Aptamers as Delivery Agents of siRNA and Chimeric Formulations for the Treatment of Cancer
Identifieur interne : 000996 ( Pmc/Checkpoint ); précédent : 000995; suivant : 000997Aptamers as Delivery Agents of siRNA and Chimeric Formulations for the Treatment of Cancer
Auteurs : Ana Paula Dinis Ano Bom ; Patrícia Cristina Da Costa Neves ; Carlos Eduardo Bonacossa De Almeida ; Dilson Silva ; Sotiris MissailidisSource :
- Pharmaceutics [ 1999-4923 ] ; 2019.
Abstract
Both aptamers and siRNA technologies have now reached maturity, and both have been validated with a product in the market. However, although pegaptanib reached the market some time ago, there has been a slow process for new aptamers to follow. Today, some 40 aptamers are in the market, but many in combination with siRNAs, in the form of specific delivery agents. This combination offers the potential to explore the high affinity and specificity of aptamers, the silencing power of siRNA, and, at times, the cytotoxicity of chemotherapy molecules in powerful combinations that promise to delivery new and potent therapies. In this review, we report new developments in the field, following up from our previous work, more specifically on the use of aptamers as delivery agents of siRNA in nanoparticle formulations, alone or in combination with chemotherapy, for the treatment of cancer.
Url:
DOI: 10.3390/pharmaceutics11120684
PubMed: 31888119
PubMed Central: 6956146
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Aptamers as Delivery Agents of siRNA and Chimeric Formulations for the Treatment of Cancer</title><author><name sortKey="Dinis Ano Bom, Ana Paula" sort="Dinis Ano Bom, Ana Paula" uniqKey="Dinis Ano Bom A" first="Ana Paula" last="Dinis Ano Bom">Ana Paula Dinis Ano Bom</name><affiliation><nlm:aff id="af1-pharmaceutics-11-00684">Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), Fundação Oswaldo Cruz. Av. Brasil, 4365-Manguinhos, Rio de Janeiro/RJ CEP 21040-900, Brazil;<email>adinis@bio.fiocruz.br</email> (A.P.D.A.B.);<email>Pcristina@bio.fiocruz.br</email> (P.C.d.C.N.);<email>dilson.silva@bio.fiocruz.br</email> (D.S.)</nlm:aff></affiliation></author><author><name sortKey="Da Costa Neves, Patricia Cristina" sort="Da Costa Neves, Patricia Cristina" uniqKey="Da Costa Neves P" first="Patrícia Cristina" last="Da Costa Neves">Patrícia Cristina Da Costa Neves</name><affiliation><nlm:aff id="af1-pharmaceutics-11-00684">Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), Fundação Oswaldo Cruz. Av. Brasil, 4365-Manguinhos, Rio de Janeiro/RJ CEP 21040-900, Brazil;<email>adinis@bio.fiocruz.br</email> (A.P.D.A.B.);<email>Pcristina@bio.fiocruz.br</email> (P.C.d.C.N.);<email>dilson.silva@bio.fiocruz.br</email> (D.S.)</nlm:aff></affiliation></author><author><name sortKey="Bonacossa De Almeida, Carlos Eduardo" sort="Bonacossa De Almeida, Carlos Eduardo" uniqKey="Bonacossa De Almeida C" first="Carlos Eduardo" last="Bonacossa De Almeida">Carlos Eduardo Bonacossa De Almeida</name><affiliation><nlm:aff id="af2-pharmaceutics-11-00684">Laboratório de Radiobiologia, Divisão de Física Médica, Instituto de Radioproteção e Dosimetria, Comissão Nacional de Energia Nuclear. Av. Salvador Allende S/N., Rio de Janeiro/RJ CEP 22783-127, Brazil;<email>ce.bonacossa@gmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Silva, Dilson" sort="Silva, Dilson" uniqKey="Silva D" first="Dilson" last="Silva">Dilson Silva</name><affiliation><nlm:aff id="af1-pharmaceutics-11-00684">Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), Fundação Oswaldo Cruz. Av. Brasil, 4365-Manguinhos, Rio de Janeiro/RJ CEP 21040-900, Brazil;<email>adinis@bio.fiocruz.br</email> (A.P.D.A.B.);<email>Pcristina@bio.fiocruz.br</email> (P.C.d.C.N.);<email>dilson.silva@bio.fiocruz.br</email> (D.S.)</nlm:aff></affiliation></author><author><name sortKey="Missailidis, Sotiris" sort="Missailidis, Sotiris" uniqKey="Missailidis S" first="Sotiris" last="Missailidis">Sotiris Missailidis</name><affiliation><nlm:aff id="af1-pharmaceutics-11-00684">Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), Fundação Oswaldo Cruz. Av. Brasil, 4365-Manguinhos, Rio de Janeiro/RJ CEP 21040-900, Brazil;<email>adinis@bio.fiocruz.br</email> (A.P.D.A.B.);<email>Pcristina@bio.fiocruz.br</email> (P.C.d.C.N.);<email>dilson.silva@bio.fiocruz.br</email> (D.S.)</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31888119</idno><idno type="pmc">6956146</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956146</idno><idno type="RBID">PMC:6956146</idno><idno type="doi">10.3390/pharmaceutics11120684</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000A98</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A98</idno><idno type="wicri:Area/Pmc/Curation">000A98</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000A98</idno><idno type="wicri:Area/Pmc/Checkpoint">000996</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000996</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Aptamers as Delivery Agents of siRNA and Chimeric Formulations for the Treatment of Cancer</title><author><name sortKey="Dinis Ano Bom, Ana Paula" sort="Dinis Ano Bom, Ana Paula" uniqKey="Dinis Ano Bom A" first="Ana Paula" last="Dinis Ano Bom">Ana Paula Dinis Ano Bom</name><affiliation><nlm:aff id="af1-pharmaceutics-11-00684">Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), Fundação Oswaldo Cruz. Av. Brasil, 4365-Manguinhos, Rio de Janeiro/RJ CEP 21040-900, Brazil;<email>adinis@bio.fiocruz.br</email> (A.P.D.A.B.);<email>Pcristina@bio.fiocruz.br</email> (P.C.d.C.N.);<email>dilson.silva@bio.fiocruz.br</email> (D.S.)</nlm:aff></affiliation></author><author><name sortKey="Da Costa Neves, Patricia Cristina" sort="Da Costa Neves, Patricia Cristina" uniqKey="Da Costa Neves P" first="Patrícia Cristina" last="Da Costa Neves">Patrícia Cristina Da Costa Neves</name><affiliation><nlm:aff id="af1-pharmaceutics-11-00684">Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), Fundação Oswaldo Cruz. Av. Brasil, 4365-Manguinhos, Rio de Janeiro/RJ CEP 21040-900, Brazil;<email>adinis@bio.fiocruz.br</email> (A.P.D.A.B.);<email>Pcristina@bio.fiocruz.br</email> (P.C.d.C.N.);<email>dilson.silva@bio.fiocruz.br</email> (D.S.)</nlm:aff></affiliation></author><author><name sortKey="Bonacossa De Almeida, Carlos Eduardo" sort="Bonacossa De Almeida, Carlos Eduardo" uniqKey="Bonacossa De Almeida C" first="Carlos Eduardo" last="Bonacossa De Almeida">Carlos Eduardo Bonacossa De Almeida</name><affiliation><nlm:aff id="af2-pharmaceutics-11-00684">Laboratório de Radiobiologia, Divisão de Física Médica, Instituto de Radioproteção e Dosimetria, Comissão Nacional de Energia Nuclear. Av. Salvador Allende S/N., Rio de Janeiro/RJ CEP 22783-127, Brazil;<email>ce.bonacossa@gmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Silva, Dilson" sort="Silva, Dilson" uniqKey="Silva D" first="Dilson" last="Silva">Dilson Silva</name><affiliation><nlm:aff id="af1-pharmaceutics-11-00684">Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), Fundação Oswaldo Cruz. Av. Brasil, 4365-Manguinhos, Rio de Janeiro/RJ CEP 21040-900, Brazil;<email>adinis@bio.fiocruz.br</email> (A.P.D.A.B.);<email>Pcristina@bio.fiocruz.br</email> (P.C.d.C.N.);<email>dilson.silva@bio.fiocruz.br</email> (D.S.)</nlm:aff></affiliation></author><author><name sortKey="Missailidis, Sotiris" sort="Missailidis, Sotiris" uniqKey="Missailidis S" first="Sotiris" last="Missailidis">Sotiris Missailidis</name><affiliation><nlm:aff id="af1-pharmaceutics-11-00684">Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), Fundação Oswaldo Cruz. Av. Brasil, 4365-Manguinhos, Rio de Janeiro/RJ CEP 21040-900, Brazil;<email>adinis@bio.fiocruz.br</email> (A.P.D.A.B.);<email>Pcristina@bio.fiocruz.br</email> (P.C.d.C.N.);<email>dilson.silva@bio.fiocruz.br</email> (D.S.)</nlm:aff></affiliation></author></analytic><series><title level="j">Pharmaceutics</title><idno type="eISSN">1999-4923</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Both aptamers and siRNA technologies have now reached maturity, and both have been validated with a product in the market. However, although pegaptanib reached the market some time ago, there has been a slow process for new aptamers to follow. Today, some 40 aptamers are in the market, but many in combination with siRNAs, in the form of specific delivery agents. This combination offers the potential to explore the high affinity and specificity of aptamers, the silencing power of siRNA, and, at times, the cytotoxicity of chemotherapy molecules in powerful combinations that promise to delivery new and potent therapies. In this review, we report new developments in the field, following up from our previous work, more specifically on the use of aptamers as delivery agents of siRNA in nanoparticle formulations, alone or in combination with chemotherapy, for the treatment of cancer.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Singh, A" uniqKey="Singh A">A. Singh</name></author><author><name sortKey="Trivedi, P" uniqKey="Trivedi P">P. Trivedi</name></author><author><name sortKey="Jain, N K" uniqKey="Jain N">N.K. Jain</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mishra, D K" uniqKey="Mishra D">D.K. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Pharmaceutics</journal-id><journal-id journal-id-type="iso-abbrev">Pharmaceutics</journal-id><journal-id journal-id-type="publisher-id">pharmaceutics</journal-id><journal-title-group><journal-title>Pharmaceutics</journal-title></journal-title-group><issn pub-type="epub">1999-4923</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31888119</article-id><article-id pub-id-type="pmc">6956146</article-id><article-id pub-id-type="doi">10.3390/pharmaceutics11120684</article-id><article-id pub-id-type="publisher-id">pharmaceutics-11-00684</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Aptamers as Delivery Agents of siRNA and Chimeric Formulations for the Treatment of Cancer</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Dinis Ano Bom</surname><given-names>Ana Paula</given-names></name><xref ref-type="aff" rid="af1-pharmaceutics-11-00684">1</xref></contrib><contrib contrib-type="author"><name><surname>da Costa Neves</surname><given-names>Patrícia Cristina</given-names></name><xref ref-type="aff" rid="af1-pharmaceutics-11-00684">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-0108-3998</contrib-id><name><surname>Bonacossa de Almeida</surname><given-names>Carlos Eduardo</given-names></name><xref ref-type="aff" rid="af2-pharmaceutics-11-00684">2</xref></contrib><contrib contrib-type="author"><name><surname>Silva</surname><given-names>Dilson</given-names></name><xref ref-type="aff" rid="af1-pharmaceutics-11-00684">1</xref></contrib><contrib contrib-type="author"><name><surname>Missailidis</surname><given-names>Sotiris</given-names></name><xref ref-type="aff" rid="af1-pharmaceutics-11-00684">1</xref><xref rid="c1-pharmaceutics-11-00684" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-pharmaceutics-11-00684"><label>1</label>Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), Fundação Oswaldo Cruz. Av. Brasil, 4365-Manguinhos, Rio de Janeiro/RJ CEP 21040-900, Brazil;<email>adinis@bio.fiocruz.br</email> (A.P.D.A.B.);<email>Pcristina@bio.fiocruz.br</email> (P.C.d.C.N.);<email>dilson.silva@bio.fiocruz.br</email> (D.S.)</aff><aff id="af2-pharmaceutics-11-00684"><label>2</label>Laboratório de Radiobiologia, Divisão de Física Médica, Instituto de Radioproteção e Dosimetria, Comissão Nacional de Energia Nuclear. Av. Salvador Allende S/N., Rio de Janeiro/RJ CEP 22783-127, Brazil;<email>ce.bonacossa@gmail.com</email></aff><author-notes><corresp id="c1-pharmaceutics-11-00684"><label>*</label>Correspondence: <email>sotiris.missailidis@bio.fiocruz.br</email></corresp></author-notes><pub-date pub-type="epub"><day>16</day><month>12</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>12</month><year>2019</year></pub-date><volume>11</volume><issue>12</issue><elocation-id>684</elocation-id><history><date date-type="received"><day>30</day><month>9</month><year>2019</year></date><date date-type="accepted"><day>30</day><month>10</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Both aptamers and siRNA technologies have now reached maturity, and both have been validated with a product in the market. However, although pegaptanib reached the market some time ago, there has been a slow process for new aptamers to follow. Today, some 40 aptamers are in the market, but many in combination with siRNAs, in the form of specific delivery agents. This combination offers the potential to explore the high affinity and specificity of aptamers, the silencing power of siRNA, and, at times, the cytotoxicity of chemotherapy molecules in powerful combinations that promise to delivery new and potent therapies. In this review, we report new developments in the field, following up from our previous work, more specifically on the use of aptamers as delivery agents of siRNA in nanoparticle formulations, alone or in combination with chemotherapy, for the treatment of cancer.</p></abstract><kwd-group><kwd>siRNA</kwd><kwd>aptamers</kwd><kwd>cancer</kwd><kwd>nanoparticles</kwd></kwd-group></article-meta></front><floats-group><fig id="pharmaceutics-11-00684-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Uses of aptamers in therapeutic delivery.</p></caption><graphic xlink:href="pharmaceutics-11-00684-g001"></graphic></fig><table-wrap id="pharmaceutics-11-00684-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">pharmaceutics-11-00684-t001_Table 1</object-id><label>Table 1</label><caption><p>Aptamers for delivery of siRNA.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">siRNA/miRNA/shRNA Target Gene</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Carrier Aptamer</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Efficacy Tests</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Ref.</th></tr></thead><tbody><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Survivin </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CD4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro knock down antiapoptosis factor survivin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B12-pharmaceutics-11-00684" ref-type="bibr">12</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ICAM 1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">FB4 (bind to transferrin receptors)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro results showed a decreased of ICAM-1 expression and blocked the adhesion of monocytes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B13-pharmaceutics-11-00684" ref-type="bibr">13</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Human immunodeficiency virus (HIV)-1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">epidermal growth factor receptor (EGFR)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro and in vivo gene silencing</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B14-pharmaceutics-11-00684" ref-type="bibr">14</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anaplastic lymphoma kinase (ALK)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CD30</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro results of growth arrest and apoptosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B17-pharmaceutics-11-00684" ref-type="bibr">17</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">P-gp</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">A6 (bind to human epidermal growth factor receptor 2 (HER-2) receptors)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro results about decreasing of resistance to chemotherapeutics</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B18-pharmaceutics-11-00684" ref-type="bibr">18</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">P-gp</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">LA1 (specific to multi-drug resistance (MDR))</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro and in vivo anti-tumor activity</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B19-pharmaceutics-11-00684" ref-type="bibr">19</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GFP</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Transferrin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro enhanced siRNA uptake and target gene knockdown</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B20-pharmaceutics-11-00684" ref-type="bibr">20</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Luciferase</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CD44</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro and in vivo results of targeted gene silencing in CD44-positive breast cancer</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B21-pharmaceutics-11-00684" ref-type="bibr">21</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">P-gp</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HER2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro confirmation of silencing disease-related genes in tumors </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B18-pharmaceutics-11-00684" ref-type="bibr">18</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">BCL-xL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prostate-specific membrane antigen (PSMA)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro anti-tumor activity</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B22-pharmaceutics-11-00684" ref-type="bibr">22</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Genes in prostate cancer</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PSMA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro anticancer effect</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B23-pharmaceutics-11-00684" ref-type="bibr">23</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prohibitin 1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PSMA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vivo gene silencing in prostate cancer tumor cells </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B24-pharmaceutics-11-00684" ref-type="bibr">24</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Survivin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EGFR</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro and in vivo antitumor effects</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B25-pharmaceutics-11-00684" ref-type="bibr">25</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GFP</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PSMA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro GFP silencing/Fluorescence imaging (quantum dots)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B27-pharmaceutics-11-00684" ref-type="bibr">27</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Insulin-like growth factor receptor 1 (IGF-1R)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MUC-1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro augment the targeting of pathways involved in tumorigenesis and metastasis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B28-pharmaceutics-11-00684" ref-type="bibr">28</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Special AT-rich sequence binding protein 1 (SATB1)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EGFR</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro and in vivo studies of gene expression decreased</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B29-pharmaceutics-11-00684" ref-type="bibr">29</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">BCL-xL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nucleolin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"> in vitro gene silencing and apoptosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B30-pharmaceutics-11-00684" ref-type="bibr">30</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">BCL-xL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nucelolin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro gene silencing and tumoricidal efficacy</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B31-pharmaceutics-11-00684" ref-type="bibr">31</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">D5D</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EpCAM</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro and in vivo inhibition of D5D expression</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B32-pharmaceutics-11-00684" ref-type="bibr">32</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">c-myc</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Transferrin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro and in vivo anti-tumor activity</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B33-pharmaceutics-11-00684" ref-type="bibr">33</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">FoxM1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PSMA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro and in vivo anti-tumor activity in prostate cancer cells and xenografts in mice</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B34-pharmaceutics-11-00684" ref-type="bibr">34</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Rab26</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MUC-1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro anti-tumor activity</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B35-pharmaceutics-11-00684" ref-type="bibr">35</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">bcl-2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EGFR</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro interference of tumor cell proliferation</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B11-pharmaceutics-11-00684" ref-type="bibr">11</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">bcl-2 and PKC-ι</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EGFR</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vivo delivery and therapeutic efficacy</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B37-pharmaceutics-11-00684" ref-type="bibr">37</xref>]</td></tr></tbody></table></table-wrap><table-wrap id="pharmaceutics-11-00684-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">pharmaceutics-11-00684-t002_Table 2</object-id><label>Table 2</label><caption><p>Aptamers and siRNA for immunotherapy.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">siRNA Target Gene</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Carrier Aptamer</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Efficacy Tests</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Ref.</th></tr></thead><tbody><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">IL-2 Rα (CD25)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">41-BB</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro using CHO cells and murine CD8<sup>+</sup> cells and in vivo using C57BL/6 mice adoptively transferred with OT-I cells and breast tumor 4T1 model</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B49-pharmaceutics-11-00684" ref-type="bibr">49</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Smad-4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">41-BB</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro using murine CD8<sup>+</sup> cells and in vivo using breast tumor 4T1 model</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B50-pharmaceutics-11-00684" ref-type="bibr">50</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">RORγT</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CD4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro using CD4+ Karpas 299 cells and primary human CD4+ T cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B51-pharmaceutics-11-00684" ref-type="bibr">51</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SMG-1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CD40 agonist</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro using human B- lymphocytes and in vivo using B-cell lymphoma-bearing mice</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B52-pharmaceutics-11-00684" ref-type="bibr">52</xref>]</td></tr></tbody></table></table-wrap><table-wrap id="pharmaceutics-11-00684-t003" orientation="portrait" position="float"><object-id pub-id-type="pii">pharmaceutics-11-00684-t003_Table 3</object-id><label>Table 3</label><caption><p>Aptamers for delivery SiRNA/chemotherapeutics for cancer therapy.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Carrier Aptamers</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">siRNA or Drug Delivered</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Target Cell Lines</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Main Effects</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Ref.</th></tr></thead><tbody><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PDGFRβ (Gint4.T) </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">STAT-3 siRNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">U87MG and T98G glioblastoma cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Reduction of anti-apoptotic factors PARP and BCL-xL, inducing cell death in two glioblastoma lineages in vitro. Reduction of tumor growth rate and pro-tumoral factors in a xenograft mouse model of glioblastoma</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B57-pharmaceutics-11-00684" ref-type="bibr">57</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HER-2 sense& antisense bivalent </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EGFR siRNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">BT474 and SKBR3 breast cancer cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Downregulation of EGFR in vitro and suppression of xenografted tumor growth in vivo</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B58-pharmaceutics-11-00684" ref-type="bibr">58</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">bivalent HER-2-HER-3 </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EGFR siRNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">BT474 and SKBR3 breast cancer cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Reduction of HER receptors, induction of cell cycle arrest and apoptosis in vitro and inhibition of tumor growth in vivo</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B59-pharmaceutics-11-00684" ref-type="bibr">59</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MUC1 multiaptamer </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">BCL-2 siRNA and Doxorubicin (DOX)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MCF-7 breast cancer cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">More efficiency in delivering doxorubicin. BCL-2 siRNA acted synergistically with DOX increasing the sensitivity of cells for apoptosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B60-pharmaceutics-11-00684" ref-type="bibr">60</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">epithelial cell adhesion molecule (EpCAM)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Doxorubicin (DOX)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EpCAM positive HT29 colorectal cancer cells; SCOV-3 ovarian cancer cell line and T47D breast cancer cell line</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Tumor growth control overcoming chemoresistance in both tumorsphere formation assay and in xenotransplanted mice</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B61-pharmaceutics-11-00684" ref-type="bibr">61</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EpCAM</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Survivin RNAi </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EpCAM positive HT29 colorectal cancer cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">The combination of the surivin downregulation with the action of 5-fluorouacil cytotoxic chemotherapeutic could increase the lethality of colorectal cancer stem cells, as well as tumor control, in colorectal cancer xenograph model</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B62-pharmaceutics-11-00684" ref-type="bibr">62</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HER-3ECD </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Doxorubicin (DOX)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MCF-7 HER3+ and BT 474HER3+ breast cancer cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Increase in the survival rate in a xenograft mouse model. Reduction of liver and cardio toxicity after chemotherapy when compared to the formulation without aptamer</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B63-pharmaceutics-11-00684" ref-type="bibr">63</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">cMET </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Doxorubicin (DOX)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCI-H1838 lung cancer cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Better efficiency in the uptake by the target cell and a precise subcellular distribution of DOX to the cell nucleus, after endocytosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B64-pharmaceutics-11-00684" ref-type="bibr">64</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anti A-172 cells aptamer</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Doxorubicin (DOX)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Glioblastoma multiforme tumor cells A-172</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Selective binding and inactivation of A-172 glioblastoma cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B65-pharmaceutics-11-00684" ref-type="bibr">65</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nucleolin (AS1411)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Paclitaxel (PCX)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Glioblastoma U87 MG cells and neo-vascular endothelial cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Improvement of cell uptake and internalization, spheroid tumor penetration and cell growth inhibition. Enhanced accumulation of AS1411-PGG-PTX nanoconjugates in glioblastoma cells, retention time in circulation penetration in glioblastoma tumors. Increase survival of the tumor bearing mice and an efficient PCX delivery to glioblastoma tissue with consequently strong cytotoxic effect</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B66-pharmaceutics-11-00684" ref-type="bibr">66</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EpCAM </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PLK1, BCL2, and STAT3 siRNA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCC RbC 51 retinoblastoma cells; MCF-7 breast cancer cells; Müller Glial Mio M1 cells; PMI 2650 Head and Neck cancer cells and HepG2 Hepatocellular cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cell death induction and tumor reduction on RB xenografts tumor model</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B67-pharmaceutics-11-00684" ref-type="bibr">67</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HL-1 (anti Maver-I cells)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cytarabine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Maver-I lymphoma cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Aptamer treatment was able to sensitize synergistically lymphoma cells in S-phase to lethal effect of cytarabine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B68-pharmaceutics-11-00684" ref-type="bibr">68</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Waz (anti-transferrin receptor—TfR)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Auristatin modified toxins</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Panc-1, MIA PaCa-2, and BxPC3 Pancreas Ductal Adenocarcinoma cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Aptamer conjugates demonstrated to be toxic to cell lines in different extends</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B69-pharmaceutics-11-00684" ref-type="bibr">69</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EGFR</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Auristatin modified toxins</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Panc-1, MIA PaCa-2 and BxPC3 Pancreas Ductal Adenocarcinoma cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Aptamer-toxin conjugates demonstrated to be toxic to cell lines in different extends</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B69-pharmaceutics-11-00684" ref-type="bibr">69</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MUC1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">cMET siRNA and Docetaxel</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SKBR3 breast cancer cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nanoparticle chitosan increased specificity and cellular uptake of the nanoconjugate and successful silencing was confirmed</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B70-pharmaceutics-11-00684" ref-type="bibr">70</xref>]</td></tr></tbody></table></table-wrap></floats-group></pmc><affiliations><list></list><tree><noCountry><name sortKey="Bonacossa De Almeida, Carlos Eduardo" sort="Bonacossa De Almeida, Carlos Eduardo" uniqKey="Bonacossa De Almeida C" first="Carlos Eduardo" last="Bonacossa De Almeida">Carlos Eduardo Bonacossa De Almeida</name><name sortKey="Da Costa Neves, Patricia Cristina" sort="Da Costa Neves, Patricia Cristina" uniqKey="Da Costa Neves P" first="Patrícia Cristina" last="Da Costa Neves">Patrícia Cristina Da Costa Neves</name><name sortKey="Dinis Ano Bom, Ana Paula" sort="Dinis Ano Bom, Ana Paula" uniqKey="Dinis Ano Bom A" first="Ana Paula" last="Dinis Ano Bom">Ana Paula Dinis Ano Bom</name><name sortKey="Missailidis, Sotiris" sort="Missailidis, Sotiris" uniqKey="Missailidis S" first="Sotiris" last="Missailidis">Sotiris Missailidis</name><name sortKey="Silva, Dilson" sort="Silva, Dilson" uniqKey="Silva D" first="Dilson" last="Silva">Dilson Silva</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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