• cancer stem cell
• fluorescent dye
• leukemia
• mito-chondria
• zebrafish

• antitumor activity
• cytostatic activity
• extract of Gratiola officinalis L.
• flavonoids
• polyelectrolyte microcapsules

Colorectal cancer (CRC) is one of the leading causes of cancer related death in the western world. Its successful treatment requires early detection and removal of precursor lesions as well as individualized treatment of advanced disease. During recent years, molecular imaging techniques have shown promising results to improve current clinical practice. For instance, molecular endoscopy resulted in higher detection rates of precursors in comparison to conventional endoscopy in preclinical and clinical studies. Molecular confocal endomicroscopy allowed a further classification of suspect lesions as well as the prediction and monitoring of the therapeutic response. In this review, we summarize recent achievements for molecular imaging of CRC in preclinical studies, initial clinical trials and the remaining challenges for future translation into clinical practice.

• Raman
• adenoma
• colorectal cancer
• confocal endomicroscopy
• endoscopy
• fluorescence
• molecular imaging
• near-infrared imaging

The prediction and final survival rate of gastrointestinal cancers are dependent on the stage of disease. The ideal would be to detect those gastrointestinal lesions at early stage or even premalignant forms which are difficult to detect by conventional endoscopy with white light optical imaging as they show minimum or no changes in morphological characteristics and are thus left untreated. The introduction of molecular imaging has greatly changed the pattern for detecting gastrointestinal lesions from purely macroscopic structural imaging to the molecular level. It allows microscopic examination of the gastrointestinal mucosa with endoscopy after the topical or systemic application of molecular probes. In recent years, major advancements in endoscopic instruments and specific molecular probes have been achieved. This review focuses on the current status of endoscopic imaging and highlights the application of molecular imaging in gastrointestinal and hepatic disease in the context of diagnosis and therapy based on recently published literature in this field. We also discuss the challenges of molecular endoscopic imaging, its future directions and potential that could have a tremendous impact on endoscopic research and clinical practice in future.

• antibody labeling
• confocal endomicroscopy
• endoscopy
• ex vivo study
• in vivo imaging
• molecular imaging

• antibody labeling
• confocal endomicroscopy
• endoscopy
• ex-vivo study
• molecular imaging

Near-infrared fluorescence (NIRF) imaging combined with enzyme-activatable NIRF probes has yielded promising results in cancer detection.

To test whether 3-dimensional (3-D) noninvasive in vivo NIRF imaging can detect effects of epidermal growth factor receptor (EGFR) inhibitor on both polypoid and flat tumor load in azoxymethane (AOM)-induced colon tumors or tumors in Apc^Min/+ mice.

The AOM-injected KK-HIJ mice received EGFR inhibitor diet or chow diet. These and Apc^Min/+ mice were given cathepsin-activatable probes (ProSense 680) before imaging. In vivo imaging was performed using quantitative tomographic NIRF imaging. Ex vivo imaging and histologic examination were performed. Dual imaging by micro computed tomography (CT) and 3D NIRF imaging was used to verify tumor location.

Tumor load reduction by EGFR inhibition was detected ex vivo using cathepsin B probes. In vivo imaging revealed intense activation of probes only in large tumors. Dual imaging with microCT and 3D NIRF imaging improved tumor detection in vivo.

The 3-D NIRF imaging with ProSense 680 can detect and quantify drug effects on colon tumors ex vivo. The NIRF imaging with ProSense 680 probe has limitations as a valid nonendoscopic method for intestinal tumor detection. Combing with other imaging modalities will improve the specificity and sensitivity of intestinal tumor detection in vivo.

• advances in optical probes
• cancer detection imaging
• cancer imaging
• fluorescent probes
• imaging in drug development
• near-infrared imaging

• Crohn’s disease
• confocal endomicroscopy
• endoscopy
• inflammatory bowel disease
• mucosal inflammation
• multiphoton microscopy
• narrow-band imaging
• ulcerative colitis

In this study, we aimed to determine an effective strategy for the synthesis of folate receptor (FR) targeted-nanoparticles (FRNPs). The nanoparticles used as ultrasound contrast agents (UCAs) were composed of a liquid core of perfluorooctyl bromide (PFOB) liposome and a targeted shell chemically conjugated with folic acid (FA) and polyethylene glycol (PEG). This was done in order to avoid recognition and clearance by the mononuclear phagocyte system [also known as the reticuloendothelial system (RES)] and enhance the targeting capability of the nanoparticles to tumors overexpressing folate receptor (FR). The FRNPs exhibited an average particle size of 301±10.8 nm and surface potential of 39.1±0.43 mV. Subsequently, in vitro, FRNPs labeled with FITC fluorescence dye were visibly uptaken into the cytoplasm of FR-overexpressing cancer cells (Bel7402 and SW620 cells), whereas the A549 cells expressing relatively low levels of FR just bound with few FRNPs. These results demonstrated that FRNPs have a high affinity to FR-overexpressing cancer cells. Additionally, in in vivo experiments, FRNPs achieved a greater enhancement of tumor ultrasound imaging and a longer enhancement time in FR-overexpressing tumors and the Cy7-labeled FRNPs exhibited a relatively high tumor-targeted distribution in FR-overexpressing tumors. Targeted ultrasound and fluorescence imaging revealed that FRNPs have the ability to target FR-overexpressing tumors and ex vivo fluorescence imaging was then used to further verify and confirm the presence of FRNPs in tumor tissues with histological analysis of the tumor slices. On the whole, our data demonstrate that the FRNPs may prove to be a promising candidate for the early diagnosis for FR-overexpressing tumors at the molecular and cellular levels.

• 5-ALA
• ICG
• confocal
• endomicroscopy
• fluorescein
• fluorescence-guided surgery
• fluorescent probe
• glioma

• Animals
• Ferric Compounds
• Human Umbilical Vein Endothelial Cells
• Humans
• Hyperthermia, Induced
• Magnetics
• Manganese
• Mice
• Nanoparticles
• Neoplasms, Experimental/therapy
• RAW 264.7 Cells
• Zinc

Animal models of colon cancer are widely used to understand the molecular mechanisms and pathogenesis of the disease. These animal models require a substantial investment of time and traditionally necessitate the killing of the animal to measure the tumor progression. Several in vivo imaging techniques are being used in both human clinics and preclinical studies, albeit at high cost and requiring particular expertise. Here, we report that the progression of splenomegaly coincides with and positively correlates to colon tumor development in Apc^min716/+ mice expressing a mutant gene encoding an adenomatous polyposis coli protein truncated at amino acid 716. Ultrasound image‐based spleen size measurement precisely mirrors splenomegaly development in vivo in the tumor‐laden Apc^min716/+ mice. Moreover, the spleen dimensions extracted from the ultrasound sonograms are positively correlated with normalized spleen weight and the number and area of colon tumors. Hence, we propose measuring the spleen size in vivo by ultrasound imaging as a novel approach to estimate splenomegaly development and to indirectly monitor colon tumor development in Apc^min716/+ mice. The widespread use of ultrasound machines in the laboratory setting, coupled with the fact that it is a noninvasive method, make it a straightforward and useful tool for monitoring the experimental progress of colon cancer in mice and determining end points without killing animals strictly for diagnostics purposes.

• Colon tumor
• in vivo imaging
• splenomegaly
• ultrasound

• Advanced endoscopic imaging
• Chromoendoscopy
• Colitis associated cancer
• Confocal laser endomicroscopy
• Crohn’s disease
• Endocytoscopy
• Molecular imaging
• Mucosal healing
• Ulcerative colitis

• Chromogenic Compounds
• Colitis, Ulcerative/diagnostic imaging
• Colitis, Ulcerative/pathology
• Crohn Disease/diagnostic imaging
• Crohn Disease/pathology
• Endoscopy, Gastrointestinal/methods
• Humans
• Intestines/diagnostic imaging
• Intestines/pathology
• Microscopy, Confocal
• Molecular Imaging/methods
• Predictive Value of Tests
• Prognosis

• Colon
• Colorectal neoplasms
• Crohn’s disease
• Gastrointestinal endoscopy
• Inflammatory bowel diseases
• Ulcerative colitis

• Chromogenic Compounds/administration & dosage
• Colitis, Ulcerative/pathology
• Crohn Disease/pathology
• Endoscopy, Gastrointestinal/methods
• Epithelial Cells/pathology
• Humans
• Image Enhancement
• Intestinal Mucosa/pathology
• Microscopy, Confocal
• Molecular Imaging
• Predictive Value of Tests

• Animals
• Breast Neoplasms/diagnosis
• Cell Line, Tumor
• Diagnostic Imaging/instrumentation
• Diagnostic Imaging/methods
• Female
• Fluorescent Dyes/chemical synthesis
• Humans
• Indoles/chemical synthesis
• Mammary Neoplasms, Experimental
• Mice
• Mice, Nude
• Phosphorylcholine/analogs & derivatives
• Phosphorylcholine/chemical synthesis
• Pilot Projects
• Tumor Burden

• 5T32CA091078-12 NCI NIH HHS

Since cancer cells are normally over-expressed cathepsin B, we synthesized dendrimer-methoxy poly(ethylene glycol) (MPEG)-doxorubicin (DOX) conjugates using a cathepsin B-cleavable peptide for anticancer drug targeting.

Gly-Phe-Leu-Gly peptide was conjugated with the carboxylic acid end groups of a dendrimer, which was then conjugated with MPEG amine and doxorubicin by aid of carbodiimide chemistry (abbreviated as DendGDP). Dendrimer-MPEG-DOX conjugates without Gly-Phe-Leu-Gly peptide linkage was also synthesized for comparison (DendDP). Nanoparticles were then prepared using a dialysis procedure.

The synthesized DendGDP was confirmed with ¹H nuclear magnetic resonance spectroscopy. The DendDP and DendGDP nanoparticles had a small particle size of less than 200 nm and had a spherical morphology. DendGDP had cathepsin B-sensitive drug release properties while DendDP did not show cathepsin B sensitivity. Further, DendGDP had improved anticancer activity when compared with doxorubicin or DendDP in an in vivo CT26 tumor xenograft model, ie, the volume of the CT26 tumor xenograft was significantly inhibited when compared with xenografts treated with doxorubicin or DendDP nanoparticles. The DendGDP nanoparticles were found to be relatively concentrated in the tumor tissue and revealed stronger fluorescence intensity than at other body sites while doxorubicin and DendDP nanoparticles showed strong fluorescence intensity in the various organs, indicating that DendGDP has cathepsin B sensitivity.

DendGDP is sensitive to cathepsin B in tumor cells and can be used as a cathepsin B-responsive drug targeting strategy. We suggest that DendGDP is a promising vehicle for cancer cell targeting.

• CT26 cell
• cathepsin B
• enzyme-sensitive dendrimer
• tetra peptide
• tumor targeting

We designed a new siRNA system which turns on RNAi responding to a cancer cell-specific protease by using a peptide nucleic acid (PNA)-peptide conjugate.

A practical and effective strategy for synthesis of Folate-NIR 797-conjugated Magnetic Albumin Nanospheres (FA-NIR 797-MAN) was developed. For this strategy, Magnetic Albumin Nanospheres (MAN), composed of superparamagnetic iron oxide nanoparticles (SPIONs) and bovine serum albumin (BSA), were covalently conjugated with folic acid (FA) ligands to enhance the targeting capability of the particles to folate receptor (FR) over-expressing tumours. Subsequently, a near-infrared (NIR) fluorescent dye NIR 797 was conjugated with FA-conjugated MAN for in vivo fluorescence imaging. The FA-NIR 797-MAN exhibited low toxicity to a human nasopharyngeal epidermal carcinoma cell line (KB cells). Additionally, in vitro and in vivo evaluation of the dynamic behaviour and targeting ability of FA-NIR 797-MAN to KB tumours validated the highly selective affinity of FA-NIR 797-MAN for FR-positive tumours. In summary, the FA-NIR 797-MAN prepared here exhibited great potential for tumour imaging, since the near-infrared fluorescence contrast agents target cells via FR-mediated endocytosis. The high fluorescence intensity together with the targeting effect makes FA-NIR 797-MAN a promising candidate for imaging, monitoring, and early diagnosis of cancer at the molecular and cellular levels.

• Colorectal carcinoma
• confocal laser endomicroscopy
• endoscopy
• gastric cancer
• molecular imaging

• Animals
• Colitis/diagnostic imaging
• Colitis/pathology
• Colonoscopy
• Decision Making
• Endosonography/methods
• Inflammation/diagnostic imaging
• Inflammation/pathology
• Male
• Microscopy, Acoustic/methods
• Predictive Value of Tests
• Rats
• Rats, Wistar

• peptide
• multimer
• colorectal cancer
• early detection
• endoscopy

• Autofluorescence endoscopy
• Confocal endomicroscopy
• Endoscopy
• Molecular imaging
• Molecular probes, Near-infrared fluorescence imaging
• Targeted endoscopic imaging

Several investigators have shown the utility of systemically delivered optical imaging probes to image tumors in small animal models of cancer. Here we demonstrate an innovative method for imaging tumors and tumor margins during surgery. Specifically, we show that optical imaging probes topically applied to tumors and surrounding normal tissue rapidly differentiate between tissues. In contrast to systemic delivery of optical imaging probes which label tumors uniformly over time, topical probe application results in rapid and robust probe activation that is detectable as early as 5 minutes following application. Importantly, labeling is primarily associated with peri-tumor spaces. This methodology provides a means for rapid visualization of tumor and potentially infiltrating tumor cells and has potential applications for directed surgical excision of tumor tissues. Furthermore, this technology could find use in surgical resections for any tumors having differential regulation of cysteine cathepsin activity.

• multispectral
• endoscopy
• colon
• wide-field
• fluorescence
• peptide
• dysplasia
• cancer

• Adenocarcinoma/pathology
• Animals
• Cell Line, Tumor
• Colonic Neoplasms/pathology
• Endoscopes, Gastrointestinal
• Equipment Design
• Equipment Failure Analysis
• Fiber Optic Technology/instrumentation
• Image Enhancement/instrumentation
• Mice
• Mice, Knockout
• Microscopy, Fluorescence, Multiphoton/instrumentation
• Molecular Imaging/instrumentation

• P50 CA93990 NCI NIH HHS
• DK34933 NIDDK NIH HHS
• U54 CA13642 NCI NIH HHS
• R01 CA142750 NCI NIH HHS
• P50 CA093990 NCI NIH HHS
• RC1 EB010900 NIBIB NIH HHS
• P30 DK034933 NIDDK NIH HHS

• Animals
• Colonic Neoplasms/diagnosis
• Colonoscopy/methods
• Female
• Male
• Mice
• Mice, Inbred BALB C
• Microscopy, Acoustic/methods
• Reproducibility of Results
• Sensitivity and Specificity

Colorectal cancer (CRC) is a major cause of cancer-related deaths in much of the world. Most CRCs arise from pre-malignant (dysplastic) lesions, such as adenomatous polyps, and current endoscopic screening approaches with white light do not detect all dysplastic lesions. Thus, new strategies to identify such lesions, including non-polypoid lesions, are needed. We aim to identify and validate novel peptides that specifically target dysplastic colonic epithelium in vivo. We used phage display to identify a novel peptide that binds to dysplastic colonic mucosa in vivo in a genetically engineered mouse model of colo-rectal tumorigenesis, based on somatic Apc (adenomatous polyposis coli) gene inactivation. Binding was confirmed using confocal microscopy on biopsied adenomas and excised adenomas incubated with peptide ex vivo. Studies of mice where a mutant Kras allele was somatically activated in the colon to generate hyperplastic epithelium were also performed for comparison. Several rounds of in vivo T7 library biopanning isolated a peptide, QPIHPNNM. The fluorescent-labeled peptide bound to dysplastic lesions on endoscopic analysis. Quantitative assessment revealed the fluorescent-labeled peptide (target/background: 2.17±0.61) binds ∼2-fold greater to the colonic adenomas when compared to the control peptide (target/background: 1.14±0.15), p<0.01. The peptide did not bind to the non-dysplastic (hyperplastic) epithelium of the Kras mice. This work is first to image fluorescence-labeled peptide binding in vivo that is specific towards colonic dysplasia on wide-area surveillance. This finding highlights an innovative strategy for targeted detection to localize pre-malignant lesions that can be generalized to the epithelium of hollow organs.

• Colon cancer
• Inflammatory bowel disease
• Matrix metalloproteinases
• Near-infrared fluorescence