plateaus during treatment, indicating a particular threshold for the antitumor effects. Therefore, we investigated the NIR laser dose across varying tumor sizes and irradiation methods until the antitumor effects of the fluorescence decay rate plateaued. Methods: Mice were subcutaneously transplanted with A431 xenografts and categorized into control, clinical dose (cylindrical irradiation at 100 J/cm², frontal irradiation at 50 J/cm²), and evaluation groups. The rate of tumor IR700 fluorescence intensity decay to reach predefined rates (−0.05%/s or −0.2%/s) until the cessation of light irradiation was calculated using a real-time fluorescence imaging system. Results: The evaluation group exhibited antitumor effects comparable to those of the clinical dose group at a low irradiation dose. Similar results were observed across tumor sizes and irradiation methods. Conclusions: In conclusion, the optimal antitumor effect of NIR-PIT is achieved when the fluorescence decay rate reaches a plateau, indicating the potential to determine the appropriate dose for PIT using a real-time fluorescence monitoring system. Full article
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15 pages, 4099 KiB  
Article
Exposed Phosphatidylserine as a Biomarker for Clear Identification of Breast Cancer Brain Metastases in Mouse Models
by Lulu Wang, Alan H. Zhao, Chad A. Arledge, Fei Xing, Michael D. Chan, Rolf A. Brekken, Amyn A. Habib and Dawen Zhao
Cancers 2024, 16(17), 3088; https://doi.org/10.3390/cancers16173088 - 5 Sep 2024
Cited by 1 | Viewed by 1841
Abstract
Brain metastasis is the most common intracranial malignancy in adults. The prognosis is extremely poor, partly because most patients have more than one brain lesion, and the currently available therapies are nonspecific or inaccessible to those occult metastases due to an impermeable blood–tumor [...] Read more.
Brain metastasis is the most common intracranial malignancy in adults. The prognosis is extremely poor, partly because most patients have more than one brain lesion, and the currently available therapies are nonspecific or inaccessible to those occult metastases due to an impermeable blood–tumor barrier (BTB). Phosphatidylserine (PS) is externalized on the surface of viable endothelial cells (ECs) in tumor blood vessels. In this study, we have applied a PS-targeting antibody to assess brain metastases in mouse models. Fluorescence microscopic imaging revealed that extensive PS exposure was found exclusively on vascular ECs of brain metastases. The highly sensitive and specific binding of the PS antibody enables individual metastases, even micrometastases containing an intact BTB, to be clearly delineated. Furthermore, the conjugation of the PS antibody with a fluorescence dye, IRDye 800CW, or a radioisotope, 125I, allowed the clear visualization of individual brain metastases by optical imaging and autoradiography, respectively. In conclusion, we demonstrated a novel strategy for targeting brain metastases based on our finding that abundant PS exposure occurs on blood vessels of brain metastases but not on normal brain, which may be useful for the development of imaging and targeted therapeutics for brain metastases. Full article
(This article belongs to the Special Issue Brain Metastases: From Mechanisms to Treatment)
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17 pages, 4581 KiB  
Article
Detection of Hepatocellular Carcinoma in an Orthotopic Patient-Derived Xenograft with an Epithelial Cell Adhesion Molecule-Specific Peptide
by Xiaoli Wu, Shuo Feng, Tse-Shao Chang, Ruoliu Zhang, Sangeeta Jaiswal, Eun-Young K. Choi, Yuting Duan, Hui Jiang and Thomas D. Wang
Cancers 2024, 16(16), 2818; https://doi.org/10.3390/cancers16162818 - 10 Aug 2024
Cited by 2 | Viewed by 1526
Abstract
Hepatocellular carcinoma (HCC) has emerged as a major contributor to the worldwide cancer burden. Improved methods are needed for early cancer detection and image-guided surgery. Peptides have small dimensions that can overcome delivery challenges to achieve high tumor concentrations and deep penetration. We [...] Read more.
Hepatocellular carcinoma (HCC) has emerged as a major contributor to the worldwide cancer burden. Improved methods are needed for early cancer detection and image-guided surgery. Peptides have small dimensions that can overcome delivery challenges to achieve high tumor concentrations and deep penetration. We used phage display methods to biopan against the extra-cellular domain of the purified EpCAM protein, and used IRDye800 as a near-infrared (NIR) fluorophore. The 12-mer sequence HPDMFTRTHSHN was identified, and specific binding to EpCAM was validated with HCC cells in vitro. A binding affinity of kd = 67 nM and onset of k = 0.136 min−1 (7.35 min) were determined. Serum stability was measured with a half-life of T1/2 = 2.6 h. NIR fluorescence images showed peak uptake in vivo by human HCC patient-derived xenograft (PDX) tumors at 1.5 h post-injection. Also, the peptide was able to bind to foci of local and distant metastases in liver and lung. Peptide biodistribution showed high uptake in tumor versus other organs. No signs of acute toxicity were detected during animal necropsy. Immunofluorescence staining of human liver showed specific binding to HCC compared with cirrhosis, adenoma, and normal specimens. Full article
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12 pages, 5869 KiB  
Article
Near-Infrared Fluorescence Imaging in Preclinical Models of Glioblastoma
by Monserrat Llaguno-Munive, Wilberto Villalba-Abascal, Alejandro Avilés-Salas and Patricia Garcia-Lopez
J. Imaging 2023, 9(10), 212; https://doi.org/10.3390/jimaging9100212 - 6 Oct 2023
Cited by 4 | Viewed by 2612
Abstract
Cancer is a public health problem requiring ongoing research to improve current treatments and discover novel therapies. More accurate imaging would facilitate such research. Near-infrared fluorescence has been developed as a non-invasive imaging technique capable of visualizing and measuring biological processes at the [...] Read more.
Cancer is a public health problem requiring ongoing research to improve current treatments and discover novel therapies. More accurate imaging would facilitate such research. Near-infrared fluorescence has been developed as a non-invasive imaging technique capable of visualizing and measuring biological processes at the molecular level in living subjects. In this work, we evaluate the tumor activity in two preclinical glioblastoma models by using fluorochrome (IRDye 800CW) coupled to different molecules: tripeptide Arg-Gly-Asp (RGD), 2-amino-2-deoxy-D-glucose (2-DG), and polyethylene glycol (PEG). These molecules interact with pathological conditions of tumors, including their overexpression of αvβ3 integrins (RGD), elevated glucose uptake (2-DG), and enhanced permeability and retention effect (PEG). IRDye 800CW RGD gave the best in vivo fluorescence signal from the tumor area, which contrasted well with the low fluorescence intensity of healthy tissue. In the ex vivo imaging (dissected tumor), the accumulation of IRDye 800CW RGD could be appreciated at the tumor site. Glioblastoma tumors were presently detected with specificity and sensitivity by utilizing IRDye 800CW RGD, a near-infrared fluorophore combined with a marker of αvβ3 integrin expression. Further research is needed on its capacity to monitor tumor growth in glioblastoma after chemotherapy. Full article
(This article belongs to the Special Issue Fluorescence Imaging and Analysis of Cellular System)
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14 pages, 2912 KiB  
Article
Near-Infrared Imaging of Colonic Adenomas In Vivo Using Orthotopic Human Organoids for Early Cancer Detection
by Xiaoli Wu, Chun-Wei Chen, Sangeeta Jaiswal, Tse-Shao Chang, Ruoliu Zhang, Michael K. Dame, Yuting Duan, Hui Jiang, Jason R. Spence, Sen-Yung Hsieh and Thomas D. Wang
Cancers 2023, 15(19), 4795; https://doi.org/10.3390/cancers15194795 - 29 Sep 2023
Cited by 2 | Viewed by 1791
Abstract
Colorectal cancer is a leading cause of cancer-related morbidity and mortality worldwide. Premalignant lesions that are flat and subtle in morphology are often missed in conventional colonoscopies. Patient-derived adenoma colonoids with high and low cMet expression and normal colonoids were implanted orthotopically in [...] Read more.
Colorectal cancer is a leading cause of cancer-related morbidity and mortality worldwide. Premalignant lesions that are flat and subtle in morphology are often missed in conventional colonoscopies. Patient-derived adenoma colonoids with high and low cMet expression and normal colonoids were implanted orthotopically in the colon of immunocompromised mice to serve as a preclinical model system. A peptide specific for cMet was labeled with IRDye800, a near-infrared (NIR) fluorophore. This peptide was administered intravenously, and in vivo imaging was performed using a small animal fluorescence endoscope. Quantified intensities showed a peak target-to-background ratio at ~1 h after intravenous peptide injection, and the signal cleared by ~24 h. The peptide was stable in serum with a half-life of 3.6 h. Co-staining of adenoma and normal colonoids showed a high correlation between peptide and anti-cMet antibody. A human-specific cytokeratin stain verified the presence of human tissues implanted among surrounding normal mouse colonic mucosa. Peptide biodistribution was consistent with rapid renal clearance. No signs of acute toxicity were found on either animal necropsy or serum hematology and chemistries. Human colonoids provide a clinically relevant preclinical model to evaluate the specific uptake of a NIR peptide to detect premalignant colonic lesions in vivo. Full article
(This article belongs to the Section Cancer Biomarkers)
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17 pages, 5489 KiB  
Article
Penetration of Nanobody-Dextran Polymer Conjugates through Tumor Spheroids
by Peter Bitsch, Eva S. Baum, Irati Beltrán Hernández, Sebastian Bitsch, Jakob Harwood, Sabrina Oliveira and Harald Kolmar
Pharmaceutics 2023, 15(10), 2374; https://doi.org/10.3390/pharmaceutics15102374 - 22 Sep 2023
Cited by 4 | Viewed by 2771
Abstract
Here we report the generation of nanobody dextran polymer conjugates (dextraknobs) that are loaded with small molecules, i.e., fluorophores or photosensitizers, for potential applications in cancer diagnostics and therapy. To this end, the molecules are conjugated to the dextran polymer which is coupled [...] Read more.
Here we report the generation of nanobody dextran polymer conjugates (dextraknobs) that are loaded with small molecules, i.e., fluorophores or photosensitizers, for potential applications in cancer diagnostics and therapy. To this end, the molecules are conjugated to the dextran polymer which is coupled to the C-terminus of an EGFR-specific nanobody using chemoenzymatic approaches. A monovalent EGFR-targeted nanobody and biparatopic version modified with different dextran average molecular weights (1000, 5000, and 10,000) were probed for their ability to penetrate tumor spheroids. For monovalent Cy5-labeled dextraknobs, the utilization of smaller sized dextran (MW 5000 vs. 10,000) was found to be beneficial for more homogeneous penetration into A431 tumor spheroids over time. For the biparatopic dual nanobody comprising MW 1000, 5000, and 10,000 dextran labeled with photosensitizer IRDye700DX, penetration behavior was comparable to that of a direct nanobody-photosensitizer conjugate lacking a dextran scaffold. Additionally, dextraknobs labeled with IRDye700DX incubated with cells in 2D and 3D showed potent cell killing upon illumination, thus inducing photodynamic therapy (PDT). In line with previous results, monovalent nanobody conjugates displayed deeper and more homogenous penetration through spheroids than the bivalent conjugates. Importantly, the smaller size dextrans did not affect the distribution of the conjugates, thus encouraging further development of dextraknobs. Full article
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11 pages, 1364 KiB  
Article
Impact of Surgical Lights on the Performance of Fluorescence-Guided Surgery Systems: A Pilot Study
by Lavinia E. Chiti, Brian Park, Faustine d’Orchymont, Jason P. Holland and Mirja C. Nolff
Animals 2023, 13(14), 2363; https://doi.org/10.3390/ani13142363 - 20 Jul 2023
Cited by 5 | Viewed by 2499
Abstract
Fluorescence-guided surgery can aid in the intraoperative visualization of target tissues, with promising applications in human and veterinary surgical oncology. The aim of this study was to evaluate the performances of two fluoresce camera systems, IC-FlowTM and VisionsenseTM VS3 Iridum, for [...] Read more.
Fluorescence-guided surgery can aid in the intraoperative visualization of target tissues, with promising applications in human and veterinary surgical oncology. The aim of this study was to evaluate the performances of two fluoresce camera systems, IC-FlowTM and VisionsenseTM VS3 Iridum, for the detection of two non-targeted (ICG and IRDye-800) and two targeted fluorophores (AngiostampTM and FAP-Cyan) under different room light conditions, including ambient light, new generation LED, and halogen artificial light sources, which are commonly used in operating theaters. Six dilutions of the fluorophores were imaged in phantom kits using the two camera systems. The limit of detection (LOD) and mean signal-to-background ratio (mSBR) were determined. The highest values of mSBR and a lower LOD were obtained in dark conditions for both systems. Under room lights, the capabilities decreased, but the mSBR remained greater than 3 (=clearly detectable signal). LOD and mSBR worsened under surgical lights for both camera systems, with a greater impact from halogen bulbs on VisionsenseTM VS3 Iridium and of the LED lights on IC-Flow due to a contribution of these lights in the near-infrared spectrum. When considering implementing FGS into the clinical routine, surgeons should cautiously evaluate the spectral contribution of the lights in the operating theater. Full article
(This article belongs to the Special Issue Recent Advances in the Treatment of Cancer in Domesticated Animals)
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13 pages, 28836 KiB  
Article
In Vitro Comparative Study of Near-Infrared Photoimmunotherapy and Photodynamic Therapy
by Susumu Yamashita, Miho Kojima, Nobuhiko Onda and Makoto Shibutani
Cancers 2023, 15(13), 3400; https://doi.org/10.3390/cancers15133400 - 28 Jun 2023
Cited by 4 | Viewed by 2573
Abstract
Near-infrared photoimmunotherapy (NIR-PIT) is a new phototherapy that utilizes a monoclonal antibody (mAb) against cancer antigens and a phthalocyanine dye, IRDye700DX (IR700) conjugate (mAb-IR700). Photodynamic therapy (PDT) is a combination therapy that utilizes photoreactive agents and light irradiation as well as NIR-PIT. In [...] Read more.
Near-infrared photoimmunotherapy (NIR-PIT) is a new phototherapy that utilizes a monoclonal antibody (mAb) against cancer antigens and a phthalocyanine dye, IRDye700DX (IR700) conjugate (mAb-IR700). Photodynamic therapy (PDT) is a combination therapy that utilizes photoreactive agents and light irradiation as well as NIR-PIT. In the present study, we compared these therapies in vitro. The characterization of cellular binding/uptake specificity and cytotoxicity were examined using two mAb-IR700 forms and a conventional PDT agent, talaporfin sodium, in three cell lines. As designed, mAb-IR700 had high molecular selectivity and visualized target molecule-positive cells at the lowest concentration examined. NIR-PIT induced necrosis and damage-associated molecular patterns (DAMPs), a surrogate maker of immunogenic cell death. In contrast, talaporfin sodium was taken up by cells regardless of cell type, and its uptake was enhanced in a concentration-dependent manner. PDT induced cell death, with the pattern of cell death shifting from apoptosis to necrosis depending on the concentration of the photosensitizer. Induction of DAMPs was observed at the highest concentration, but their sensitivity differed among cell lines. Overall, our data suggest that molecule-specific NIR-PIT may have potential advantages compared with PDT in terms of the efficiency of tumor visualization and induction of DAMPs. Full article
(This article belongs to the Special Issue Near-Infrared Photoimmunotherapy for Cancer Treatment)
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15 pages, 2687 KiB  
Article
Fibroblast Activation Protein-Targeting Minibody-IRDye700DX for Ablation of the Cancer-Associated Fibroblast with Photodynamic Therapy
by Esther M. M. Smeets, Daphne N. Dorst, Gerben M. Franssen, Merijn S. van Essen, Cathelijne Frielink, Martijn W. J. Stommel, Marija Trajkovic-Arsic, Phyllis F. Cheung, Jens T. Siveke, Ian Wilson, Alessandro Mascioni, Erik H. J. G. Aarntzen and Sanne A. M. van Lith
Cells 2023, 12(10), 1420; https://doi.org/10.3390/cells12101420 - 18 May 2023
Cited by 9 | Viewed by 3938
Abstract
Fibroblast activation protein (FAP), expressed on cancer-associated fibroblasts, is a target for diagnosis and therapy in multiple tumour types. Strategies to systemically deplete FAP-expressing cells show efficacy; however, these induce toxicities, as FAP-expressing cells are found in normal tissues. FAP-targeted photodynamic therapy offers [...] Read more.
Fibroblast activation protein (FAP), expressed on cancer-associated fibroblasts, is a target for diagnosis and therapy in multiple tumour types. Strategies to systemically deplete FAP-expressing cells show efficacy; however, these induce toxicities, as FAP-expressing cells are found in normal tissues. FAP-targeted photodynamic therapy offers a solution, as it acts only locally and upon activation. Here, a FAP-binding minibody was conjugated to the chelator diethylenetriaminepentaacetic acid (DTPA) and the photosensitizer IRDye700DX (DTPA-700DX-MB). DTPA-700DX-MB showed efficient binding to FAP-overexpressing 3T3 murine fibroblasts (3T3-FAP) and induced the protein’s dose-dependent cytotoxicity upon light exposure. Biodistribution of DTPA-700DX-MB in mice carrying either subcutaneous or orthotopic tumours of murine pancreatic ductal adenocarcinoma cells (PDAC299) showed maximal tumour uptake of 111In-labelled DTPA-700DX-MB at 24 h post injection. Co-injection with an excess DTPA-700DX-MB reduced uptake, and autoradiography correlated with FAP expression in the stromal tumour region. Finally, in vivo therapeutic efficacy was determined in two simultaneous subcutaneous PDAC299 tumours; only one was treated with 690 nm light. Upregulation of an apoptosis marker was only observed in the treated tumours. In conclusion, DTPA-700DX-MB binds to FAP-expressing cells and targets PDAC299 tumours in mice with good signal-to-background ratios. Furthermore, the induced apoptosis indicates the feasibility of targeted depletion of FAP-expressing cells with photodynamic therapy. Full article
(This article belongs to the Special Issue Photodynamic Therapy for Cancers: Advances and Perspectives)
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