Search

Complete resection of head and neck cancers with negative surgical margins improves the prognosis of the disease and decreases the recurrence rate. Near-infrared fluorescence-guided surgery of head and neck cancer is a rapidly evolving field that represents an invaluable tool for tumor detection and resection. Here, we present a literature review of the principles of near-infrared fluorescence imaging and its use in head and neck cancer surgery. We discuss important studies in both animal models and humans that have been carried out up to this point. We also outline the important fluorescent molecules and devices used in head and neck fluorescence imaging-guided surgery. Although near-infrared fluorescence-guided surgery for head and neck cancers showed efficacy in animal models, its use in humans is limited by the small number of fluorescent probes that are approved for clinical use. However, it is considered as a novel surgical aid that helps delineate tumor margins preoperatively and could spare patients from the added morbidity that is associated with additional surgery or chemoradiation. In addition, it is a useful tool to detect sentinel lymph nodes as well as metastatic lymph nodes. [ABSTRACT FROM AUTHOR]

Objective: To study the biodistribution and lung pharmacokinetics of tracheally administered gadolinium-based contrast agents [gadoteric acid and multimodal ultra-small rigid platforms (USRPs)], to validate their pharmacokinetics against optical imaging of fluorescent USRPs, and to test their short-term toxicity. Materials and methods: Ultrashort echo-time (UTE) lung proton magnetic resonance imaging (MRI) was performed at 4.7-Tesla (T) after the intratracheal instillation of different concentrations of contrast agent solutions in mice. Pharmacokinetic models were implemented on the absolute concentration calculated from the MRI signal enhancement measurements. Fluorescent USRPs were used to obtain optical images with the same protocol. Bronchoalveolar lavage inflammatory cell count and serum creatinine measurement were performed on four groups of instilled mice (sham, saline, USRPs, lipopolysaccharide). Results: MR and optical imaging showed similar kinetics of the USRPs, passing from the airways to the lung tissue and to the kidneys, with negligible hepatic clearance. No significant increase of lung and renal inflammation markers were observed in USRP-instilled animals. Conclusion: A T-weighted radial UTE sequence was found to be valuable in quantitatively monitoring the biodistribution and pharmacokinetics of nanoparticles in the lungs of mice. The observed favorable pharmacokinetics, which was validated by fluorescence imaging, ensures the negligible toxicity of the nanoprobes, making the USRPs and the developed protocol good candidates for applications on selected lung diseases. [ABSTRACT FROM AUTHOR]

To select the appropriate patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), it is important to gain a better understanding of the intracellular pathways leading to EGFR-TKI resistance, which is a common problem in patients with lung cancer. We recently reported that mutant KRAS adenocarcinoma is resistant to gefitinib as a result of amphiregulin and insulin-like growth factor-1 receptor overexpression. This resistance leads to inhibition of Ku70 acetylation, thus enhancing the BAX/Ku70 interaction and preventing apoptosis. Here, we determined the intracellular pathways involved in gefitinib resistance in lung cancers and explored the impact of their inhibition. We analyzed the activation of the phosphatidyl inositol-3-kinase (PI3K)/AKT pathway and the mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) pathway in lung tumors. The activation of AKT was associated with disease progression in tumors with wild-type EGFR from patients treated with gefitinib (phase II clinical trial IFCT0401). The administration of IGF1R-TKI or amphiregulin-directed shRNA decreased AKT signaling and restored gefitinib sensitivity in mutant KRAS cells. The combination of PI3K/AKT inhibition with gefitinib restored apoptosis via Ku70 downregulation and BAX release from Ku70. Deacetylase inhibitors, which decreased the BAX/Ku70 interaction, inhibited AKT signaling and induced gefitinib-dependent apoptosis. The PI3K/AKT pathway is thus a major pathway contributing to gefitinib resistance in lung tumors with KRAS mutation, through the regulation of the BAX/Ku70 interaction. This finding suggests that combined treatments could improve the outcomes for this subset of lung cancer patients, who have a poor prognosis. [ABSTRACT FROM AUTHOR]

A new contrast agent, LipImage™ 815, has been designed and compared to previously described indocyanine green (ICG)-loaded lipid nanoparticles (ICG-lipidots®). Both contrast agents display similar size (50-nm diameter), zeta potential, high IC50 in cellular studies, near-infrared absorption and emission wavelengths in the "imaging window," long-term shelf colloidal and optical stabilities with high brightness (>106 Lmol-1 cm-1) in ready-to-use storage conditions in aqueous buffer (4°C in dark), therefore being promising fluorescence contrast agents for in vivo imaging. However, while ICG-lipidots® display a relatively short plasma lifetime, LipImage™815 circulates in blood for longer times, allowing the efficient uptake of fluorescence signal in human prostate cancer cells implanted in mice. Prolonged tumor labeling is observed for more than 21 days. [ABSTRACT FROM AUTHOR]

Purpose: There is a real need to adapt simple and reproducible imaging methodologies to evaluate noninvasively pro- and antiangiogenic activities of new treatments in a physiological context in mice. Procedure: The angiogenic response to fibroblast growth factor 2 (FGF-2) in a model of subcutaneously implanted cellulose sponges was measured in parallel after an intravenous injection of a fluorescent αβ integrin-targeting molecule (Angiolone) and an fluorescence diffuse optical tomography optical imaging system and by measuring the hemoglobin content in the sponges. Results: Optical measurements of angiogenesis correlated perfectly with the values obtained using hemoglobin quantification. This assay can be used to follow the activity of a pro- or antiangiogenic treatment like demonstrated after FGF-2 or angiostatin, respectively. Conclusion: The perfectly controlled quality of cellulose sponges combined to this noninvasive optical method allow rapid, accurate, and reproducible measurements of angiogenic activities in vivo at the preclinical level. [ABSTRACT FROM AUTHOR]

Cu-cyclam-RAFT-c(-RGDfK-) is a novel multimeric positron emission tomography (PET) probe for αβ integrin imaging. Its uptake and αβ expression in tumors showed a linear correlation. Since αβ integrin is strongly expressed on activated endothelial cells during angiogenesis, we aimed to determine whether Cu-cyclam-RAFT-c(-RGDfK-) PET can be used to image tumor angiogenesis and monitor the antiangiogenic effect of a novel multi-targeted tyrosine kinase inhibitor, TSU-68. Athymic nude mice bearing human hepatocellular carcinoma HuH-7 xenografts, which expressed negligible αβ levels on the tumor cells, received intraperitoneal injections of TSU-68 or the vehicle for 14 days. Antiangiogenic effects were determined at the end of therapy in terms of Cu-cyclam-RAFT-c(-RGDfK-) uptake evaluated using PET, biodistribution assay, and autoradiography, and they were compared with microvessel density (MVD) determined by CD31 immunostaining. Cu-cyclam-RAFT-c(-RGDfK-) PET enabled clear tumor visualization by targeting the vasculature, and the biodistribution assay indicated high tumor-to-blood and tumor-to-muscle ratios of 31.6 ± 6.3 and 6.7 ± 1.1, respectively, 3 h after probe injection. TSU-68 significantly slowed tumor growth and reduced MVD; these findings were consistent with a significant reduction in the tumor Cu-cyclam-RAFT-c(-RGDfK-) uptake. Moreover, a linear correlation was observed between tumor MVD and the corresponding standardized uptake value (SUV) (r = 0.829, P = 0.011 for SUV; r = 0.776, P = 0.024 for SUV) determined by quantitative PET. Autoradiography and immunostaining showed that the distribution of intratumoral radioactivity and tumor vasculature corresponded. We concluded that Cu-cyclam-RAFT-c(-RGDfK-) PET can be used for in vivo angiogenesis imaging and monitoring of tumor response to antiangiogenic therapy. [ABSTRACT FROM AUTHOR]

Integrin αvβ3 expression is upregulated during tumor growth and invasion in newly formed endothelial cells in tumor neovasculature and in some tumor cells. A tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 ( RAFT- RGD), specifically targets integrin αvβ3 in vitro and in vivo. When labeled with indium-111, the RAFT- RGD is partially reabsorbed and trapped in the kidneys, limiting its use for further internal targeted radiotherapy and imaging investigations. We studied the effect of Gelofusine on RAFT- RGD renal retention in tumor-bearing mice. Mice were imaged using single photon emission computed tomography and optical imaging 1 and 24 h following tracer injection. Distribution of RAFT- RGD was further investigated by tissue removal and direct counting of the tracer. Kidney sections were analyzed by confocal microscopy. Gelofusine significantly induced a >50% reduction of the renal reabsorption of 111 In- DOTA- RAFT- RGD and A700- RAFT- RGD, without affecting tumor uptake. Injection of Gelofusine significantly reduced the renal retention of labeled RAFT- RGD, while increasing the tumor over healthy tissue ratio. These results will lead to the development of future therapeutic approaches. ( C ancer S ci 2012; 103: 1105-1110) [ABSTRACT FROM AUTHOR]

Carcinoembryonic antigen (CEA, CEACAM5, and CD66e) has been found to be associated with various types of cancers, particularly colorectal carcinoma, and developed to be a molecular target for cancer diagnosis and therapy. In present study, we generated a novel anti-CEACAM5 monoclonal antibody, namely mAb CC4, by immunizing mice with living colorectal cancer LS174T cells. Immunohistochemical studies found that mAb CC4 specifically and strongly binds to tumor tissues, especially colorectal adenocarcinoma. In xenografted mice, mAb CC4 is specifically accumulated in tumor site and remarkably represses colorectal tumor growth. In vitro functional analysis showed that mAb CC4 significantly suppresses cell proliferation, migration and aggregation of colorectal cancer cells and also raises strong ADCC reaction. More interestingly, mAb CC4 is able to enhance NK cytotoxicity against MHC-I-deficient colorectal cancer cells by blocking intercellular interaction between epithelial CEACAM5 and NK inhibitory receptor CEACAM1. These data suggest that mAb CC4 has the potential to be developed as a novel tumor-targeting carrier and cancer therapeutic. [ABSTRACT FROM AUTHOR]

Background: The cRGD peptide is a promising probe for early non-invasive detection of tumors. This study aimed to demonstrate how RAFT-c(-RGDfK-)4, a molecule allowing a tetrameric presentation of cRGD, improved cRGD-targeting potential using in vivo models of αVβ3-positive or negative tumors. Results: We chose the human embryonic kidney cells HEK293(β3) (high levels of αVβ3) or HEK293(β1) (αVβ3-negative but expressing αV and β1) engrafted subcutaneously (s.c.) in mice. Non-invasive in vivo optical imaging demonstrated that as compared to its monomeric cRGD analogue, Cy5-RAFT-c(-RGDfK-)4 injected intravenously had higher uptake, prolonged retention and markedly enhanced contrast in HEK293(β3) than in the HEK293(β1) tumors. Blocking studies further demonstrated the targeting specificity and competitive binding ability of the tetramer. Conclusion: In conclusion, we demonstrated that Cy5-RAFT-c(-RGDfK-)4 was indeed binding to the αVβ3 receptor and with an improved activity as compared to its monomeric analog, confirming the interest of using multivalent ligands. Intravenous injection of Cy5-RAFT-c(-RGDfK-)4 in this novel pair of HEK293(β3) and HEK293(β1) tumors, provided tumor/skin ratio above 15. Such an important contrast plus the opportunity to use the HEK293(β1) negative control cell line are major assets for the community of researchers working on the design and amelioration of RGD-targeted vectors or on RGD-antagonists. [ABSTRACT FROM AUTHOR]