Hideo Saji

Kyoto University, Kioto, Kyōto, Japan

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Publications (473)1269.13 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Poly(ethylene glycol) (PEG) is an artificial but biocompatible hydrophilic polymer that has been widely used in clinical products. To evaluate the feasibility of using PEG derivative itself as a tumor imaging carrier via an enhanced permeability and retention (EPR) effect, we prepared indium-111-labeled PEG (111In-DTPA-PEG) and indocyanine green (ICG)-labeled PEG (ICG-PEG) with PEG molecular weights of 5–40 kDa and investigated their in vivo biodistribution in colon26 tumor-bearing mice. Thereafter, single-photon emission computed tomography (SPECT) and photoacoustic (PA) imaging studies were performed. The in vivo biodistribution studies demonstrated increased tumor uptake and a prolongation of circulation half-life as the molecular weight of PEG increased. Although the observed differences in in vivo biodistribution were dependent on the labeling method (111In or ICG), the tumor-to-normal tissue ratios were comparable. Because PEG-based probes with a molecular weight of 20 kDa (PEG20) showed a preferable biodistribution (highest accumulation among tissues excised and relatively high tumor-to-blood ratios), an imaging study using 111In-DTPA-PEG20 and ICG-PEG20 was performed. Colon26 tumors inoculated in the right shoulder or flank were clearly visualized by SPECT 24 h after administration. Furthermore, PA imaging using ICG-PEG20 also detected tumor regions, and the detected PA signals increased in proportion with the injected dose. These results suggest that PEG derivatives (20 kDa) serve as robust diagnostic drug carriers for tumor imaging.
    No preview · Article · Feb 2016 · Journal of Controlled Release
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    ABSTRACT: Context: Although adrenal vein sampling (AVS) is the standard method to distinguish unilateral from bilateral forms of primary aldosteronism (PA), it is an invasive and technically difficult procedure. (11)C-metomidate (MTO)-positron emission tomography (PET) was reported as a potential replacement for AVS. However, MTO has low selectivity for CYP11B2 over CYP11B1. Objective: This study aimed to determine the selectivity of (18)F-CDP2230, a new imaging agent, for CYP11B2 over CYP11B1 and determine whether the biodistribution profile of (18)F-CDP2230 is favorable for imaging CYP11B2. Methods: The half maximal inhibitory concentration (IC50) of CDP2230 for the enzymatic activities of CYP11B2 and CYP11B1 was determined using cells with stable expression of either enzyme. In vitro autoradiography (ARG) of human adrenal sections with aldosterone-producing adenomas was performed to confirm the specific binding ability of (18)F-CDP2230 to CYP11B2-expressing regions. Furthermore, PET and magnetic resonance imaging (MRI) were performed to evaluate the biodistribution of (18)F-CDP2230 in rats. Results: Although CDP2230 showed a significantly lower affinity for CYP11B2 and CYP11B1 than did metomidate analogues, its selectivity for CYP11B2 over CYP11B1 was higher than that of metomidate analogues. In vitro ARG revealed that the binding of (18)F-CDP2230 to CYP11B2-expressing regions in the adrenal gland was more specific than that of (123)I-IMTO. Moreover, the biodistribution study showed that (18)F-CDP2230 accumulated in adrenal glands with low background uptake. Conclusions: Our study showed a high selectivity of (18)F-CDP2230 for CYP11B2 over CYP11B1 with a favorable biodistribution for imaging CYP11B2. (18)F-CDP2230 is a promising imaging agent for detecting unilateral subtypes of PA.
    No preview · Article · Jan 2016 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: Front Cover: Bleeding from vessels in clinical practice is controlled by cauterization with a thermal coagulator (TC). However, the mechanical contact and heat produced by the TC injures tissues and causes long-lasting infl ammation (upper panel). In contrast, hemostasis with non-thermal plasma (NTP) does not induce tissue damage. Positron emission tomography imaging with 18F-FDG, which is a radiopharmaceutical targeting infl ammation, noninvasively reveals that less invasiveness of hemostasis with NTP (lower panel). Further details can be found in the article by Masashi Ueda et al. on page 1338.
    No preview · Article · Dec 2015 · Plasma Processes and Polymers
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    ABSTRACT: Since the processing activity of the matrix metalloproteinase MT1-MMP regulates various cellular functions such as motility, invasion, growth, differentiation and apoptosis, precise in vivo evaluation of MT1-MMP activity in cancers can provide beneficial information for both basic and clinical studies. For this purpose, we designed a cleavable Positron Emission Tomography (PET)/optical imaging probe consisting of BODIPY650/665 and polyethylene glycol (PEG) conjugated to opposite ends of MT1-MMP substrate peptides. We used in vitro and in vivo fluorescence experiments to select suitable substrate peptide sequences and PEG sizes for the MT1-MMP probes and obtained an optimized structure referred to here as MBP-2k. Radiofluorinated MBP-2k ([(18)F]MBP-2k) was then successfully synthesized via an (18)F-(19)F isotopic exchange reaction in BODIPY650/665. After intravenous injection into mice with xenografted tumors, [(18)F]MBP-2k showed significantly higher accumulation in HT1080 tumors with high MT1-MMP activity than in A549 tumors that have low MT1-MMP activity. Moreover, PET images showed better contrast in HT1080 tumors. These results show that [(18)F]MBP-2k can be used as a hybrid PET/optical imaging agent and is a promising probe for non-invasive monitoring of MT1-MMP activity in cancers. This probe may also efficiently combine targeted tumor imaging with image-guided surgery that could be beneficial for patients in the future.
    No preview · Article · Nov 2015 · Journal of Controlled Release
  • Hiroyuki Watanabe · Masahiro Ono · Hideo Saji
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    ABSTRACT: In vivo fluorescence imaging of β-amyloid (Aβ) plaques in the brain is expected to be used as a new method for detecting Alzheimer's disease (AD). We synthesized novel push-pull dimethylaminothiophenyl (DTM) derivatives and evaluated their utility as in vivo fluorescence imaging probes targeting Aβ plaques. As a result, we found that DTM-2 is a promising fluorescent probe for Aβ plaques in the AD brains.
    No preview · Article · Oct 2015 · Chemical Communications
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    ABSTRACT: Photoacoustic imaging (PAI) contributes to tumor diagnosis through the use of PAI probes that effectively accumulate in tumors. Previously, we developed a symmetrical cyanine dye, IC7-1-Bu, which showed high potential as a PAI probe because of its high tumor targeting ability and sufficient in vivo PA signal. However, IC7-1-Bu lacks photostability for multiple laser irradiations, so we developed stabilized PAI probes using IC7-1-Bu as a lead compound. We focused on the effect of singlet oxygen (O12) generated by excited PAI probes on probe degeneration. We introduced a triplet-state quencher (TSQ) moiety into IC7-1-Bu to quench O12 generation and designed three IC-n-T derivatives with different linker lengths (n indicates linker length). The IC-n-T derivatives emitted in vitro PA signals that were comparable to IC7-1-Bu and significantly reduced O12 generation while showing improved photostability against multiple irradiations. Of the three derivatives evaluated, IC-5-T accumulated in tumors effectively to allow clear PAI of tumors in vivo. Furthermore, the photostability of IC-5-T was 1.5-fold higher than that of IC7-1-Bu in in vivo sequential PAI. These results suggest that IC-5-T is a potential PAI probe for in vivo sequential tumor imaging. © 2015 Society of Photo-Optical Instrumentation Engineers (SPIE).
    No preview · Article · Sep 2015 · Journal of Biomedical Optics
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    ABSTRACT: Membrane type-1 matrix metalloproteinase (MT1-MMP) plays pivotal roles in tumor progression and metastasis, and holds great promise as an early biomarker for malignant tumors. Therefore, the ability to evaluate MT1-MMP expression could be valuable for molecular biological and clinical studies. For this purpose, we aimed to develop short peptide-based nuclear probes because of their facile radiosynthesis, chemically uniform structures, and high specific activity, as compared to antibody-based probes, which could allow them to be more effective for in vivo MT1-MMP imaging. To the best of our knowledge, there have been no reports of radiolabeled peptide probes for the detection of MT1-MMP in cancer tissues. In this study, we designed and prepared four probes which consist of a MT1-MMP-specific binding peptide sequence (consisting of L or D amino acid isomers) and an additional cysteine (at the N or C-terminus) for conjugation with N-(m-[(123/125)I]iodophenyl) maleimide. We investigated probe affinity, probe stability in mice plasma, and probe biodistribution in tumor-bearing mice. Finally, in vivo micro single photon emission computed tomography (SPECT) imaging and ex vivo autoradiography were performed. Consequently, [(123)I]I-DC, a D-form peptide probe radioiodinated at the C-terminus, demonstrated greater than 1000-fold higher specific activity than previously reported antibody probes, and revealed comparably moderate binding affinity. [(125)I]I-DC showed higher stability as expected, and [(123)I]I-DC successfully identified MT1-MMP expressing tumor tissue by SPECT imaging. Furthermore, ex vivo autoradiographic analysis revealed that the radioactivity distribution profiles corresponded to MT1-MMP-positive areas. These findings suggest that [(123)I]I-DC is a promising peptide probe for the in vivo detection of MT1-MMP in cancers.
    Preview · Article · Sep 2015 · Biological & Pharmaceutical Bulletin
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    ABSTRACT: A new radiolabeling method using a microreactor was developed for the rapid synthesis of [(11)C]raclopride. A chip bearing a Y-shaped mixing junction with a 200 µm (width)×20 µm (depth)×250 mm (length) flow channel was designed, and the efficiency of O-[(11)C]methylation was evaluated. Dimethyl sulfoxide solutions containing the O-desmethyl precursor or [(11)C]CH3I were introduced into separate injection ports by infusion syringes, and the radiochemical yields were measured under various conditions. The decay-corrected radiochemical yield of microreactor-derived [(11)C]raclopride reached 12% in 20 s at 25°C, which was observed to increase with increasing temperature. In contrast, batch synthesis at 25°C produced a yield of 5%: this indicates that this device could effectively achieve O-[(11)C]methylation in a shorter period of time. The microreactor technique may facilitate simple and efficient routine production of (11)C-labeled compounds via O-[(11)C]methylation with [(11)C]CH3I.
    Preview · Article · Sep 2015 · Chemical & pharmaceutical bulletin
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    ABSTRACT: In order to explore novel tau-imaging agents that can selectively detect neurofibrillary tangles in Alzheimer's disease (AD) brains, we designed and synthesized a series of heterocyclic phenylethenyl and (3-pyridinyl)ethenyl derivatives with or without a dimethyl amino group. In in vitro autoradiography using AD brain sections, all radioiodinated ligands with a dimethyl amino group bound to Aβ deposits in the sections. In contrast, the ligands without a dimethyl amino group showed different patterns of radioactivity accumulation in the sections depending on the kind of heterocycle contained in their molecules. Particularly, a phenylethenyl benzimidazole derivative ([(125)I]64) showed marked radioactivity accumulation in the temporal lobe which corresponded with the distribution of tau deposits. [(125)I]64 also showed the most favorable pharmacokinetics in normal mouse brains (3.69 and 0.06% ID/g at 2 and 60 min postinjection, respectively) among all ligands in this study. Taken together, these results suggest that [(123)I]64 may be a new candidate tau-imaging agent.
    No preview · Article · Sep 2015 · Journal of Medicinal Chemistry
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    ABSTRACT: The objective of this study is to examine the invasiveness of hemostasis by non-thermal plasma (NTP) compared with hemostasis by thermal coagulation (TC). The inflammation recovery process after hemostasis by TC and NTP was compared by using histological methods and nuclear medical molecular imaging. The necrotic areas in the NTP group disappeared after 5 days, whereas they remained 15 days after hemostasis in the TC group. The accumulation of 2-deoxy-2-[18F]fluoro-d-glucopyranose (18F-FDG), which reflects the existence of inflammatory cells, was higher in the TC group than in the NTP group on day 15. Thus, this study indicates that hemostasis by NTP is less inflammatory than TC. This report is the first to evaluate inflammation that occurred after hemostasis with medical devices noninvasively.
    No preview · Article · Sep 2015 · Plasma Processes and Polymers
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    ABSTRACT: Phosphatidylinositol 3-kinase (PI3K) activity and protein expression levels are often increased in tumor regions. Since PI3K plays a crucial role in regulating cell growth and proliferation, inhibiting PI3K-dependent pathways could be a promising approach for cancer treatment. In clinical practice, however, evaluation of PI3K expression levels is limited to immunohistochemistry of patient samples, which requires invasive biopsies. Here we report the synthesis of three candidate compounds, FMTA-1, 2 and 3, and evaluate their capacity to detect PI3K expression levels with positron emission tomography (PET). Among the three candidates, FMTA-2 showed a lower IC50 value for PI3K. (18)F Radiolabeling of FMTA-2 to produce [(18)F]FMTA-2 was accomplished and its capacity for detecting PI3K expression levels was evaluated in vitro and in vivo. Cell uptake of [(18)F]FMTA-2 correlated well with cellular PI3K expression levels, and was suppressed by the ATP-competitive PI3K inhibitor ZSTK474. In an in vivo experiment using tumor-transplanted model mice, a higher signal-to-noise ratio (S/N) was seen with [(18)F]FMTA-2 in animals transplanted with DMS114 cells (expressing high PI3K levels) relative to DU145 cells (expressing low PI3K levels). However, in vivo pharmacokinetics of [(18)F]FMTA-2 was undesirable and the absolute amount of this compound that accumulated at the tumor region was low. To the best of our knowledge, this study represents the first trial of a PET tracer for detecting PI3K. Although further improvement of the probe is required prior to clinical application, these results should encourage future work.
    No preview · Article · Sep 2015 · Nuclear Medicine and Biology
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    ABSTRACT: Photoacoustic (PA) imaging is a promising imaging modality that provides biomedical information with high sensitivity and resolution. Iron oxide nanoparticles (IONPs) have been regarded as remarkable PA contrast agents because of their low toxicity and biodegradable properties. However, IONP delivery is restricted by its modest leakage and retention in tumors. In this study, we designed IONPs (20nm, 50nm, and 100nm) conjugated with anti-HER2 moieties [whole IgG, single-chain fragment variable (scFv), and peptide] for HER2-targeted PA tumor imaging. The binding affinity, cellular uptake, and in vivo biodistribution were examined. We propose 20-nm anti-HER2 scFv-conjugated IONPs (SNP20) as a novel PA contrast agent. SNP20 demonstrated high affinity and specific binding to HER2-expressing cells; it selectively visualized HER2-positive tumors in PA imaging studies. These data indicate that SNP20 is a potential PA contrast agent for imaging of HER2-expressing tumors. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jul 2015 · Nanomedicine: nanotechnology, biology, and medicine
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    ABSTRACT: Photoacoustic (PA) imaging is an attractive imaging modality for sensitive and depth imaging of biomolecules with high resolution in vivo. The aim of this study was to evaluate the effectiveness of an anti-epidermal growth factor receptor (EGFR) monoclonal antibody (panitumumab; Pan) labeled with indocyanine green derivative (ICG-EG4-Sulfo-OSu), Pan-EG4-ICG, as a PA imaging probe to target cancer-associated EGFR. In vitro PA imaging studies demonstrated that Pan-EG4-ICG yielded high EGFR-specific PA signals in EGFR-positive cells. To determine the optimal injection dose and scan timing, we investigated the biodistribution of radiolabeled Pan-EG4-ICG (200-400 μg) in A431 tumor (EGFR++)-bearing mice. The highest tumor accumulation (29.4% injected dose/g) and high tumor-to-blood ratio (2.1) was observed 7 days after injection of Pan-EG4-ICG (400 μg). In in vivo PA imaging studies using Pan-EG4-ICG (400 μg), the increase in PA signal (114%) was observed in A431 tumors inoculated in the mammary glands 7 days post-injection. Co-injection of excess Pan resulted in a 35 % inhibition of this PA signal, indicating the EGFR-specific accumulation. In conclusion, the ICG-labeled monoclonal antibody (i.e., panitumumab) has the potential to enhance target-specific PA signal, leading to the discrimination of aggressiveness and metastatic potential of tumors and the selection of effective therapeutic strategies. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jul 2015 · Biochemical and Biophysical Research Communications
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    ABSTRACT: A high-affinity and low-molecular-weight fluorescent Zn2+ sensor 1 based on a 2,2′-bipyridine scaffold, which functions as both the chelating moiety for Zn2+ and the fluorophore, was developed and evaluated in biological applications. Controlling the occurrence of tautomerism of the chelating moiety for Zn2+ by introducing an amino group at the 6-position of the pyridine ring dramatically increased the binding affinity toward Zn2+. Fluorescent sensor 1 exhibited a nanomolar-range dissociation constant (Kd = 2.2 nM), a large Stokes shift (140 nm), and an 8.6-fold turn-on response to Zn2+ under physiological conditions. Fluorescence images revealed that fluorescent sensor 1 exhibits good properties with respect to aqueous solubility and cell permeability and can quantitatively detect the Zn2+ levels in living cells. Furthermore, a 65Zn2+ radioactive zinc isotope uptake study revealed the real concentration of accumulated Zn2+ at the detection limit. The novel fluorescent sensor 1 is a promising sensor for use in biological applications.
    No preview · Article · Jul 2015 · Sensors and Actuators B Chemical
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    ABSTRACT: Positron emission tomography (PET)/computed tomography (CT) using (68)Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid-D-Phe(1)-Tyr(3)-octreotide (DOTATOC) has been used to detect neuroendocrine tumors (NETs). The purpose of this study was to investigate the clinical efficacy of DOTATOC-PET/CT for detecting clinically suspected NETs when conventional imaging modalities were negative or inconclusive, in terms of additional value. A total of 46 patients were analyzed retrospectively. Among them, 14 patients underwent a DOTATOC-PET/CT scan for detecting unknown primary tumors after histopathological confirmation of a NET at metastatic sites (group A): 7 patients for detecting metastasis or recurrence after surgery for NET because of their high hormone levels but with no recurrence detected by other imaging modalities (group B); the remaining 25 patients for detecting suspected NETs because their hormone levels were high with no history of histopathologically proven NET (group C). Additional information was assessed, according to each situation. In group A, unknown primary tumors were suspected by DOTATOC-PET/CT in 8 of 14 patients (gastrointestinal/pancreatic NET in 7 patients, prostatic cancer in 1 patient), but prostatic cancer was not confirmed by histopathology (i.e., false positive). In group B, DOTATOC-PET/CT depicted lesions in six of seven patients, including nodal metastasis (n = 5) and liver metastasis (n = 1). In group C, DOTATOC-PET/CT did not demonstrate any abnormal foci except in one case of pancreatic NET. Additional information was obtained in 50, 86, and 4 % of cases, in groups A, B, and C, respectively. DOTATOC-PET/CT was useful for detecting NETs, especially when recurrence or metastases were suspected because of high hormone levels after surgery for a NET. It is unlikely, however, that additional information can be acquired in patients with no history of NET simply based on high hormone levels.
    Preview · Article · Apr 2015 · Annals of Nuclear Medicine
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    Hiroyuki Watanabe · Masahiro Ono · Hideo Saji
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    ABSTRACT: As the world’s population ages, the number of patients with Alzheimer’s disease (AD) is predicted to increase rapidly. The presence of neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau protein, is one of the neuropathological hallmarks of AD brain. Since the presence of NFTs is well correlated with neurodegeneration and cognitive decline in AD, imaging of tau using positron emission tomography (PET) and single-photon emission computed tomography (SPECT) is useful for presymptomatic diagnosis and monitoring of the progression of AD. Therefore, novel PET/SPECT probes for the imaging of tau have been developed. More recently, several probes were tested clinically and evaluated for their utility. This paper reviews the current state of research on the development and evaluation of PET/SPECT probes for the imaging of tau in AD brain.
    Preview · Article · Apr 2015
  • Hideo Saji
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    ABSTRACT: Radioisotopes emit radiation with various characteristics. These characteristics have been used for various applications of radioisotopes in clinical fields. For example, diagnostic nuclear medicine is a technique that uses gamma-emitted radionuclides with high permeability into the body and can visualize changes in physiological and biochemical processes throughout the distributed and interrelated systems of living tissues and organs. Therapeutic nuclear medicine is a technique that uses beta-emitted radionuclides with high radiation damage to the cell and can be used for internal radiation therapy. Therefore, a strategy in which the same ligand is labeled with beta-emitted or gamma-emitted radioisotopes, i.e., a theranostics approach, is useful because an extensive availability of diagnostics and therapeutics is possible. In this presentation, some examples of a theranostics approach for radiolabeled compounds will be reported, including the results of our recent research.
    No preview · Article · Apr 2015 · YAKUGAKU ZASSHI
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    ABSTRACT: Novel, low-molecular-weight fluorescent sensors based on a pyridine-pyridone core structure, which functions as both the chelating part moiety for Zn2+ and as the fluorophore, were investigated. The length of the methylene spacer between the phenyl ring and the 3-position of the pyridone ring greatly influenced the emission wavelength and intensity upon Zn2+ binding. 5-Benzyl-4-(methylsulfanyl)-[2,2'-bipyridin]-6(1H)-one (2) (MW = 308) with a methylene spacer of n = 1 showed good water solubility, a 30 nm bathochromic shift in its emission wavelength and an 18-fold fluorescence enhancement in response to Zn2+. In addition, fluorescence microscopy imaging showed that 2 could be used to detect Zn2+ in living cells.
    No preview · Article · Feb 2015 · Dyes and Pigments
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    ABSTRACT: The present study investigates the human leucocyte antigen (HLA) allele and haplotype frequencies in Japanese population. We carried out the frequency analysis in 5824 families living across Japanese archipelago. The studied population has mainly been typed for the purpose of transplant, especially the hematopoietic stem cell transplantation (HSCT). We determined HLA class I (A, B, and C) and HLA class II (DRB1) using Luminex technology. The haplotypes were directly counted by segregation. A total of 44 HLA-A, 29 HLA-C, 75 HLA-B, and 42 HLA-DRB1 alleles were identified. In the HLA haplotypes of A-C-B-DRB1 and C-B, the pattern of linkage disequilibrium peculiar to Japanese population has been confirmed. Moreover, the haplotype frequencies based on family study was compared with the frequencies estimated by maximum likelihood estimation (MLE), and the equivalent results were obtained. The allele and haplotype frequencies obtained in this study could be useful for anthropology, transplantation therapy, and disease association studies. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
    No preview · Article · Feb 2015 · Tissue Antigens
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    ABSTRACT: We previously succeeded in the visualization of tissue distribution of B16BL6 cells-derived exosomes by labeling with Gaussia luciferase (gLuc)-LA, a fusion protein of gLuc (a reporter protein) and lactadherin (LA; an exosome-tropic protein). However, total amount of B16BL6-derived exosomes delivered to each organ could not be evaluated because of the reduction of luminescent signal from gLuc-LA. The aim of the present study was to quantitatively evaluate the tissue distribution of B16BL6-derived exosomes. To this end, we labeled B16BL6-derived exosomes with iodine-125 ((125) I) based on streptavidin (SAV)-biotin system. A plasmid vector encoding fusion protein, SAV-LA, was constructed, and B16BL6 cells were transfected with the plasmid to obtain SAV-LA-coupled exosomes. SAV-LA-coupled exosomes were incubated with (3-(125) I-iodobenzoyl) norbiotinamide ((125) I-IBB) to obtain (125) I-labeled B16BL6 exosomes. After intravenous injection of (125) I-labeled B16BL6 exosomes into mice, radioactivity quickly disappeared from the blood circulation. At 4 h, 28%, 1.6%, and 7% of the injected radioactivity/organ was detected in the liver, spleen, and lung, respectively. These results indicate that (125) I-labeling of exosomes using SAV-biotin system is a useful method to quantitatively evaluate the amount of exogenously administered exosomes delivered to each organ and that the liver is the major organ in the clearance of exogenously administered B16BL6-derived exosomes. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
    No preview · Article · Feb 2015 · Journal of Pharmaceutical Sciences

Publication Stats

6k Citations
1,269.13 Total Impact Points


  • 1976-2015
    • Kyoto University
      • Division of Pharmaceutical Sciences
      Kioto, Kyōto, Japan
  • 2012
    • Nagasaki University
      • Faculty of Environmental Studies
      Nagasaki, Nagasaki, Japan
  • 1988-2012
    • Kyoto Pharmaceutical University
      • Laboratory of Medicinal Chemistry
      Kioto, Kyōto, Japan
  • 2007
    • Chiba University
      • Graduate School of Pharmaceutical Sciences
      Chiba-shi, Chiba-ken, Japan
  • 2004
    • Hokkaido University
      • Department of Internal Medicine II
      Sapporo, Hokkaidō, Japan
  • 2001
    • Kyoto Prefectural University of Medicine
      Kioto, Kyōto, Japan
  • 1997-2000
    • Kyoto Daini Red Cross Hospital
      Kioto, Kyōto, Japan
    • Japanese Red Cross
      Edo, Tokyo, Japan
  • 1991
    • Shinshu University
      • Department of Medicine
      Shonai, Nagano, Japan
    • Tokyo University of Science
      • Department of Pharmaceutical Sciences
      Edo, Tōkyō, Japan