• 2019-07
  • 2019-08
  • 2019-09
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  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • br Md Sarwar Kamal Nilanjan


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    Journal of Pharmacological Sciences
    Full Paper
    Boron delivery for boron neutron capture therapy targeting a cancer-upregulated oligopeptide transporter
    Junji Miyabe a, b, Ryuichi Ohgaki a, Keijiro Saito c, Ling Wei a, Lili Quan a, Chunhuan Jin a, Xingming Liu a, Suguru Okuda a, Shushi Nagamori a, Hiroshi Ohki c, Kazuo Yoshino c, Hidenori Inohara b, Yoshikatsu Kanai a, * a Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
    b Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
    c Department of Chemistry, Faculty of Science, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
    Article history:
    Received in revised form
    Available online 18 February 2019
    Boron delivery
    Boron neutron capture therapy p-Borono-L-phenylalanine-containing dipeptide
    Oligopeptide transporter
    Boron neutron capture therapy (BNCT) is a radiotherapy utilizing the neutron capture and nuclear fission reaction of 10B taken up into tumor cells. The most commonly used boron agent in BNCT, p-borono-L-phenylalanine (BPA), is accumulated in tumors by amino ZD-1839 transporters upregulated in tumor cells. Here, by using dipeptides of BPA and tyrosine (BPA-Tyr and Tyr-BPA), we propose a novel strategy of selective boron delivery into tumor cells via oligopeptide transporter PEPT1 upregulated in various cancers. Kinetic analyses indicated that BPA-Tyr and Tyr-BPA are transported by oligopeptide trans-porters, PEPT1 and PEPT2. The intrinsic oligopeptide transport activity in tumor cells clearly correlated with PEPT1 protein expression level but not with PEPT2, suggesting that PEPT1 is the predominant oligopeptide transporter at least in tumor cell lines. Furthermore, using BPA-Tyr and Tyr-BPA, boron was successfully delivered into PEPT1-expressing pancreatic cancer AsPC-1 cells via a PEPT1-mediated mechanism. Intravenous administration of BPA-Tyr into the mice bearing AsPC-1 xenograft tumors resulted in significant boron accumulation in the tumors. It is proposed that the oligopeptide trans-porters, especially PEPT1, are promising candidates for molecular targets of boron delivery in BNCT. The BPA-containing dipeptides would have a potential for the development of novel boron carriers targeting PEPT1.
    © 2019 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license ( licenses/by-nc-nd/4.0/).
    1. Introduction
    Boron neutron capture therapy (BNCT) is a promising cancer treatment based on the neutron capture and fission reactions that occur when non-radioactive 10B atoms capture low-energy neu-trons upon the irradiation of cancer tissues with thermal or
    Abbreviations: ATB0,þ, amino acid transporter B0,þ; 10B, Boron-10; BNCT, boron neutron capture therapy; BPA, p-borono-L-phenylalanine; BPA-Tyr, p-L-BPA-L-tyro-sine; BSH, disodium mercapto-closo-undecahydrododecacarborate; 18F-BPA, 4-borono-2-18F-fluoro-L-phenylalanine; [3H]Gly-Sar, tritium-labeled glycylsarcosine; ICP-AES, inductively coupled plasma atomic emission spectroscopy; Ki, inhibitory constant; LAT1, L-type amino acid transporter 1; PEPT1, peptide transporter 1; PEPT2, peptide transporter 2; Tyr-BPA, L-tyrosine-p-L-BPA.
    E-mail address: [email protected] (Y. Kanai).
    Peer review under responsibility of Japanese Pharmacological Society. 
    epithermal neutron beams. The reaction yields high liner energy transfer a particles (4He) and recoiling 7Li nuclei. Because the path-lengths of these particles are approximately within the size of cell diameter (<10 mm), only 10B-containing ZD-1839 tumor cells will be destroyed in theory leaving the surrounding normal cells undam-aged.1 BNCT is, thus, emerging as an ideal targeted radiotherapy. Now, clinical trials are ongoing focusing on high grade gliomas, melanomas, and recurrent head and neck cancers. Its application for other types of cancer such as hepatic cancers and lung cancers is also under consideration.2e4