Enhanced blood-brain-barrier penetrability and tumor-targeting efficiency by peptide-functionalized poly(amidoamine) dendrimer for the therapy of gliomas
Identifieur interne : 000B72 ( Ncbi/Merge ); précédent : 000B71; suivant : 000B73Enhanced blood-brain-barrier penetrability and tumor-targeting efficiency by peptide-functionalized poly(amidoamine) dendrimer for the therapy of gliomas
Auteurs : Changliang Liu [République populaire de Chine] ; Zijian Zhao [République populaire de Chine] ; Houqian Gao [République populaire de Chine] ; Iman Rostami [République populaire de Chine] ; Qing You [République populaire de Chine] ; Xinru Jia [République populaire de Chine] ; Chen Wang [République populaire de Chine] ; Ling Zhu [République populaire de Chine] ; Yanlian Yang [République populaire de Chine]Source :
- Nanotheranostics [ 2206-7418 ] ; 2019.
Abstract
Glioblastoma is one of the most common primary tumor types of central nervous system (CNS) with high malignance and lethality. Although many treatment options are currently available, the therapy of brain cancers remains challenging because of blood-brain-barrier (BBB) which prevents most of the chemotherapeutics into the CNS. In this work, a poly(amidoamine) dendrimer-based carrier was fabricated and modified with angiopep-2 (Ang2) peptide that has been demonstrated to bind to low density lipoprotein receptor-relative protein-1 (LRP1) on the endothelial cells of BBB and could therefore induce BBB penetration of the carrier. To improve tumor-targeting effect towards the glioma sites, the dendrimer was simultaneously functionalized with an epidermal growth factor receptor (EGFR)-targeting peptide (EP-1) which was screened from a “one-bead one-compound” (OBOC) combinatorial library. EP-1 peptide was demonstrated to have high affinity and specificity to EGFR at both the molecular and cellular levels. The dual-targeting dendrimer exhibited outstanding BBB penetrability and glioma targeting efficiency both
Url:
DOI: 10.7150/ntno.38954
PubMed: 31687320
PubMed Central: 6821994
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Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">University of Chinese Academy of Sciences, Beijing 100049, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>University of Chinese Academy of Sciences, Beijing 100049</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Zhao, Zijian" sort="Zhao, Zijian" uniqKey="Zhao Z" first="Zijian" last="Zhao">Zijian Zhao</name><affiliation wicri:level="1"><nlm:aff id="A1">CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Gao, Houqian" sort="Gao, Houqian" uniqKey="Gao H" first="Houqian" last="Gao">Houqian Gao</name><affiliation wicri:level="1"><nlm:aff id="A1">CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">University of Chinese Academy of Sciences, Beijing 100049, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>University of Chinese Academy of Sciences, Beijing 100049</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Rostami, Iman" sort="Rostami, Iman" uniqKey="Rostami I" first="Iman" last="Rostami">Iman Rostami</name><affiliation wicri:level="1"><nlm:aff id="A1">CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="You, Qing" sort="You, Qing" uniqKey="You Q" first="Qing" last="You">Qing You</name><affiliation wicri:level="1"><nlm:aff id="A1">CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">University of Chinese Academy of Sciences, Beijing 100049, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>University of Chinese Academy of Sciences, Beijing 100049</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Jia, Xinru" sort="Jia, Xinru" uniqKey="Jia X" first="Xinru" last="Jia">Xinru Jia</name><affiliation wicri:level="4"><nlm:aff id="A3">Department of Chemistry, Peking University, Beijing 100871, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Chemistry, Peking University, Beijing 100871</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName><orgName type="university">Université de Pékin</orgName><placeName><settlement type="city">Pékin</settlement><region type="capitale">Pékin</region></placeName></affiliation></author><author><name sortKey="Wang, Chen" sort="Wang, Chen" uniqKey="Wang C" first="Chen" last="Wang">Chen Wang</name><affiliation wicri:level="1"><nlm:aff id="A1">CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">University of Chinese Academy of Sciences, Beijing 100049, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>University of Chinese Academy of Sciences, Beijing 100049</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Zhu, Ling" sort="Zhu, Ling" uniqKey="Zhu L" first="Ling" last="Zhu">Ling Zhu</name><affiliation wicri:level="1"><nlm:aff id="A1">CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Yang, Yanlian" sort="Yang, Yanlian" uniqKey="Yang Y" first="Yanlian" last="Yang">Yanlian Yang</name><affiliation wicri:level="1"><nlm:aff id="A1">CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">University of Chinese Academy of Sciences, Beijing 100049, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>University of Chinese Academy of Sciences, Beijing 100049</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author></analytic><series><title level="j">Nanotheranostics</title><idno type="eISSN">2206-7418</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>Glioblastoma is one of the most common primary tumor types of central nervous system (CNS) with high malignance and lethality. Although many treatment options are currently available, the therapy of brain cancers remains challenging because of blood-brain-barrier (BBB) which prevents most of the chemotherapeutics into the CNS. In this work, a poly(amidoamine) dendrimer-based carrier was fabricated and modified with angiopep-2 (Ang2) peptide that has been demonstrated to bind to low density lipoprotein receptor-relative protein-1 (LRP1) on the endothelial cells of BBB and could therefore induce BBB penetration of the carrier. To improve tumor-targeting effect towards the glioma sites, the dendrimer was simultaneously functionalized with an epidermal growth factor receptor (EGFR)-targeting peptide (EP-1) which was screened from a “one-bead one-compound” (OBOC) combinatorial library. EP-1 peptide was demonstrated to have high affinity and specificity to EGFR at both the molecular and cellular levels. The dual-targeting dendrimer exhibited outstanding BBB penetrability and glioma targeting efficiency both <italic>in vitro</italic> and <italic>in vivo</italic>, which strikingly enhanced the anti-gliomas effect of the drugs and prolonged the survival of gliomas-bearing mice. These results show the potential of the dual-targeting dendrimer-based carrier in the therapy of gliomas through enhancing BBB penetrability and tumor targeting.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Goodenberger, Ml" uniqKey="Goodenberger M">ML Goodenberger</name></author><author><name sortKey="Jenkins, Rb" uniqKey="Jenkins R">RB Jenkins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tan, Z" uniqKey="Tan Z">Z Tan</name></author><author><name sortKey="Song, L" uniqKey="Song L">L Song</name></author><author><name sortKey="Wu, W" uniqKey="Wu W">W Wu</name></author><author><name sortKey="Zhou, Y" uniqKey="Zhou Y">Y Zhou</name></author><author><name sortKey="Zhu, J" uniqKey="Zhu J">J Zhu</name></author><author><name sortKey="Wu, G" uniqKey="Wu G">G Wu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Meir, Eg" uniqKey="Van Meir E">EG Van 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Nanotheranostics</journal-id><journal-id journal-id-type="iso-abbrev">Nanotheranostics</journal-id><journal-id journal-id-type="publisher-id">ntno</journal-id><journal-title-group><journal-title>Nanotheranostics</journal-title></journal-title-group><issn pub-type="epub">2206-7418</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">31687320</article-id><article-id pub-id-type="pmc">6821994</article-id><article-id pub-id-type="doi">10.7150/ntno.38954</article-id><article-id pub-id-type="publisher-id">ntnov03p0311</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Paper</subject></subj-group></article-categories><title-group><article-title>Enhanced blood-brain-barrier penetrability and tumor-targeting efficiency by peptide-functionalized poly(amidoamine) dendrimer for the therapy of gliomas</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Changliang</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="author-notes" rid="FNA_star">*</xref></contrib><contrib contrib-type="author"><name><surname>Zhao</surname><given-names>Zijian</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FNA_star">*</xref></contrib><contrib contrib-type="author"><name><surname>Gao</surname><given-names>Houqian</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>Rostami</surname><given-names>Iman</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>You</surname><given-names>Qing</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>Jia</surname><given-names>Xinru</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Chen</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="corresp" rid="FNA_envelop">✉</xref></contrib><contrib contrib-type="author"><name><surname>Zhu</surname><given-names>Ling</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="corresp" rid="FNA_envelop">✉</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Yanlian</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="corresp" rid="FNA_envelop">✉</xref></contrib></contrib-group><aff id="A1"><label>1</label>CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China</aff><aff id="A2"><label>2</label>University of Chinese Academy of Sciences, Beijing 100049, China</aff><aff id="A3"><label>3</label>Department of Chemistry, Peking University, Beijing 100871, China</aff><author-notes><corresp id="FNA_envelop">✉ Corresponding authors: E-mail: <email>wangch@nanoctr.cn</email>, <email>zhul@nanoctr.cn</email>, <email>yangyl@nanoctr.cn</email></corresp><fn fn-type="equal" id="FNA_star"><p><sup>*</sup>These authors contributed equally to this paper.</p></fn><fn fn-type="COI-statement"><p>Competing Interests: The authors have declared that no competing interest exists.</p></fn></author-notes><pub-date pub-type="collection"><year>2019</year></pub-date><pub-date pub-type="epub"><day>19</day><month>9</month><year>2019</year></pub-date><volume>3</volume><issue>4</issue><fpage>311</fpage><lpage>330</lpage><history><date date-type="received"><day>4</day><month>8</month><year>2019</year></date><date date-type="accepted"><day>14</day><month>9</month><year>2019</year></date></history><permissions><copyright-statement>© The author(s)</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>This is an open access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">https://creativecommons.org/licenses/by/4.0/</ext-link>). See <ext-link ext-link-type="uri" xlink:href="http://ivyspring.com/terms">http://ivyspring.com/terms</ext-link> for full terms and conditions.</license-p></license></permissions><abstract><p>Glioblastoma is one of the most common primary tumor types of central nervous system (CNS) with high malignance and lethality. Although many treatment options are currently available, the therapy of brain cancers remains challenging because of blood-brain-barrier (BBB) which prevents most of the chemotherapeutics into the CNS. In this work, a poly(amidoamine) dendrimer-based carrier was fabricated and modified with angiopep-2 (Ang2) peptide that has been demonstrated to bind to low density lipoprotein receptor-relative protein-1 (LRP1) on the endothelial cells of BBB and could therefore induce BBB penetration of the carrier. To improve tumor-targeting effect towards the glioma sites, the dendrimer was simultaneously functionalized with an epidermal growth factor receptor (EGFR)-targeting peptide (EP-1) which was screened from a “one-bead one-compound” (OBOC) combinatorial library. EP-1 peptide was demonstrated to have high affinity and specificity to EGFR at both the molecular and cellular levels. The dual-targeting dendrimer exhibited outstanding BBB penetrability and glioma targeting efficiency both <italic>in vitro</italic> and <italic>in vivo</italic>, which strikingly enhanced the anti-gliomas effect of the drugs and prolonged the survival of gliomas-bearing mice. These results show the potential of the dual-targeting dendrimer-based carrier in the therapy of gliomas through enhancing BBB penetrability and tumor targeting.</p></abstract><kwd-group><kwd>poly(amidoamine) dendrimer</kwd><kwd>central nervous system</kwd><kwd>dual-targeting</kwd><kwd>blood-brain-barrier</kwd><kwd>glioblastoma</kwd></kwd-group></article-meta></front><floats-group><fig id="SC1" position="float"><label>Scheme 1</label><caption><p>(a) Construction of the dual-targeting dendrimer-based drug carrier. Reagents and conditions: (i) H<sub>2</sub>O, room temperature (RT), 30 min; (ii) H<sub>2</sub>O, RT, 30 min; (iii) H<sub>2</sub>O, RT, Argon, 1 h; (iv) H<sub>2</sub>O, RT, Argon, 4 h; (v) stirring in dark place, 24 h. (b) Schematic illustration of glioma targeting therapy across the BBB using the dual-targeting drug delivery system.</p></caption><graphic xlink:href="ntnov03p0311g001"></graphic></fig><fig id="F1" position="float"><label>Figure 1</label><caption><p>Evaluation of the affinity and specificity of peptide EP-1 towards EGFR. (a) Schematic illustration of high-throughput peptide library screening using surface plasmon resonance imaging (SPRi). The synthesized thiol-containing peptides were immobilized on the gold-coated SPRi chip. EGFR was passed through the flow chamber at various concentrations to check its binding with the peptides. (b) Representative SPRi sensorgram shows the binding of EP-1 to different concentrations of EGFR. The <italic>K<sub>D</sub></italic> value was determined to be 1.51 × 10<sup>-9</sup> M using BIAevaluation version 4.1 software (Biacore, Inc.). (c) SPRi binding signals of EP-1 towards EGFR, HSA, Tf, IgG, IgM, HER2, EGF and FGF. Error bars represent the standard deviation (n = 3). **p < 0.01, ***p < 0.001 (Student's t-test). (d) Binding affinity of EP-1 towards EGFR in MDA-MB-231, U87-MG and MCF-7 cell lines. The percentage of cells bound with FITC-labeled EP-1 was detected by flow cytometry. Error bars represent the standard deviation (n = 3). (e) Confocal microscopic images showing the binding of FITC-labeled EP-1 to MDA-MB-231 (upper), U87-MG (middle) and MCF-7 (bottom). Cells were incubated with 40 μM of FITC-EP1 for 1 h. Scale bar: 50 μm.</p></caption><graphic xlink:href="ntnov03p0311g002"></graphic></fig><fig id="F2" position="float"><label>Figure 2</label><caption><p>Characterization of the dendrimer-based carriers. (a) <sup>1</sup>H NMR spectrum of G4 PAMAM (P4, brown), PEGylated PAMAM (P4P, olive), PAMAM-PEG-EP1 (P4PE, green), PAMAM-PEG-Ang2 (P4PA, blue) and PAMAM-PEG-EP1-ANG2 (P4PEA, purple) in D<sub>2</sub>O. (b) Size distribution of the dendrimer-based carriers characterized by DLS. (c-e) Morphological characterization of (c) P4, (d) P4P and (E) P4PEA by TEM.</p></caption><graphic xlink:href="ntnov03p0311g003"></graphic></fig><fig id="F3" position="float"><label>Figure 3</label><caption><p><italic>In vitro</italic> drug release of P4PEAD at pH 5.5 and pH 7.4. Error bars represent the standard deviation (n = 3).</p></caption><graphic xlink:href="ntnov03p0311g004"></graphic></fig><fig id="F4" position="float"><label>Figure 4</label><caption><p><italic>In vitro</italic> evaluation of biocompatibility and antitumor efficacy of the dual-targeting drug delivery system. (a, b) Cytotoxicity of peptides (a) Ang2 and (b) EP-1 to HBMEC and U87-MG cells. (c, d) Cytotoxicity of blank dendrimer-based carriers (P4, P4P and P4PEA), free DOX, P4PD and P4PEAD to (c) HBMEC and (d) U87-MG cells. The cells viability was checked by MTS assay after incubating the cells with different concentrations of peptides, blank carriers and DOX-loaded dendrimer carriers for 48 h. Error bars represent standard deviation (n = 5). (e)<italic> IC<sub>50</sub></italic> values of different DOX-loaded dendrimers fitted by Origin 8.1 software. Error bars represent standard deviation (n = 5). (f) Short-term cytotoxicity of different DOX formulations to HBMEC cells after incubating the cells with the DOX formulations for 3 h at the DOX concentration of 20 μΜ. Error bars represent standard deviation (n=5). *p < 0.1, **p < 0.01, ***p < 0.001 (Student's t-test).</p></caption><graphic xlink:href="ntnov03p0311g005"></graphic></fig><fig id="F5" position="float"><label>Figure 5</label><caption><p>(a, b) Intracellular uptake of different DOX-loaded dendrimers by (a) HBMEC and (b) U87-MG cells detected by flow cytometry. Dendrimers were incubated with the cells for 2 h before flow cytometry measurement. Cells without treatment were used as control. Error bars represent standard deviation (n=5). **p < 0.01, ***p < 0.001, ****p < 0.0001 (Student's t-test). (c, d) Subcellular trafficking of different DOX formulations in (c) HBMEC and (d) U87-MG cells detected by LSCM. Cells were incubated with Cy5.5-labeled different dendrimers for 2 h at the dendrimer concentration of 1 μM. LysoTracker Green DND-26 was used to stain lysosomes at the concentration of 0.1 μM. Hoechst was used to stain nucleus. Scale bar: 50 μm.</p></caption><graphic xlink:href="ntnov03p0311g006"></graphic></fig><fig id="F6" position="float"><label>Figure 6</label><caption><p>Evaluation of the BBB penetration and the dual-targeting efficacy of the DOX-loaded dual-targeting dendrimers. (a, b) Schematic illustration of the <italic>in vitro</italic> BBB model. (a) A monolayer of HBMEC cells were cultured on the transwell inserts, and (b) U87-MG cells were co-cultured. (c) The transport ratio of DOX across the BBB within 3 h. Error bars represent standard deviation (n = 3). *p < 0.05, **p < 0.01, ***p < 0.001 (Student's t-test). (d) The cell viability of U87-MG cells in the co-cultured BBB model. Error bars represent standard deviation (n = 3). *p < 0.05, ***p < 0.001 (Student's t-test). (2) The intracellular uptake of DOX by U87-MG cells after crossing BBB by flow cytometry.</p></caption><graphic xlink:href="ntnov03p0311g007"></graphic></fig><fig id="F7" position="float"><label>Figure 7</label><caption><p>Dual-targeting efficient of the dual-functionalized dendrimer evaluated <italic>in vivo</italic> using glioma-bearing CB-17 SCID mice as model. (a) Dual-targeting effect detected by <italic>in vivo</italic> imaging system after accumulating for 6 h, 12 h, 24 h and 48 h. The glioma-bearing mice were administrated with Cy5.5-labeled dendrimers at a Cy5.5 dose of 2 mg/kg. (b) Glioma-targeting effect of the dual-targeting dendrimer through observing the accumulated Cy5.5-labeled dendrimer in the excised brains at 24 h after administrating. (c) Dual-targeting efficacy was evaluated by calculating the fluorescent intensity accumulated in the brain of the glioma-bearing mice by LiveImaging software.</p></caption><graphic xlink:href="ntnov03p0311g008"></graphic></fig><fig id="F8" position="float"><label>Figure 8</label><caption><p><italic>In vivo</italic> evaluation of the anti-glioma efficacy and the systemic toxicity of the dual-targeting dendrimer. (a) Treatment procedure of the glioma bearing BALB/c nude mice (n = 6). (b) Kaplan-Meier survival curves of different treatment. The Data was recorded after the glioma inoculation. (c) Body weight of the mice during treatment. Error bars represent standard deviation (n = 3).</p></caption><graphic xlink:href="ntnov03p0311g009"></graphic></fig></floats-group></pmc><affiliations><list><country><li>République populaire de Chine</li></country><region><li>Pékin</li></region><settlement><li>Pékin</li></settlement><orgName><li>Université de Pékin</li></orgName></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Liu, Changliang" sort="Liu, Changliang" uniqKey="Liu C" first="Changliang" last="Liu">Changliang Liu</name></noRegion><name sortKey="Gao, Houqian" sort="Gao, Houqian" uniqKey="Gao H" first="Houqian" last="Gao">Houqian Gao</name><name sortKey="Gao, Houqian" sort="Gao, Houqian" uniqKey="Gao H" first="Houqian" last="Gao">Houqian Gao</name><name sortKey="Jia, Xinru" sort="Jia, Xinru" uniqKey="Jia X" first="Xinru" last="Jia">Xinru Jia</name><name sortKey="Liu, Changliang" sort="Liu, Changliang" uniqKey="Liu C" first="Changliang" last="Liu">Changliang Liu</name><name sortKey="Rostami, Iman" sort="Rostami, Iman" uniqKey="Rostami I" first="Iman" last="Rostami">Iman Rostami</name><name sortKey="Wang, Chen" sort="Wang, Chen" uniqKey="Wang C" first="Chen" last="Wang">Chen Wang</name><name sortKey="Wang, Chen" sort="Wang, Chen" uniqKey="Wang C" first="Chen" last="Wang">Chen Wang</name><name sortKey="Yang, Yanlian" sort="Yang, Yanlian" uniqKey="Yang Y" first="Yanlian" last="Yang">Yanlian Yang</name><name sortKey="Yang, Yanlian" sort="Yang, Yanlian" uniqKey="Yang Y" first="Yanlian" last="Yang">Yanlian Yang</name><name sortKey="You, Qing" sort="You, Qing" uniqKey="You Q" first="Qing" last="You">Qing You</name><name sortKey="You, Qing" sort="You, Qing" uniqKey="You Q" first="Qing" last="You">Qing You</name><name sortKey="Zhao, Zijian" sort="Zhao, Zijian" uniqKey="Zhao Z" first="Zijian" last="Zhao">Zijian Zhao</name><name sortKey="Zhu, Ling" sort="Zhu, Ling" uniqKey="Zhu L" first="Ling" last="Zhu">Ling Zhu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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