Near-infrared Fluorescence Imaging Using a Protease-activatable Nanoprobe in Tumor Detection: Comparison with Narrow-band Imaging

BACKGROUND/AIMS: Advances in endoscopic technology seek to improve the accuracy of neoplastic tumor detection. Recently developed endoscopy devices such as narrow-band imaging (NBI) nevertheless have limitations in morphologic diagnosis. The purpose of this study was to investigate whether a novel imaging technique-near-infrared fluorescence (NIRF) imaging using a protease-activatable nanoprobe-could provide more accurate neoplastic tumor detection, compared to NBI. METHODS: Images of the intestines of Apc(Min/+) mice were obtained by NIRF using a matrix metalloproteinase (MMP)-sensing probe, which was based on a nanoparticle platform. Immediately after imaging, endoscopy with NBI capability was performed on the same excised intestine. Macroscopic and microscopic findings in the intestines were assessed, and MMP expression was analyzed by Western blotting and real-time polymerase chain reaction. RESULTS: Numerous tiny polypoid lesions were present in the intestines of aged Apc(Min/+) mice. These lesions included adenomas, lymphoid follicles, and protruding normal tissues. When using NIRF imaging with an MMP-activatable nanoprobe, adenomatous polyps showed higher fluorescence, compared to lymphoid follicles or adjacent normal tissues. The expression of MMP was higher in the adenomatous tissue than in the other tissues. The sensitivity and specificity for adenoma detection were 88.9% and 82.2%, respectively, when using NIRF imaging with a MMP-nanoprobe, compared to 77.8% and 66.7%, respectively, when using NBI (P<0.05). CONCLUSIONS: Near-infrared fluorescence imaging with a protease-activatable nanoprobe could aid in the differentiation of tumor characteristics. Clinical application of this approach may improve the endoscopic detection of neoplastic tumors.

Assessment of Collagen-Induced Arthritis Using Cyanine 5.5 Conjugated with Hydrophobically Modified Glycol Chitosan Nanoparticles: Correlation with 18F-Fluorodeoxyglucose Positron Emission Tomography Data

OBJECTIVE: To evaluate the potential and correlation between near-infrared fluorescence (NIRF) imaging using cyanine 5.5 conjugated with hydrophobically modified glycol chitosan nanoparticles (HGC-Cy5.5) and 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) imaging of collagen-induced arthritis (CIA). MATERIALS AND METHODS: We used 10 CIA and 3 normal mice. Nine days after the injecting collagen twice, microPET imaging was performed 40 minutes after the intravenous injection of 9.3 MBq 18F-FDG in 200 microL PBS. One day later, NIRF imaging was performed two hours after the intravenous injection of HGC-cy5.5 (5 mg/kg). We assessed the correlation between these two modalities in the knees and ankles of CIA mice. RESULTS: The mean standardized uptake values of 18F-FDG for knees and ankles were 1.68 +/- 0.76 and 0.79 +/- 0.71, respectively, for CIA mice; and 0.57 +/- 0.17 and 0.54 +/- 0.20 respectively for control mice. From the NIRF images, the total photon counts per 30 mm2 for knees and ankles were 2.32 +/- 1.54 x 10(5) and 2.75 +/- 1.51 x 10(5), respectively, for CIA mice, and 1.22 +/- 0.27 x 10(5) and 0.88 +/- 0.24 x 10(5), respectively, for control mice. These two modalities showed a moderate correlation for knees (r = 0.604, p = 0.005) and ankles (r = 0.464, p = 0.039). Moreover, both HGC-Cy5.5 (p = 0.002) and 18F-FDG-PET (p = 0.005) imaging also showed statistically significant differences between CIA and normal mice. CONCLUSION: NIRF imaging using HGC-Cy5.5 was moderately correlated with 18F-FDG-PET imaging in the CIA model. As such, HGC-Cy5.5 imaging can be used for the early detection of rheumatoid arthritis.

Near-Infrared Fluorescence Imaging Using a Protease-Specific Probe for the Detection of Colon Tumors

BACKGROUND/AIMS: Early tumor detection is crucial for the prevention of colon cancer. Near-infrared fluorescence (NIRF) imaging using a target-activatable probe may permit earlier disease detection. Matrix metalloproteinases (MMPs) participate in tumorigenesis and tumor growth. The aim of this study was to determine whether NIRF imaging using an MMP-activatable probe can detect colon tumors at early stages. METHODS: We utilized two murine colon cancer models: a sporadic colon cancer model induced by azoxymethane (AOM), and a colitis-associated cancer model induced by a combination of AOM and dextran sodium sulfate (DSS). Colonic lesions were analyzed by histologic examination, Western blotting, immunohistochemical staining, and NIRF imaging using an MMP-activatable probe. RESULTS: Multiple variable-sized tumors developed in both models and progressed from adenomas to adenocarcinomas over time. At the early stage of the AOM/DSS model, diffuse inflammation was observed within the tumors. MMP expression increased progressively through normal, inflammation, adenoma, and adenocarcionoma stages. NIRF signal intensities were strongly correlated with each tumor stage from adenoma to adenocarcinoma. NIRF imaging also distinguished tumors from inflamed mucosa. CONCLUSIONS: NIRF imaging using a protease-activatable probe may be a useful tool for early tumor detection. This approach could translate to improve the endoscopic detection of colon tumors, especially in patients with inflammatory bowel disease.

Multifunctional Nanoparticles for Molecular Imaging

Molecular imaging is a bioimaging that can detect biochemically and genetically relevant events in molecular level in cells and tissues via quantitative imaging signal. Molecular imaging provides potential advantages to examine early diagnosis of specific diseases, to screen new candidates of a drug, to monitor therapeutic effects in real time, and to communicate with both diagnosis and therapeutics. These diverse advantages of molecular imaging can be allowed by development of nanoplatform technology. The nanoplatform-based probes for molecular imaging is widely investigated to grant multimodal molecular imaging and drug delivery together with medical imagings, which includes the issues of biocompatibility, targeting moiety, proteasespecific peptide substrate, quenching/dequenching system etc. In this paper, nanoplatformbased probes are reviewed in aspects of cancer targeting for diagnosis and therapy and multimodal molecular imaging with inorganic/organic hybrid nanoparticles.

Multifunctional Nanoparticles for Molecular Imaging

Molecular imaging is a bioimaging that can detect biochemically and genetically relevant events in molecular level in cells and tissues via quantitative imaging signal. Molecular imaging provides potential advantages to examine early diagnosis of specific diseases, to screen new candidates of a drug, to monitor therapeutic effects in real time, and to communicate with both diagnosis and therapeutics. These diverse advantages of molecular imaging can be allowed by development of nanoplatform technology. The nanoplatform-based probes for molecular imaging is widely investigated to grant multimodal molecular imaging and drug delivery together with medical imagings, which includes the issues of biocompatibility, targeting moiety, proteasespecific peptide substrate, quenching/dequenching system etc. In this paper, nanoplatformbased probes are reviewed in aspects of cancer targeting for diagnosis and therapy and multimodal molecular imaging with inorganic/organic hybrid nanoparticles.