Photothermal Therapeutic Response of Cancer Cells to Aptamer–Gold Nanoparticle-Hybridized Graphene Oxide under NIR Illumination

The objective of this study was to synthesize a nanocomposite, aptamer–gold nanoparticle-hybridized graphene oxide (Apt-AuNP–GO), to facilitate targeted treatment of tumor cells by near-infrared (NIR) light-activatable photothermal therapy. We also investigated whether Apt-AuNP–GO with NIR illuminat...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:ACS applied materials & interfaces 2015-03, Vol.7 (9), p.5097-5106
Hauptverfasser: Yang, Lingyan, Tseng, Yu-Ting, Suo, Guangli, Chen, Liliang, Yu, Jiantao, Chiu, Wei-Jane, Huang, Chih-Ching, Lin, Chia-Hua
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 5106
container_issue 9
container_start_page 5097
container_title ACS applied materials & interfaces
container_volume 7
creator Yang, Lingyan
Tseng, Yu-Ting
Suo, Guangli
Chen, Liliang
Yu, Jiantao
Chiu, Wei-Jane
Huang, Chih-Ching
Lin, Chia-Hua
description The objective of this study was to synthesize a nanocomposite, aptamer–gold nanoparticle-hybridized graphene oxide (Apt-AuNP–GO), to facilitate targeted treatment of tumor cells by near-infrared (NIR) light-activatable photothermal therapy. We also investigated whether Apt-AuNP–GO with NIR illumination modulates heat shock proteins (HSPs) expression leading to therapeutic response in human breast cancer cells. These findings can provide strategies for improving the photothermal therapy efficacy of cancer. The self-assembled Apt-AuNP–GO nanocomposite could selectively target MUC1-positive human breast cancer cells (MCF-7) due to the specific interaction between the MUC1-binding-aptamer and the MUC1 (type I transmembrane mucin glycoprotein) on cell membrane. In addition, Apt-AuNP–GO has a high light-to-heat conversion capability for photoabsorption of NIR light, and it is able to exert therapeutic effects on MCF-7 cells at an ultralow concentration without inducing adverse effects in healthy cells. The Apt-AuNP–GO nanocomposites combine the advantages of GOs, AuNPs, and Apts, possess specific targeting capability, excellent biocompatibility, and tumor cell destruction ability, suggesting great potential for application in the photothermal therapy of breast cancer. Under NIR illumination, Apt-AuNP–GO induced transient increase in HSP70 expression, which decreased thereafter. This phenomenon may cause irreversible damage to Apt-AuNP–GO-treated MCF-7 cell under NIR illumination. We also demonstrated that the combination therapy of heat and HSP70 inhibitor could synergistically generate marked tumoricidal effects against breast cancer. These results suggest that the degree and duration of HSP70 protein expression are correlated with therapeutic effects against breast cancer for Apt-AuNP–GO-assisted photothermal therapy. We believe that such a nanocomposite can be readily extended to the construction of HSP70 inhibitors-loaded Apt-AuNP–GO, which could deliver both heat and HSP70 inhibitors to tumorigenic regions for the chemo-photothermal therapy.
doi_str_mv 10.1021/am508117e
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1663656304</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1663656304</sourcerecordid><originalsourceid>FETCH-LOGICAL-a315t-e4d4c3ff9d9c5bb756b8a4492fe6c870739c64c9ef84bfecd3b1b0e619e4dd353</originalsourceid><addsrcrecordid>eNptkM1KxDAUhYMo_owufAHJRtBFNWl-2i5l0HFAHBFdlzS5ZSptUpMW1JU-g2_okxgZnZWrcxff-eAehA4pOaMkpeeqEySnNIMNtEsLzpM8Fenm-uZ8B-2F8ESIZCkR22gnFRkRWV7soo-7pRvcsATfqRY_xFQ9jEOj8T2E3tkA2NV4qqwGj6fQtgEPDl_0g-rAf71_zlxr8K2yrlc-tlpIrl8r35jmDQyeRdkSLODFS2MAj9ZEye38Hs_bduwaq4bG2X20Vas2wMFvTtDj1eXD9Dq5Wczm04ubRDEqhgS44ZrVdWEKLaoqE7LKFedFWoPUeUYyVmjJdQF1zqsatGEVrQhIWsSmYYJN0MnK23v3PEIYyq4JOn6kLLgxlFRKJoVkhEf0dIVq70LwUJe9bzrlX0tKyp_Fy_XikT361Y5VB2ZN_k0cgeMVoHQon9zobfzyH9E3fkeLBA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1663656304</pqid></control><display><type>article</type><title>Photothermal Therapeutic Response of Cancer Cells to Aptamer–Gold Nanoparticle-Hybridized Graphene Oxide under NIR Illumination</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>Yang, Lingyan ; Tseng, Yu-Ting ; Suo, Guangli ; Chen, Liliang ; Yu, Jiantao ; Chiu, Wei-Jane ; Huang, Chih-Ching ; Lin, Chia-Hua</creator><creatorcontrib>Yang, Lingyan ; Tseng, Yu-Ting ; Suo, Guangli ; Chen, Liliang ; Yu, Jiantao ; Chiu, Wei-Jane ; Huang, Chih-Ching ; Lin, Chia-Hua</creatorcontrib><description>The objective of this study was to synthesize a nanocomposite, aptamer–gold nanoparticle-hybridized graphene oxide (Apt-AuNP–GO), to facilitate targeted treatment of tumor cells by near-infrared (NIR) light-activatable photothermal therapy. We also investigated whether Apt-AuNP–GO with NIR illumination modulates heat shock proteins (HSPs) expression leading to therapeutic response in human breast cancer cells. These findings can provide strategies for improving the photothermal therapy efficacy of cancer. The self-assembled Apt-AuNP–GO nanocomposite could selectively target MUC1-positive human breast cancer cells (MCF-7) due to the specific interaction between the MUC1-binding-aptamer and the MUC1 (type I transmembrane mucin glycoprotein) on cell membrane. In addition, Apt-AuNP–GO has a high light-to-heat conversion capability for photoabsorption of NIR light, and it is able to exert therapeutic effects on MCF-7 cells at an ultralow concentration without inducing adverse effects in healthy cells. The Apt-AuNP–GO nanocomposites combine the advantages of GOs, AuNPs, and Apts, possess specific targeting capability, excellent biocompatibility, and tumor cell destruction ability, suggesting great potential for application in the photothermal therapy of breast cancer. Under NIR illumination, Apt-AuNP–GO induced transient increase in HSP70 expression, which decreased thereafter. This phenomenon may cause irreversible damage to Apt-AuNP–GO-treated MCF-7 cell under NIR illumination. We also demonstrated that the combination therapy of heat and HSP70 inhibitor could synergistically generate marked tumoricidal effects against breast cancer. These results suggest that the degree and duration of HSP70 protein expression are correlated with therapeutic effects against breast cancer for Apt-AuNP–GO-assisted photothermal therapy. We believe that such a nanocomposite can be readily extended to the construction of HSP70 inhibitors-loaded Apt-AuNP–GO, which could deliver both heat and HSP70 inhibitors to tumorigenic regions for the chemo-photothermal therapy.</description><identifier>ISSN: 1944-8244</identifier><identifier>EISSN: 1944-8252</identifier><identifier>DOI: 10.1021/am508117e</identifier><identifier>PMID: 25705789</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Apoptosis Regulatory Proteins - metabolism ; Aptamers, Nucleotide - chemistry ; Breast Neoplasms - pathology ; Breast Neoplasms - therapy ; Cell Survival - drug effects ; Cell Survival - radiation effects ; Female ; Gold - chemistry ; Graphite - chemistry ; HSP70 Heat-Shock Proteins - antagonists &amp; inhibitors ; HSP70 Heat-Shock Proteins - metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; Infrared Rays ; MCF-7 Cells ; Metal Nanoparticles - chemistry ; Microscopy, Fluorescence ; Mucin-1 - metabolism ; Nanocomposites - chemistry ; Nanocomposites - therapeutic use ; Oxides - chemistry ; Phototherapy ; Purine Nucleosides - chemistry ; Purine Nucleosides - pharmacology ; Purine Nucleosides - therapeutic use ; Rhodamines - chemistry ; Temperature</subject><ispartof>ACS applied materials &amp; interfaces, 2015-03, Vol.7 (9), p.5097-5106</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-e4d4c3ff9d9c5bb756b8a4492fe6c870739c64c9ef84bfecd3b1b0e619e4dd353</citedby><cites>FETCH-LOGICAL-a315t-e4d4c3ff9d9c5bb756b8a4492fe6c870739c64c9ef84bfecd3b1b0e619e4dd353</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/am508117e$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/am508117e$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25705789$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Lingyan</creatorcontrib><creatorcontrib>Tseng, Yu-Ting</creatorcontrib><creatorcontrib>Suo, Guangli</creatorcontrib><creatorcontrib>Chen, Liliang</creatorcontrib><creatorcontrib>Yu, Jiantao</creatorcontrib><creatorcontrib>Chiu, Wei-Jane</creatorcontrib><creatorcontrib>Huang, Chih-Ching</creatorcontrib><creatorcontrib>Lin, Chia-Hua</creatorcontrib><title>Photothermal Therapeutic Response of Cancer Cells to Aptamer–Gold Nanoparticle-Hybridized Graphene Oxide under NIR Illumination</title><title>ACS applied materials &amp; interfaces</title><addtitle>ACS Appl. Mater. Interfaces</addtitle><description>The objective of this study was to synthesize a nanocomposite, aptamer–gold nanoparticle-hybridized graphene oxide (Apt-AuNP–GO), to facilitate targeted treatment of tumor cells by near-infrared (NIR) light-activatable photothermal therapy. We also investigated whether Apt-AuNP–GO with NIR illumination modulates heat shock proteins (HSPs) expression leading to therapeutic response in human breast cancer cells. These findings can provide strategies for improving the photothermal therapy efficacy of cancer. The self-assembled Apt-AuNP–GO nanocomposite could selectively target MUC1-positive human breast cancer cells (MCF-7) due to the specific interaction between the MUC1-binding-aptamer and the MUC1 (type I transmembrane mucin glycoprotein) on cell membrane. In addition, Apt-AuNP–GO has a high light-to-heat conversion capability for photoabsorption of NIR light, and it is able to exert therapeutic effects on MCF-7 cells at an ultralow concentration without inducing adverse effects in healthy cells. The Apt-AuNP–GO nanocomposites combine the advantages of GOs, AuNPs, and Apts, possess specific targeting capability, excellent biocompatibility, and tumor cell destruction ability, suggesting great potential for application in the photothermal therapy of breast cancer. Under NIR illumination, Apt-AuNP–GO induced transient increase in HSP70 expression, which decreased thereafter. This phenomenon may cause irreversible damage to Apt-AuNP–GO-treated MCF-7 cell under NIR illumination. We also demonstrated that the combination therapy of heat and HSP70 inhibitor could synergistically generate marked tumoricidal effects against breast cancer. These results suggest that the degree and duration of HSP70 protein expression are correlated with therapeutic effects against breast cancer for Apt-AuNP–GO-assisted photothermal therapy. We believe that such a nanocomposite can be readily extended to the construction of HSP70 inhibitors-loaded Apt-AuNP–GO, which could deliver both heat and HSP70 inhibitors to tumorigenic regions for the chemo-photothermal therapy.</description><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>Aptamers, Nucleotide - chemistry</subject><subject>Breast Neoplasms - pathology</subject><subject>Breast Neoplasms - therapy</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - radiation effects</subject><subject>Female</subject><subject>Gold - chemistry</subject><subject>Graphite - chemistry</subject><subject>HSP70 Heat-Shock Proteins - antagonists &amp; inhibitors</subject><subject>HSP70 Heat-Shock Proteins - metabolism</subject><subject>Human Umbilical Vein Endothelial Cells</subject><subject>Humans</subject><subject>Infrared Rays</subject><subject>MCF-7 Cells</subject><subject>Metal Nanoparticles - chemistry</subject><subject>Microscopy, Fluorescence</subject><subject>Mucin-1 - metabolism</subject><subject>Nanocomposites - chemistry</subject><subject>Nanocomposites - therapeutic use</subject><subject>Oxides - chemistry</subject><subject>Phototherapy</subject><subject>Purine Nucleosides - chemistry</subject><subject>Purine Nucleosides - pharmacology</subject><subject>Purine Nucleosides - therapeutic use</subject><subject>Rhodamines - chemistry</subject><subject>Temperature</subject><issn>1944-8244</issn><issn>1944-8252</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkM1KxDAUhYMo_owufAHJRtBFNWl-2i5l0HFAHBFdlzS5ZSptUpMW1JU-g2_okxgZnZWrcxff-eAehA4pOaMkpeeqEySnNIMNtEsLzpM8Fenm-uZ8B-2F8ESIZCkR22gnFRkRWV7soo-7pRvcsATfqRY_xFQ9jEOj8T2E3tkA2NV4qqwGj6fQtgEPDl_0g-rAf71_zlxr8K2yrlc-tlpIrl8r35jmDQyeRdkSLODFS2MAj9ZEye38Hs_bduwaq4bG2X20Vas2wMFvTtDj1eXD9Dq5Wczm04ubRDEqhgS44ZrVdWEKLaoqE7LKFedFWoPUeUYyVmjJdQF1zqsatGEVrQhIWsSmYYJN0MnK23v3PEIYyq4JOn6kLLgxlFRKJoVkhEf0dIVq70LwUJe9bzrlX0tKyp_Fy_XikT361Y5VB2ZN_k0cgeMVoHQon9zobfzyH9E3fkeLBA</recordid><startdate>20150311</startdate><enddate>20150311</enddate><creator>Yang, Lingyan</creator><creator>Tseng, Yu-Ting</creator><creator>Suo, Guangli</creator><creator>Chen, Liliang</creator><creator>Yu, Jiantao</creator><creator>Chiu, Wei-Jane</creator><creator>Huang, Chih-Ching</creator><creator>Lin, Chia-Hua</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20150311</creationdate><title>Photothermal Therapeutic Response of Cancer Cells to Aptamer–Gold Nanoparticle-Hybridized Graphene Oxide under NIR Illumination</title><author>Yang, Lingyan ; Tseng, Yu-Ting ; Suo, Guangli ; Chen, Liliang ; Yu, Jiantao ; Chiu, Wei-Jane ; Huang, Chih-Ching ; Lin, Chia-Hua</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-e4d4c3ff9d9c5bb756b8a4492fe6c870739c64c9ef84bfecd3b1b0e619e4dd353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Apoptosis Regulatory Proteins - metabolism</topic><topic>Aptamers, Nucleotide - chemistry</topic><topic>Breast Neoplasms - pathology</topic><topic>Breast Neoplasms - therapy</topic><topic>Cell Survival - drug effects</topic><topic>Cell Survival - radiation effects</topic><topic>Female</topic><topic>Gold - chemistry</topic><topic>Graphite - chemistry</topic><topic>HSP70 Heat-Shock Proteins - antagonists &amp; inhibitors</topic><topic>HSP70 Heat-Shock Proteins - metabolism</topic><topic>Human Umbilical Vein Endothelial Cells</topic><topic>Humans</topic><topic>Infrared Rays</topic><topic>MCF-7 Cells</topic><topic>Metal Nanoparticles - chemistry</topic><topic>Microscopy, Fluorescence</topic><topic>Mucin-1 - metabolism</topic><topic>Nanocomposites - chemistry</topic><topic>Nanocomposites - therapeutic use</topic><topic>Oxides - chemistry</topic><topic>Phototherapy</topic><topic>Purine Nucleosides - chemistry</topic><topic>Purine Nucleosides - pharmacology</topic><topic>Purine Nucleosides - therapeutic use</topic><topic>Rhodamines - chemistry</topic><topic>Temperature</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Lingyan</creatorcontrib><creatorcontrib>Tseng, Yu-Ting</creatorcontrib><creatorcontrib>Suo, Guangli</creatorcontrib><creatorcontrib>Chen, Liliang</creatorcontrib><creatorcontrib>Yu, Jiantao</creatorcontrib><creatorcontrib>Chiu, Wei-Jane</creatorcontrib><creatorcontrib>Huang, Chih-Ching</creatorcontrib><creatorcontrib>Lin, Chia-Hua</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>ACS applied materials &amp; interfaces</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Lingyan</au><au>Tseng, Yu-Ting</au><au>Suo, Guangli</au><au>Chen, Liliang</au><au>Yu, Jiantao</au><au>Chiu, Wei-Jane</au><au>Huang, Chih-Ching</au><au>Lin, Chia-Hua</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Photothermal Therapeutic Response of Cancer Cells to Aptamer–Gold Nanoparticle-Hybridized Graphene Oxide under NIR Illumination</atitle><jtitle>ACS applied materials &amp; interfaces</jtitle><addtitle>ACS Appl. Mater. Interfaces</addtitle><date>2015-03-11</date><risdate>2015</risdate><volume>7</volume><issue>9</issue><spage>5097</spage><epage>5106</epage><pages>5097-5106</pages><issn>1944-8244</issn><eissn>1944-8252</eissn><abstract>The objective of this study was to synthesize a nanocomposite, aptamer–gold nanoparticle-hybridized graphene oxide (Apt-AuNP–GO), to facilitate targeted treatment of tumor cells by near-infrared (NIR) light-activatable photothermal therapy. We also investigated whether Apt-AuNP–GO with NIR illumination modulates heat shock proteins (HSPs) expression leading to therapeutic response in human breast cancer cells. These findings can provide strategies for improving the photothermal therapy efficacy of cancer. The self-assembled Apt-AuNP–GO nanocomposite could selectively target MUC1-positive human breast cancer cells (MCF-7) due to the specific interaction between the MUC1-binding-aptamer and the MUC1 (type I transmembrane mucin glycoprotein) on cell membrane. In addition, Apt-AuNP–GO has a high light-to-heat conversion capability for photoabsorption of NIR light, and it is able to exert therapeutic effects on MCF-7 cells at an ultralow concentration without inducing adverse effects in healthy cells. The Apt-AuNP–GO nanocomposites combine the advantages of GOs, AuNPs, and Apts, possess specific targeting capability, excellent biocompatibility, and tumor cell destruction ability, suggesting great potential for application in the photothermal therapy of breast cancer. Under NIR illumination, Apt-AuNP–GO induced transient increase in HSP70 expression, which decreased thereafter. This phenomenon may cause irreversible damage to Apt-AuNP–GO-treated MCF-7 cell under NIR illumination. We also demonstrated that the combination therapy of heat and HSP70 inhibitor could synergistically generate marked tumoricidal effects against breast cancer. These results suggest that the degree and duration of HSP70 protein expression are correlated with therapeutic effects against breast cancer for Apt-AuNP–GO-assisted photothermal therapy. We believe that such a nanocomposite can be readily extended to the construction of HSP70 inhibitors-loaded Apt-AuNP–GO, which could deliver both heat and HSP70 inhibitors to tumorigenic regions for the chemo-photothermal therapy.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>25705789</pmid><doi>10.1021/am508117e</doi><tpages>10</tpages></addata></record>
fulltext fulltext
identifier ISSN: 1944-8244
ispartof ACS applied materials & interfaces, 2015-03, Vol.7 (9), p.5097-5106
issn 1944-8244
1944-8252
language eng
recordid cdi_proquest_miscellaneous_1663656304
source MEDLINE; American Chemical Society Journals
subjects Apoptosis Regulatory Proteins - metabolism
Aptamers, Nucleotide - chemistry
Breast Neoplasms - pathology
Breast Neoplasms - therapy
Cell Survival - drug effects
Cell Survival - radiation effects
Female
Gold - chemistry
Graphite - chemistry
HSP70 Heat-Shock Proteins - antagonists & inhibitors
HSP70 Heat-Shock Proteins - metabolism
Human Umbilical Vein Endothelial Cells
Humans
Infrared Rays
MCF-7 Cells
Metal Nanoparticles - chemistry
Microscopy, Fluorescence
Mucin-1 - metabolism
Nanocomposites - chemistry
Nanocomposites - therapeutic use
Oxides - chemistry
Phototherapy
Purine Nucleosides - chemistry
Purine Nucleosides - pharmacology
Purine Nucleosides - therapeutic use
Rhodamines - chemistry
Temperature
title Photothermal Therapeutic Response of Cancer Cells to Aptamer–Gold Nanoparticle-Hybridized Graphene Oxide under NIR Illumination
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-28T22%3A52%3A52IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Photothermal%20Therapeutic%20Response%20of%20Cancer%20Cells%20to%20Aptamer%E2%80%93Gold%20Nanoparticle-Hybridized%20Graphene%20Oxide%20under%20NIR%20Illumination&rft.jtitle=ACS%20applied%20materials%20&%20interfaces&rft.au=Yang,%20Lingyan&rft.date=2015-03-11&rft.volume=7&rft.issue=9&rft.spage=5097&rft.epage=5106&rft.pages=5097-5106&rft.issn=1944-8244&rft.eissn=1944-8252&rft_id=info:doi/10.1021/am508117e&rft_dat=%3Cproquest_cross%3E1663656304%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1663656304&rft_id=info:pmid/25705789&rfr_iscdi=true