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Toxicity studies of coumarin 6-encapsulated polystyrene nanospheres conjugated with peanut agglutinin and poly(N-vinylacetamide) as a colonoscopic imaging agent in rats.
Sakuma S, Kumagai H, Shimosato M, Kitamura T, Mohri K, Ikejima T, Hiwatari K, Koike S, Tobita E, McClure R, Gore JC, Pham W
(2015) Nanomedicine 11: 1227-36
MeSH Terms: Acetamides, Animals, Body Weight, CHO Cells, Caco-2 Cells, Colon, Colonoscopy, Colorectal Neoplasms, Coumarins, Cricetulus, Drinking, Eating, Fluorescent Dyes, Humans, Male, Nanospheres, Peanut Agglutinin, Polystyrenes, Polyvinyls, Rats, Rectum, Thiazoles
Show Abstract · Added February 15, 2016
UNLABELLED - We are investigating an imaging agent that detects early-stage primary colorectal cancer on the mucosal surface in real time under colonoscopic observation. The imaging agent, which is named the nanobeacon, is fluorescent nanospheres conjugated with peanut agglutinin and poly(N-vinylacetamide). Its potential use as an imaging tool for colorectal cancer has been thoroughly validated in numerous studies. Here, toxicities of the nanobeacon were assessed in rats. The nanobeacon was prepared according to the synthetic manner which is being established as the Good Manufacturing Practice-guided production. The rat study was performed in accordance with Good Laboratory Practice regulations. No nanobeacon treatment-related toxicity was observed. The no observable adverse effect levels (NOAEL) of the nanobeacon in 7-day consecutive oral administration and single intrarectal administration were estimated to be more than 1000mg/kg/day and 50mg/kg/day, respectively. We concluded that the nanobeacon could be developed as a safe diagnostic agent for colonoscopy applications.
FROM THE CLINICAL EDITOR - Colon cancer remains a major cause of death. Early detection can result in early treatment and thus survival. In this article, the authors tested potential systemic toxicity of coumarin 6-encapsulated polystyrene nanospheres conjugated with peanut agglutinin (PNA) and poly(N-vinylacetamide) (PNVA), which had been shown to bind specifically to colonic cancer cells and thus very promising in colonoscopic detection of cancer cells.
Copyright © 2015 Elsevier Inc. All rights reserved.
0 Communities
2 Members
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22 MeSH Terms
Fluorescence-based endoscopic imaging of Thomsen-Friedenreich antigen to improve early detection of colorectal cancer.
Sakuma S, Yu JY, Quang T, Hiwatari K, Kumagai H, Kao S, Holt A, Erskind J, McClure R, Siuta M, Kitamura T, Tobita E, Koike S, Wilson K, Richards-Kortum R, Liu E, Washington K, Omary R, Gore JC, Pham W
(2015) Int J Cancer 136: 1095-103
MeSH Terms: Adenocarcinoma, Animals, Antigens, Tumor-Associated, Carbohydrate, Biomarkers, Tumor, Colonoscopy, Colorectal Neoplasms, Diagnostic Imaging, Early Detection of Cancer, Female, Fluorescence, Fluorescent Dyes, Immunoenzyme Techniques, Mice, Mice, Inbred C57BL, Nanospheres, Rats, Rats, Nude, Tumor Cells, Cultured
Show Abstract · Added February 12, 2015
Thomsen-Friedenreich (TF) antigen belongs to the mucin-type tumor-associated carbohydrate antigen. Notably, TF antigen is overexpressed in colorectal cancer (CRC) but is rarely expressed in normal colonic tissue. Increased TF antigen expression is associated with tumor invasion and metastasis. In this study, we sought to validate a novel nanobeacon for imaging TF-associated CRC in a preclinical animal model. We developed and characterized the nanobeacon for use with fluorescence colonoscopy. In vivo imaging was performed on an orthotopic rat model of CRC. Both white light and fluorescence colonoscopy methods were utilized to establish the ratio-imaging index for the probe. The nanobeacon exhibited specificity for TF-associated cancer. Fluorescence colonoscopy using the probe can detect lesions at the stage which is not readily confirmed by conventional visualization methods. Further, the probe can report the dynamic change of TF expression as tumor regresses during chemotherapy. Data from this study suggests that fluorescence colonoscopy can improve early CRC detection. Supplemented by the established ratio-imaging index, the probe can be used not only for early detection, but also for reporting tumor response during chemotherapy. Furthermore, since the data obtained through in vivo imaging confirmed that the probe was not absorbed by the colonic mucosa, no registered toxicity is associated with this nanobeacon. Taken together, these data demonstrate the potential of this novel probe for imaging TF antigen as a biomarker for the early detection and prediction of the progression of CRC at the molecular level.
© 2014 UICC.
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3 Members
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18 MeSH Terms
Specificity of lectin-immobilized fluorescent nanospheres for colorectal tumors in a mouse model which better resembles the clinical disease.
Kitamura T, Sakuma S, Shimosato M, Higashino H, Masaoka Y, Kataoka M, Yamashita S, Hiwatari K, Kumagai H, Morimoto N, Koike S, Tobita E, Hoffman RM, Gore JC, Pham W
(2015) Contrast Media Mol Imaging 10: 135-43
MeSH Terms: Animals, Cell Line, Tumor, Colorectal Neoplasms, Female, Fluorescent Dyes, Humans, Intestinal Mucosa, Lectins, Mice, Mice, Nude, Nanospheres, Neoplasms, Experimental, Optical Imaging
Show Abstract · Added February 12, 2015
We have been investigating an imaging agent that enables real-time and accurate diagnosis of early colorectal cancer at the intestinal mucosa by colonoscopy. The imaging agent is peanut agglutinin-immobilized polystyrene nanospheres with surface poly(N-vinylacetamide) chains encapsulating coumarin 6. Intracolonically-administered lectin-immobilized fluorescent nanospheres detect tumor-derived changes through molecular recognition of lectin for the terminal sugar of cancer-specific antigens on the mucosal surface. The focus of the present study was to evaluate imaging abilities of the nanospheres in animal models that reflect clinical environments. We previously developed an orthotopic mouse model with human colorectal tumors growing on the mucosa of the descending colon to better resemble the clinical disease. The entire colon of the mice in the exposed abdomen was monitored in real time with an in vivo imaging apparatus. Fluorescence from the nanospheres was observed along the entire descending colon after intracolonical administration from the anus. When the luminal side of the colon was washed with phosphate-buffered saline, most of the nanospheres were flushed. However, fluorescence persisted in areas where cancer cells were implanted. Histological evaluation demonstrated that tumors were present in the mucosal epithelia where the nanospheres fluoresced. In contrast, no fluorescence was observed when control mice, without tumors were tested. The lectin-immobilized fluorescent nanospheres were tumor-specific and remained bound to tumors even after vigorous washing. The nanospheres nonspecifically bound to normal mucosa were easily removed through mild washing. These results indicate that the nanospheres combined with colonoscopy, will be a clinically-valuable diagnostic tool for early-stage primary colon carcinoma.
Copyright © 2014 John Wiley & Sons, Ltd.
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1 Members
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13 MeSH Terms
Multifunctional nanobeacon for imaging Thomsen-Friedenreich antigen-associated colorectal cancer.
Kumagai H, Pham W, Kataoka M, Hiwatari K, McBride J, Wilson KJ, Tachikawa H, Kimura R, Nakamura K, Liu EH, Gore JC, Sakuma S
(2013) Int J Cancer 132: 2107-17
MeSH Terms: Animals, Antigens, Tumor-Associated, Carbohydrate, Blotting, Western, Case-Control Studies, Colon, Colorectal Neoplasms, Coumarins, Diagnostic Imaging, Fluorescent Dyes, Humans, Immunoenzyme Techniques, Male, Mice, Mice, Transgenic, Nanospheres, Peanut Agglutinin, Polystyrenes, RNA, Messenger, Real-Time Polymerase Chain Reaction, Rectum, Reverse Transcriptase Polymerase Chain Reaction, Surface Properties, Thiazoles, Tissue Distribution, Tumor Cells, Cultured
Show Abstract · Added March 7, 2014
This research aimed to validate the specificity of the newly developed nanobeacon for imaging the Thomsen-Friedenreich (TF) antigen, a potential biomarker of colorectal cancer. The imaging agent is comprised of a submicron-sized polystyrene nanosphere encapsulated with a Coumarin 6 dye. The surface of the nanosphere was modified with peanut agglutinin (PNA) and poly(N-vinylacetamide (PNVA) moieties. The former binds to Gal-β(1-3)GalNAc with high affinity while the latter enhances the specificity of PNA for the carbohydrates. The specificity of the nanobeacon was evaluated in human colorectal cancer cells and specimens, and the data were compared with immunohistochemical staining and flow cytometric analysis. Additionally, distribution of the nanobeacon in vivo was assessed using an "intestinal loop" mouse model. Quantitative analysis of the data indicated that approximately 2 μg of PNA were detected for each milligram of the nanobeacon. The nanobeacon specifically reported colorectal tumors by recognizing the tumor-specific antigen through the surface-immobilized PNA. Removal of TF from human colorectal cancer cells and tissues resulted in a loss of fluorescence signal, which suggests the specificity of the probe. Most importantly, the probe was not absorbed systematically in the large intestine upon topical application. As a result, no registered toxicity was associated with the probe. These data demonstrate the potential use of this novel nanobeacon for imaging the TF antigen as a biomarker for the early detection and prediction of the progression of colorectal cancer at the molecular level.
Copyright © 2012 UICC.
0 Communities
3 Members
0 Resources
25 MeSH Terms
Essence of affinity and specificity of peanut agglutinin-immobilized fluorescent nanospheres with surface poly(N-vinylacetamide) chains for colorectal cancer.
Sakuma S, Higashino H, Oshitani H, Masaoka Y, Kataoka M, Yamashita S, Hiwatari K, Tachikawa H, Kimura R, Nakamura K, Kumagai H, Gore JC, Pham W
(2011) Eur J Pharm Biopharm 79: 537-43
MeSH Terms: Acetamides, Animals, Antigens, Tumor-Associated, Carbohydrate, Cecum, Chemistry, Pharmaceutical, Colonoscopy, Colorectal Neoplasms, Contrast Media, Female, Fluorescent Dyes, HT29 Cells, Humans, Intestinal Mucosa, Mice, Mice, SCID, Microscopy, Fluorescence, Nanospheres, Neoplasm Transplantation, Peanut Agglutinin, Polyvinyls, Surface Properties
Show Abstract · Added May 27, 2014
We have designed a novel colonoscopic imaging agent that is composed of submicron-sized fluorescent polystyrene nanospheres with two functional groups - peanut agglutinin (PNA) and poly(N-vinylaceamide) (PNVA) - on their surfaces. PNA is a targeting moiety that binds to β-d-galactosyl-(1-3)-N-acetyl-d-galactosamine (Gal-β(1-3)GalNAc), which is the terminal sugar of the Thomsen-Friedenreich antigen that is specifically expressed on the mucosal side of colorectal cancer cells; it is anchored on the nanosphere surface via a poly(methacrylic) acid (PMAA) linker. PNVA is immobilized to enhance the specificity of PNA by reducing nonspecific interactions between the imaging agent and normal tissues. The essential nature of both functional groups was evaluated through in vivo experiments using PNA-free and PNVA-free nanospheres. The imaging agent recognized specifically tumors on the cecal mucosa of immune-deficient mice in which human colorectal cancer cells had been implanted; however, the recognition capability disappeared when PNA was replaced with wheat germ agglutinin, which has no affinity for Gal-β(1-3)GalNAc. PNA-free nanospheres with exclusively surface PNVA chains rarely adhered to the cecal mucosa of normal mice that did not undergo the cancer cell implantation. In contrast, there were strong nonspecific interactions between normal tissues and PNA-free nanospheres with exclusively surface PMAA chains. In vivo data proved that PNA and PNVA were essential for biorecognition for tumor tissues and a reduction of nonspecific interactions with normal tissues, respectively.
Copyright © 2011 Elsevier B.V. All rights reserved.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Lectin-immobilized fluorescent nanospheres for targeting to colorectal cancer from a physicochemical perspective.
Sakuma S, Yamashita S, Hiwatari K, Hoffman RM, Pham W
(2011) Curr Drug Discov Technol 8: 367-78
MeSH Terms: Acetamides, Animals, Colonoscopy, Colorectal Neoplasms, Coumarins, Drug Delivery Systems, Fluorescent Dyes, Humans, Nanospheres, Peanut Agglutinin, Polystyrenes, Polyvinyls, Thiazoles
Show Abstract · Added May 27, 2014
The goal of this research is to develop an imaging agent that enables real-time and accurate diagnosis of small-sized colorectal cancer. Since colorectal cancer initially develops in the mucous membrane of the large intestine, a nonabsorbable colonoscopic imaging agent capable of being administered intracolonically was designed. The imaging agent is peanut agglutinin (PNA)-immobilized polystyrene nanospheres with surface poly(N-vinylacetamide) (PNVA) chains encapsulating coumarin 6. PNA is a targeting moiety that binds to β-D-galactosyl-(1-3)-N-acetyl-D-galactosamine, which is the terminal sugar of the Thomsen-Friedenreich antigen that is specifically expressed on the mucosal side of colorectal cancer cells. PNVA is immobilized with the aim of reducing nonspecific interactions between the imaging agent and normal tissues, because the initial tumor-derived change is very small throughout the entire large intestine. Coumarin 6 is encapsulated into nanosphere cores to provide endoscopically-detectable fluorescence intensity. It is anticipated that the intracolonically-administered imaging agent recognizes tumor-derived changes in the large intestinal mucosa with high affinity and specificity. Real-time and accurate diagnosis of small-sized early colorectal cancer can be achieved through an imaging agent providing clear fluorescence contrast between normal and cancer tissues observed with a florescence endoscope. This review describes the design concept of this nanoprobe from a physicochemical perspective.
0 Communities
1 Members
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13 MeSH Terms
A potential of peanut agglutinin-immobilized fluorescent nanospheres as a safe candidate of diagnostic drugs for colonoscopy.
Sakuma S, Kataoka M, Higashino H, Yano T, Masaoka Y, Yamashita S, Hiwatari K, Tachikawa H, Kimura R, Nakamura K, Kumagai H, Gore JC, Pham W
(2011) Eur J Pharm Sci 42: 340-7
MeSH Terms: Animals, Caco-2 Cells, Colon, Colonoscopy, Colorectal Neoplasms, Coumarins, Early Detection of Cancer, Female, Fluorescent Dyes, Humans, Indicators and Reagents, Intestinal Mucosa, Mice, Nanospheres, Peanut Agglutinin, Thiazoles
Show Abstract · Added May 27, 2014
We designed peanut agglutinin (PNA)-immobilized fluorescent nanospheres as a non-absorbable endoscopic imaging agent capable of being administered intracolonically. Following our previous researches with evidence that the imaging agent recognized small-sized colorectal tumors on the mucosal surface with high affinity and specificity in animal experiments, a potential of this nanoprobe as a drug candidate was evaluated from a safety perspective. The imaging agent detects colorectal tumors through recognition of the tumor-specific antigen by PNA immobilized on the nanosphere surface, and the detection is made via the fluorescent signal derived from coumarin 6 encapsulated into the nanosphere core. The stability studies revealed that the high activity of PNA was maintained and there was no significant leakage of coumarin 6 after intracolonic administration of the imaging agent. Cytotoxicity studies indicated that no local damage to the large intestinal membrane was induced by the imaging agent. Further, in vitro and in vivo permeation studies demonstrated that there was no significant permeation of the imaging agent through the monolayer of cultured cells and that the imaging agent administered locally to the luminal side of the large intestine was almost completely recovered from the administration site. Therefore, we concluded that the imaging agent is a safe and stable probe which remains in the large intestine without systemic exposure.
Copyright © 2011 Elsevier B.V. All rights reserved.
0 Communities
1 Members
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16 MeSH Terms
Photothermal optical coherence tomography of epidermal growth factor receptor in live cells using immunotargeted gold nanospheres.
Skala MC, Crow MJ, Wax A, Izatt JA
(2008) Nano Lett 8: 3461-7
MeSH Terms: Animals, Contrast Media, Equipment Design, ErbB Receptors, Fourier Analysis, Gold, Humans, Immunohistochemistry, Metal Nanoparticles, Microscopy, Microscopy, Fluorescence, Nanoparticles, Nanospheres, Nanotechnology, Tomography, Optical Coherence
Show Abstract · Added March 11, 2014
Molecular imaging is a powerful tool for investigating disease processes and potential therapies in both in vivo and in vitro systems. However, high resolution molecular imaging has been limited to relatively shallow penetration depths that can be accessed with microscopy. Optical coherence tomography (OCT) is an optical analogue to ultrasound with relatively good penetration depth (1-2 mm) and resolution (approximately 1-10 microm). We have developed and characterized photothermal OCT as a molecular contrast mechanism that allows for high resolution molecular imaging at deeper penetration depths than microscopy. Our photothermal system consists of an amplitude-modulated heating beam that spatially overlaps with the focused spot of the sample arm of a spectral-domain OCT microscope. Validation experiments in tissuelike phantoms containing gold nanospheres that absorb at 532 nm revealed a sensitivity of 14 ppm nanospheres (weight/weight) in a tissuelike environment. The nanospheres were then conjugated to anti-EGFR, and molecular targeting was confirmed in cells that overexpress EGFR (MDA-MB-468) and cells that express low levels of EGFR (MDA-MB-435). Molecular imaging in three-dimensional tissue constructs was confirmed with a significantly lower photothermal signal (p<0.0001) from the constructs composed of cells that express low levels of EGFR compared to the overexpressing cell constructs (300% signal increase). This technique could potentially augment confocal and multiphoton microscopy as a method for deep-tissue, depth-resolved molecular imaging with relatively high resolution and target sensitivity, without photobleaching or cytotoxicity.
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15 MeSH Terms