Bioluminescence-Activated Deep-Tissue Photodynamic Therapy of Cancer
Identifieur interne : 001468 ( Pmc/Checkpoint ); précédent : 001467; suivant : 001469Bioluminescence-Activated Deep-Tissue Photodynamic Therapy of Cancer
Auteurs : Yi Rang Kim [Corée du Sud] ; Seonghoon Kim [Corée du Sud] ; Jin Woo Choi [Corée du Sud, États-Unis] ; Sung Yong Choi [Corée du Sud] ; Sang-Hee Lee [Corée du Sud] ; Homin Kim [Corée du Sud] ; Sei Kwang Hahn [Corée du Sud] ; Gou Young Koh [Corée du Sud] ; Seok Hyun Yun [Corée du Sud, États-Unis]Source :
- Theranostics [ 1838-7640 ] ; 2015.
Abstract
Optical energy can trigger a variety of photochemical processes useful for therapies. Owing to the shallow penetration of light in tissues, however, the clinical applications of light-activated therapies have been limited. Bioluminescence resonant energy transfer (BRET) may provide a new way of inducing photochemical activation. Here, we show that efficient bioluminescence energy-induced photodynamic therapy (PDT) of macroscopic tumors and metastases in deep tissue. For monolayer cell culture
Url:
DOI: 10.7150/thno.11520
PubMed: 26000054
PubMed Central: 4440439
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Bioluminescence-Activated Deep-Tissue Photodynamic Therapy of Cancer</title><author><name sortKey="Kim, Yi Rang" sort="Kim, Yi Rang" uniqKey="Kim Y" first="Yi Rang" last="Kim">Yi Rang Kim</name><affiliation wicri:level="1"><nlm:aff id="A1">1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A3">3. Department of Oncology, Asan Medical Center, Univ. Ulsan College of Medicine, Seoul , Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>3. Department of Oncology, Asan Medical Center, Univ. Ulsan College of Medicine, Seoul </wicri:regionArea><wicri:noRegion>Seoul </wicri:noRegion></affiliation></author><author><name sortKey="Kim, Seonghoon" sort="Kim, Seonghoon" uniqKey="Kim S" first="Seonghoon" last="Kim">Seonghoon Kim</name><affiliation wicri:level="1"><nlm:aff id="A1">1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation></author><author><name sortKey="Choi, Jin Woo" sort="Choi, Jin Woo" uniqKey="Choi J" first="Jin Woo" last="Choi">Jin Woo Choi</name><affiliation wicri:level="1"><nlm:aff id="A4">4. Department of Pharmacology, Wonkwang Institute of Dental Research, School of Dentistry, Wonkwang University, Iksan, Chonbuk, 570-749, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>4. Department of Pharmacology, Wonkwang Institute of Dental Research, School of Dentistry, Wonkwang University, Iksan, Chonbuk, 570-749</wicri:regionArea><wicri:noRegion>570-749</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">5. Wellman Center for Photomedicine, Massachusetts General Hospital, 65 Landsdowne St. UP-525, Cambridge, MA 02139, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>5. 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Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Sang Hee" sort="Lee, Sang Hee" uniqKey="Lee S" first="Sang-Hee" last="Lee">Sang-Hee Lee</name><affiliation wicri:level="1"><nlm:aff id="A2">2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation></author><author><name sortKey="Kim, Homin" sort="Kim, Homin" uniqKey="Kim H" first="Homin" last="Kim">Homin Kim</name><affiliation wicri:level="1"><nlm:aff id="A2">2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation></author><author><name sortKey="Hahn, Sei Kwang" sort="Hahn, Sei Kwang" uniqKey="Hahn S" first="Sei Kwang" last="Hahn">Sei Kwang Hahn</name><affiliation wicri:level="1"><nlm:aff id="A6">6. Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk 790-784, Korea.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Corée du Sud</country><wicri:regionArea>6. Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk 790-784</wicri:regionArea><wicri:noRegion>Gyeongbuk 790-784</wicri:noRegion></affiliation></author><author><name sortKey="Koh, Gou Young" sort="Koh, Gou Young" uniqKey="Koh G" first="Gou Young" last="Koh">Gou Young Koh</name><affiliation wicri:level="1"><nlm:aff id="A1">1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation></author><author><name sortKey="Yun, Seok Hyun" sort="Yun, Seok Hyun" uniqKey="Yun S" first="Seok Hyun" last="Yun">Seok Hyun Yun</name><affiliation wicri:level="1"><nlm:aff id="A1">1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">5. Wellman Center for Photomedicine, Massachusetts General Hospital, 65 Landsdowne St. UP-525, Cambridge, MA 02139, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>5. Wellman Center for Photomedicine, Massachusetts General Hospital, 65 Landsdowne St. UP-525, Cambridge, MA 02139</wicri:regionArea><wicri:noRegion>MA 02139</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A7">7. Department of Dermatology, Harvard Medical School, Massachusetts General Hospital, 40 Blossom St. Boston, MA 02114, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>7. Department of Dermatology, Harvard Medical School, Massachusetts General Hospital, 40 Blossom St. Boston, MA 02114</wicri:regionArea><wicri:noRegion>MA 02114</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26000054</idno><idno type="pmc">4440439</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440439</idno><idno type="RBID">PMC:4440439</idno><idno type="doi">10.7150/thno.11520</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000476</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000476</idno><idno type="wicri:Area/Pmc/Curation">000476</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000476</idno><idno type="wicri:Area/Pmc/Checkpoint">001468</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">001468</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Bioluminescence-Activated Deep-Tissue Photodynamic Therapy of Cancer</title><author><name sortKey="Kim, Yi Rang" sort="Kim, Yi Rang" uniqKey="Kim Y" first="Yi Rang" last="Kim">Yi Rang Kim</name><affiliation wicri:level="1"><nlm:aff id="A1">1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A3">3. Department of Oncology, Asan Medical Center, Univ. Ulsan College of Medicine, Seoul , Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>3. Department of Oncology, Asan Medical Center, Univ. Ulsan College of Medicine, Seoul </wicri:regionArea><wicri:noRegion>Seoul </wicri:noRegion></affiliation></author><author><name sortKey="Kim, Seonghoon" sort="Kim, Seonghoon" uniqKey="Kim S" first="Seonghoon" last="Kim">Seonghoon Kim</name><affiliation wicri:level="1"><nlm:aff id="A1">1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation></author><author><name sortKey="Choi, Jin Woo" sort="Choi, Jin Woo" uniqKey="Choi J" first="Jin Woo" last="Choi">Jin Woo Choi</name><affiliation wicri:level="1"><nlm:aff id="A4">4. Department of Pharmacology, Wonkwang Institute of Dental Research, School of Dentistry, Wonkwang University, Iksan, Chonbuk, 570-749, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>4. Department of Pharmacology, Wonkwang Institute of Dental Research, School of Dentistry, Wonkwang University, Iksan, Chonbuk, 570-749</wicri:regionArea><wicri:noRegion>570-749</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">5. Wellman Center for Photomedicine, Massachusetts General Hospital, 65 Landsdowne St. UP-525, Cambridge, MA 02139, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>5. Wellman Center for Photomedicine, Massachusetts General Hospital, 65 Landsdowne St. UP-525, Cambridge, MA 02139</wicri:regionArea><wicri:noRegion>MA 02139</wicri:noRegion></affiliation></author><author><name sortKey="Choi, Sung Yong" sort="Choi, Sung Yong" uniqKey="Choi S" first="Sung Yong" last="Choi">Sung Yong Choi</name><affiliation wicri:level="1"><nlm:aff id="A2">2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Sang Hee" sort="Lee, Sang Hee" uniqKey="Lee S" first="Sang-Hee" last="Lee">Sang-Hee Lee</name><affiliation wicri:level="1"><nlm:aff id="A2">2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation></author><author><name sortKey="Kim, Homin" sort="Kim, Homin" uniqKey="Kim H" first="Homin" last="Kim">Homin Kim</name><affiliation wicri:level="1"><nlm:aff id="A2">2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation></author><author><name sortKey="Hahn, Sei Kwang" sort="Hahn, Sei Kwang" uniqKey="Hahn S" first="Sei Kwang" last="Hahn">Sei Kwang Hahn</name><affiliation wicri:level="1"><nlm:aff id="A6">6. Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk 790-784, Korea.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Corée du Sud</country><wicri:regionArea>6. Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk 790-784</wicri:regionArea><wicri:noRegion>Gyeongbuk 790-784</wicri:noRegion></affiliation></author><author><name sortKey="Koh, Gou Young" sort="Koh, Gou Young" uniqKey="Koh G" first="Gou Young" last="Koh">Gou Young Koh</name><affiliation wicri:level="1"><nlm:aff id="A1">1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation></author><author><name sortKey="Yun, Seok Hyun" sort="Yun, Seok Hyun" uniqKey="Yun S" first="Seok Hyun" last="Yun">Seok Hyun Yun</name><affiliation wicri:level="1"><nlm:aff id="A1">1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701</wicri:regionArea><wicri:noRegion>Daejon 305-701</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">5. Wellman Center for Photomedicine, Massachusetts General Hospital, 65 Landsdowne St. UP-525, Cambridge, MA 02139, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>5. Wellman Center for Photomedicine, Massachusetts General Hospital, 65 Landsdowne St. UP-525, Cambridge, MA 02139</wicri:regionArea><wicri:noRegion>MA 02139</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A7">7. Department of Dermatology, Harvard Medical School, Massachusetts General Hospital, 40 Blossom St. Boston, MA 02114, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>7. Department of Dermatology, Harvard Medical School, Massachusetts General Hospital, 40 Blossom St. Boston, MA 02114</wicri:regionArea><wicri:noRegion>MA 02114</wicri:noRegion></affiliation></author></analytic><series><title level="j">Theranostics</title><idno type="eISSN">1838-7640</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Optical energy can trigger a variety of photochemical processes useful for therapies. Owing to the shallow penetration of light in tissues, however, the clinical applications of light-activated therapies have been limited. Bioluminescence resonant energy transfer (BRET) may provide a new way of inducing photochemical activation. Here, we show that efficient bioluminescence energy-induced photodynamic therapy (PDT) of macroscopic tumors and metastases in deep tissue. For monolayer cell culture <italic>in vitro</italic> incubated with Chlorin e6, BRET energy of about 1 nJ per cell generated as strong cytotoxicity as red laser light irradiation at 2.2 mW/cm<sup>2</sup> for 180 s. Regional delivery of bioluminescence agents via draining lymphatic vessels killed tumor cells spread to the sentinel and secondary lymph nodes, reduced distant metastases in the lung and improved animal survival. Our results show the promising potential of novel bioluminescence-activated PDT.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Agostinis, P" uniqKey="Agostinis P">P Agostinis</name></author><author><name sortKey="Berg, K" uniqKey="Berg K">K Berg</name></author><author><name sortKey="Cengel, Ka" uniqKey="Cengel K">KA Cengel</name></author><author><name sortKey="Foster, Th" uniqKey="Foster T">TH Foster</name></author><author><name sortKey="Girotti, Aw" uniqKey="Girotti A">AW Girotti</name></author><author><name sortKey="Gollnick, So" uniqKey="Gollnick S">SO Gollnick</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brown, Sb" uniqKey="Brown S">SB Brown</name></author><author><name sortKey="Brown, Ea" uniqKey="Brown E">EA Brown</name></author><author><name sortKey="Walker, I" uniqKey="Walker I">I Walker</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Castano, Ap" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Theranostics</journal-id><journal-id journal-id-type="iso-abbrev">Theranostics</journal-id><journal-id journal-id-type="publisher-id">thno</journal-id><journal-title-group><journal-title>Theranostics</journal-title></journal-title-group><issn pub-type="epub">1838-7640</issn><publisher><publisher-name>Ivyspring International Publisher</publisher-name><publisher-loc>Sydney</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26000054</article-id><article-id pub-id-type="pmc">4440439</article-id><article-id pub-id-type="doi">10.7150/thno.11520</article-id><article-id pub-id-type="publisher-id">thnov05p0805</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Paper</subject></subj-group></article-categories><title-group><article-title>Bioluminescence-Activated Deep-Tissue Photodynamic Therapy of Cancer</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Yi Rang</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Seonghoon</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Choi</surname><given-names>Jin Woo</given-names></name><xref ref-type="aff" rid="A4">4</xref><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Choi</surname><given-names>Sung Yong</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Sang-Hee</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Homin</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Hahn</surname><given-names>Sei Kwang</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Koh</surname><given-names>Gou Young</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Yun</surname><given-names>Seok Hyun</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A5">5</xref><xref ref-type="aff" rid="A7">7</xref><xref ref-type="corresp" rid="FNA_envelop">✉</xref></contrib></contrib-group><aff id="A1">1. Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</aff><aff id="A2">2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-Ro, Yusong-Gu, Daejon 305-701, Korea</aff><aff id="A3">3. Department of Oncology, Asan Medical Center, Univ. Ulsan College of Medicine, Seoul , Korea</aff><aff id="A4">4. Department of Pharmacology, Wonkwang Institute of Dental Research, School of Dentistry, Wonkwang University, Iksan, Chonbuk, 570-749, Korea</aff><aff id="A5">5. Wellman Center for Photomedicine, Massachusetts General Hospital, 65 Landsdowne St. UP-525, Cambridge, MA 02139, USA</aff><aff id="A6">6. Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk 790-784, Korea.</aff><aff id="A7">7. Department of Dermatology, Harvard Medical School, Massachusetts General Hospital, 40 Blossom St. Boston, MA 02114, USA</aff><author-notes><corresp id="FNA_envelop">✉ Corresponding author: S. H. Andy Yun, Ph.D., Associate Professor. Tel: 1-617-768-8704; Email: <email>syun@hms.harvard.edu</email></corresp><fn fn-type="conflict"><p>Competing Interests: The authors have declared that no competing interest exists.</p></fn></author-notes><pub-date pub-type="collection"><year>2015</year></pub-date><pub-date pub-type="epub"><day>18</day><month>4</month><year>2015</year></pub-date><volume>5</volume><issue>8</issue><fpage>805</fpage><lpage>817</lpage><history><date date-type="received"><day>7</day><month>1</month><year>2015</year></date><date date-type="accepted"><day>23</day><month>3</month><year>2015</year></date></history><permissions><copyright-statement>© 2015 Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. See http://ivyspring.com/terms for terms and conditions.</copyright-statement><copyright-year>2015</copyright-year></permissions><abstract><p>Optical energy can trigger a variety of photochemical processes useful for therapies. Owing to the shallow penetration of light in tissues, however, the clinical applications of light-activated therapies have been limited. Bioluminescence resonant energy transfer (BRET) may provide a new way of inducing photochemical activation. Here, we show that efficient bioluminescence energy-induced photodynamic therapy (PDT) of macroscopic tumors and metastases in deep tissue. For monolayer cell culture <italic>in vitro</italic> incubated with Chlorin e6, BRET energy of about 1 nJ per cell generated as strong cytotoxicity as red laser light irradiation at 2.2 mW/cm<sup>2</sup> for 180 s. Regional delivery of bioluminescence agents via draining lymphatic vessels killed tumor cells spread to the sentinel and secondary lymph nodes, reduced distant metastases in the lung and improved animal survival. Our results show the promising potential of novel bioluminescence-activated PDT.</p></abstract><kwd-group><kwd>Photodynamic Therapy</kwd><kwd>Bioluminescence</kwd><kwd>Photosensitizers</kwd><kwd>Resonance Energy Transfer</kwd><kwd>Cancer</kwd><kwd>Photobiology</kwd><kwd>Photomedicine</kwd></kwd-group></article-meta></front><floats-group><fig id="F1" position="float"><label>Figure 1</label><caption><p><bold> Radiation- vs. resonant energy transfer-induced activation of photosensitizers.</bold> Conventional light delivery by external illumination suffers from superficial therapeutic depths due to the small absorption cross-section of a molecule and the optical propagation loss in tissue. By contrast, the resonance energy transfer from an injectable, or biologically producible, bioluminescence source can activate a target molecule more effectively due to strong near-field interaction, in the regions inaccessible by the external light.</p></caption><graphic xlink:href="thnov05p0805g001"></graphic></fig><fig id="F2" position="float"><label>Figure 2</label><caption><p><bold> The design and principle of BL-PDT. a</bold>, Illustration of the proposed mechanism based on resonance energy transfer at cellular membrane. <bold>b</bold>, TEM image of Luc-QD conjugate. <bold>c</bold>, Luminescence from RLuc8 and Luc-QD. <bold>d</bold>, Emission spectrum of Luc-QD. The BRET ratio was calculated from the ratio of the area under curve of RLuc8 emission between 390 and 600 nm and that of QD emission between 600 and 710 nm. <bold>e</bold>, Confocal images of red fluorescence from QD, showing the distribution of Luc-QD outside cells (CT26 cells; green: intracellular dye). <bold>f</bold>, Confocal fluorescence image of Ce6, showing its distribution in the cytosol. <bold>g</bold>, Luminescence power generated after administration of 28 nmol CTZ. Scale bars in <bold>e</bold> and <bold>f</bold>, 50 µm.</p></caption><graphic xlink:href="thnov05p0805g002"></graphic></fig><fig id="F3" position="float"><label>Figure 3</label><caption><p><bold> Effects of BL-PDT on cancer cells <italic>in vitro</italic>. a</bold>, MTT analysis of CT26 cells treated with BL-PDT. <bold>b</bold>, The efficiency of conventional PDT at different laser powers. <bold>c</bold>, Time-lapse images of LLC-GFP cells during BL-PDT. <bold>d</bold>, Time-lapse images of LLC-GFP cells during laser-PDT. Control cells without laser irradiation showed no change in GFP fluorescence. <bold>e</bold>, Confocal image of LLC cells 4 h after BL-PDT. Damaged cells with PI-positive nuclei are surrounded heavily by Luc-QD (squares), whereas live cells with intact PI-negative nuclei have no or less Luc-QD around their cell surfaces (arrows). <bold>f</bold>, TEM image showing membrane disruption and leak of intracellular components after BL-PDT. <bold>g</bold>, DCF assay to measure intracellular ROS level. <bold>h</bold>, Lipid peroxidation assay. <bold>i</bold>, Time-lapse confocal images of SOSG and Luc-QD. Cells surrounded by more Luc-QD show earlier infiltration of SOSG. ANOVA test <italic>p</italic> values: * <0.05, ** <0.01. Error bars, s.d. Scale bars, 50 µm in <bold>c</bold> and <bold>d</bold>; 100 µm in <bold>e</bold> and <bold>i</bold>.</p></caption><graphic xlink:href="thnov05p0805g003"></graphic></fig><fig id="F4" position="float"><label>Figure 4</label><caption><p><bold> Effects of BL-PDT on tumors <italic>in vivo</italic>. a</bold>, Luminescence (575-650nm) from tumors injected with Luc-QD (50 pmol i.t.) and CTZ (28 nmol i.v.). <bold>b</bold>, Luminescence intensity from the tumor over time. <bold>c</bold>, Tumor growth curves for various treatment conditions. Arrows indicate the three sessions of BL-PDT. <bold>d</bold>, Tumor growth curves for extended BL-PDT protocols with 2-3 day treatment intervals (arrows). <bold>e</bold>, Photos of mice (at day 23) treated 0, 3, and 9 times, respectively. <bold>f</bold>, Tumor sizes measured at day 30 for control, sham-treated, BL-, and laser-PDT-treated mice (calculated from the data in <bold>b</bold>: N=3 or N=9 indicates groups that received three or nine treatment sessions.) <bold>g</bold>, Immunohistology with APR648 indicating apoptotic cell death within a tumor. Scale bars, 1 mm in (g). Error bars, mean +/- s.d. Two-sided Student test <italic>p</italic> values: * <0.05, ** <0.01, *** <0.001.</p></caption><graphic xlink:href="thnov05p0805g004"></graphic></fig><fig id="F5" position="float"><label>Figure 5</label><caption><p><bold> Treatment of lymph-node metastases. a</bold>, A schematic of LN metastasis and BL-PDT procedure. <bold>b</bold>, Photo of a mouse with CT-26 tumor grown in the footpad at day 11. <bold>c</bold>, Fluorescence image after injection of Ce6 into the foot. Draining Ce6 visualizes the lymphatic vessel and the popliteal LN (p-LN). <bold>d</bold>, Time-lapse luminescence images after CTZ injection into the dorsum of the foot. Strong luminescence is generated from the p-LN. <bold>e</bold>, Histology images of untreated LN sections harvested at day 13, stained with H&E, TUNEL, and pancytokeratin. <bold>f</bold>, Images of LN sections harvested at day 13, two days after BL-PDT, stained with H&E, TUNEL, and pancytokeratin. Cell death along the expanded lymphatic vessels is evident. <bold>f</bold>, Integrated pancytokeratin signals within the untreated and treated LN's.</p></caption><graphic xlink:href="thnov05p0805g005"></graphic></fig><fig id="F6" position="float"><label>Figure 6</label><caption><p><bold> Treatment of lymph-node metastases. a</bold>, BL image of a C57/BL6 mouse with B16F10 tumor in the footpad (day 21), after injection of Luc-QD and CTZ into the foot. <bold>b</bold>, IHC images of p-LN sections harvested from an untreated mouse at day 23, stained for blood vessels (CD31), lymphatics (VEGFR3/CD31), melanoma cells (melan-A), and apoptosis (caspase-3). Strong green autofluorescence indicates germinal centers. <bold>c</bold>, Images of p-LN sections harvested from a treated mouse at day 23, two days after BL-PDT. <bold>d</bold>, Images of the regions marked in <bold>b</bold> and <bold>c</bold>. Arrows indicate damaged blood vessels. <bold>e</bold>, Integrated melan-A fluorescence magnitudes of the untreated (U) and treated (T) p-LNs. <bold>f</bold>, Inguinal LN sections harvested from the untreated mouse. <bold>g</bold>, Inguinal LN sections harvested from the treated mouse. <bold>h</bold>, The regions marked in <bold>f</bold> and <bold>g</bold>. Scale bars, 500 µm. Error bars, s.d. **, Kruskal-Wallis test<italic> p</italic> <0.01.</p></caption><graphic xlink:href="thnov05p0805g006"></graphic></fig><fig id="F7" position="float"><label>Figure 7</label><caption><p><bold> Therapeutic effects of LN BL-PDT on animal survival and lung metastasis. a</bold>. Kaplan-Meier survival curve of CT26 bearing mice. <bold>b</bold>. H&E stained images of lung harvested 14 days after LN PDT. Arrows indicate small nodules in treated mice (top) and larger nodules with the sign of metastatic infiltration (bottom). Scale bar, 1 mm. <bold>c</bold>. The total number of metastatic lung nodules found from each animal group (6 lung sections per mouse, 12 mice). <bold>d</bold>. Kaplan-Meier survival curve of LLC-GFP bearing mice. <bold>e</bold>. Photographs of the lungs harvested at day 25. Circles indicate macroscopic metastatic nodules. <bold>f</bold>. The numbers of lung surface metastases. <bold>g</bold>. The weights of the lungs. *, Kruskal-Wallis test<italic> p</italic> <0.05; **, <italic>p</italic> <0.01.</p></caption><graphic xlink:href="thnov05p0805g007"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Corée du Sud</li><li>États-Unis</li></country></list><tree><country name="Corée du Sud"><noRegion><name sortKey="Kim, Yi Rang" sort="Kim, Yi Rang" uniqKey="Kim Y" first="Yi Rang" last="Kim">Yi Rang Kim</name></noRegion><name sortKey="Choi, Jin Woo" sort="Choi, Jin Woo" uniqKey="Choi J" first="Jin Woo" last="Choi">Jin Woo Choi</name><name sortKey="Choi, Sung Yong" sort="Choi, Sung Yong" uniqKey="Choi S" first="Sung Yong" last="Choi">Sung Yong Choi</name><name sortKey="Hahn, Sei Kwang" sort="Hahn, Sei Kwang" uniqKey="Hahn S" first="Sei Kwang" last="Hahn">Sei Kwang Hahn</name><name sortKey="Kim, Homin" sort="Kim, Homin" uniqKey="Kim H" first="Homin" last="Kim">Homin Kim</name><name sortKey="Kim, Seonghoon" sort="Kim, Seonghoon" uniqKey="Kim S" first="Seonghoon" last="Kim">Seonghoon Kim</name><name sortKey="Kim, Yi Rang" sort="Kim, Yi Rang" uniqKey="Kim Y" first="Yi Rang" last="Kim">Yi Rang Kim</name><name sortKey="Kim, Yi Rang" sort="Kim, Yi Rang" uniqKey="Kim Y" first="Yi Rang" last="Kim">Yi Rang Kim</name><name sortKey="Koh, Gou Young" sort="Koh, Gou Young" uniqKey="Koh G" first="Gou Young" last="Koh">Gou Young Koh</name><name sortKey="Koh, Gou Young" sort="Koh, Gou Young" uniqKey="Koh G" first="Gou Young" last="Koh">Gou Young Koh</name><name sortKey="Lee, Sang Hee" sort="Lee, Sang Hee" uniqKey="Lee S" first="Sang-Hee" last="Lee">Sang-Hee Lee</name><name sortKey="Yun, Seok Hyun" sort="Yun, Seok Hyun" uniqKey="Yun S" first="Seok Hyun" last="Yun">Seok Hyun Yun</name></country><country name="États-Unis"><noRegion><name sortKey="Choi, Jin Woo" sort="Choi, Jin Woo" uniqKey="Choi J" first="Jin Woo" last="Choi">Jin Woo Choi</name></noRegion><name sortKey="Yun, Seok Hyun" sort="Yun, Seok Hyun" uniqKey="Yun S" first="Seok Hyun" last="Yun">Seok Hyun Yun</name><name sortKey="Yun, Seok Hyun" sort="Yun, Seok Hyun" uniqKey="Yun S" first="Seok Hyun" last="Yun">Seok Hyun Yun</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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