A follicle-stimulating hormone receptor-targeted near-infrared fluorescent probe for tumor-selective imaging and photothermal therapy
Qiyu LiuTao PuXiaobo ZhouJiaan SunWei YuanZhang SidiMingxing ZhangMeng ZhangJing PengFuyou LiXiaoyan ZhangCongjian Xu
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Abstract:
Late detection, peritoneal dissemination, chemoresistance and weak response to targeted therapeutics lead to high mortality in ovarian cancer. More efficient and specific tumor imaging and therapeutic agents are needed to improve the resection rate of surgery and to eliminate residual disease. The expression patterns of follicle-stimulating hormone (FSH) receptor make it a suitable target for ovarian cancer. Here, we report a strategy to develop an organic near-infrared probe for FSH receptor-targeted tumor imaging and photothermal therapy. The FSH-Rh760 probe was conjugated from the Rh760 fluorophore with the FSH β subunit 33-53 peptide. FSH-Rh760 specifically distinguished peritoneal metastatic ovarian cancerous foci from surrounding normal tissues with a high tumor-to-background ratio. The fluorescence signals in tumors peaked at 2 h and were cleared at 120 h postinjection. FSH-Rh760 treatment rapidly increased the abdomen temperature of mice up to ∼43 °C upon exposure to a near-infrared laser and effectively suppressed peritoneal tumor growth with tumor specificity. No significant systemic toxicities were observed. This study demonstrates the targeting ability and biocompatibility of FSH receptor-targeted theranostics and highlights its potential for clinical application in imaging-guided precision tumor resection and photothermal therapy to eliminate cancer lesions intraoperatively and postoperatively.Keywords:
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Photothermal therapy is a new type of tumor therapy with great potential. An ideal photothermal therapy agent should have high photothermal conversion effect, low biological toxicity, and degradability. The development of novel photothermal therapy agents with these properties is of great demand. In this study, we synthesized boron quantum dots (BQDs) with an ultrasmall hydrodynamic diameter. Both
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In vivo imaging of molecular events in small animals has great potential to impact basic science and drug development. For this reason, several imaging technologies have been adapted to small animal research, including X-ray, magnetic resonance, and radioisotope imaging. Despite this plethora of visualization techniques, fluorescence imaging is emerging as an important alternative because of its operational simplicity, safety, and cost-effectiveness. Fluorescence imaging has recently become particularly interesting because of advances in fluorescent probe technology, including targeted fluorochromes as well as fluorescent “switches” sensitive to specific biochemical events. While past biological investigations using fluorescence have focused on microscopic examination of ex vivo, in vitro, or intravital specimens, techniques for macroscopic fluorescence imaging are now emerging for in vivo molecular imaging applications. This review illuminates fluorescence imaging technologies that hold promise for small animal imaging. In particular we focus on planar illumination techniques, also known as Fluorescence Reflectance Imaging (FRI), and discuss its performance and current use. We then discuss fluorescence molecular tomography (FMT), an evolving technique for quantitative three-dimensional imaging of fluorescence in vivo. This technique offers the promise of non-invasively quantifying and visualizing specific molecular activity in living subjects in three dimensions.
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Combining specific and quantitative F-19 magnetic resonance imaging (MRI) with sensitive and convenient optical imaging provides complementary information about the distribution and viability of transplanted pancreatic islet grafts. In this study, pancreatic islets (PIs) were labeled with positively charged multimodal nanoparticles based on poly(lactic-co-glycolic acid) (PLGA-NPs) with encapsulated perfluoro-15-crown-5-ether and the near-infrared fluorescent dye indocyanine green.One thousand and three thousand bioluminescent PIs were transplanted into subcutaneous artificial scaffolds, which served as an alternative transplant site. The grafts were monitored using in vivo F-19 MR, fluorescence, and bioluminescence imaging in healthy rats for 2 weeks.Transplanted PIs were unambiguously localized in the scaffolds by F-19 MRI throughout the whole experiment. Fluorescence was detected in the first 4 days after transplantation only. Importantly, in vivo bioluminescence correlated with the F-19 MRI signal.We developed a trimodal imaging platform for in vivo examination of transplanted PIs. Fluorescence imaging revealed instability of the fluorescent dye and its limited applicability for longitudinal in vivo studies. A correlation between the bioluminescence signal and the F-19 MRI signal indicated the fast clearance of PLGA-NPs from the transplantation site after cell death, which addresses a major issue with intracellular imaging labels. Therefore, the proposed PLGA-NP platform is reliable for reflecting the status of transplanted PIs in vivo.
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Reporter gene-based strategies are widely used in experimental oncology. Bioluminescence imaging (BLI) using the firefly luciferase (Fluc) as a reporter gene and d-luciferin as a substrate is currently the most widely employed technique. The present paper compares the performances of BLI imaging with fluorescence imaging using the near infrared fluorescent protein (iRFP) to monitor brain tumor growth in mice. Fluorescence imaging includes fluorescence reflectance imaging (FRI), fluorescence diffuse optical tomography (fDOT), and fluorescence molecular Imaging (FMT®). A U87 cell line was genetically modified for constitutive expression of both the encoding Fluc and iRFP reporter genes and assayed for cell, subcutaneous tumor and brain tumor imaging. On cultured cells, BLI was more sensitive than FRI; in vivo, tumors were first detected by BLI. Fluorescence of iRFP provided convenient tools such as flux cytometry, direct detection of the fluorescent protein on histological slices, and fluorescent tomography that allowed for 3D localization and absolute quantification of the fluorescent signal in brain tumors.
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Abstract Molecular-genetic imaging in living organisms has become a new field with the exceptional growth over the past 5 years. Modern imaging is based on three technologies: nuclear, magnetic resonance and optical imaging. Most current molecular-genetic imaging strategies are “indirect,” coupling a “reporter gene” with a complimentary “reporter probe.” The reporter transgene usually encodes for an enzyme, receptor or transporter that selectively interacts with a radiolabeled probe and results in accumulation of radioactivity in the transduced cell. In addition, reporter systems based on the expression of fluorescence or bioluminescence proteins are becoming more widely applied in small animal imaging. This review begins with a description of Positron Emission Tomography (PET)-based imaging genes and their complimentary radiolabeled probes that we think will be the first to enter clinical trials. Then we describe other imaging genes, mostly for optical imaging, which have been developed by investigators working with a variety of disease models in mice. Such optical reporters are unlikely to enter the clinic, at least not in the near-term. Reporter gene constructs can be driven by constitutive promoter elements and used to monitor gene therapy vectors and the efficacy of gene targeting and transduction, as well as to monitor adoptive cell-based therapies. Inducible promoters can be used as “sensors” to monitor endogenous cell processes, including specific intracellular molecular-genetic events and the activity of signaling pathways, by regulating the magnitude of reporter gene expression.
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Abstract As a new minimally invasive technique, photothermal therapy has attracted worldwide attention in the treatment of cancer. Photothermal therapy kills cancer cells by converting photon energy into heat energy. At the time of selection, the photothermal agents will be required to be water solubility, cytotoxicity, high photothermal conversion efficiency, metabolic pathway and so on. This report introduces the current research status of various nanoparticles used in photothermal therapy, and looks forward to the future development of photothermal therapy.
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In this talk I will present an array of fluorescence molecular imaging technologies for multi-scale imaging from microscopic to macroscopic scales. Specific methods include planar fluorescence imaging for macroscopic samples, fluorescence laminar optical tomography (LOT) for mesoscopic (millimeter scale) samples, and two-photon fluorescence microscopy for intravital microscopic imaging. In addition, needle-based endoscopic imaging of deep tissues will be presented. Specific biomedical examples will include in vivo imaging of renal and brain function, 3D imaging of stem cell migration in scaffolds, and molecular imaging of cancer. Lastly, I will introduce our ongoing efforts in collaboration with FDA scientists on the development of standard testing methods for evaluation of optical molecular imaging devices.
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