PubMed:31213813 JSONTXT

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dual-functional HER2 aptamer-conjugated, pH-activated mesoporous silica nanocarrier-based drug delivery system provides in vitro synergistic cytotoxicity in HER2-positive breast cancer cells.\nPurpose: As well as functioning as a ligand that is selectively internalized by cells overexpressing human epidermal growth factor receptor-2 (HER2), HApt can exert cytotoxic effects by inducing cross-linking and subsequent translocation of HER2 to cytoplasmic vesicles, such downregulation of HER2 inhibits cell proliferation and induces apoptosis. We aimed to exploit the potential of HApt as both a targeting agent and antagonist to maximize the efficacy of mesoporous silica nanoparticle (MSN)-based drug release systems for HER2-positive breast cancer. Materials and methods: We fabricated novel HApt aptamer-functionalized pH-sensitive β-cyclodextrin (β-CD)-capped doxorubicin (DOX)-loaded mesoporous silica nanoparticles (termed MSN-BM/CD-HApt@DOX) for targeted delivery and selective targeting of HER2-positive cells. MSN-functionalized benzimidazole (MSN-BM) was used to load and achieve pH stimuli-responsive release of the chemotherapeutic agent doxorubicin (DOX). β-cyclodextrin was introduced as a gatekeeper for encapsulated DOX and HApt as a selective HER2-targeting moiety and biotherapeutic agent. Results: Physical and chemical characterizations (FT-IR, XRD, TEM and BET) confirmed successful construction of MSN-BM/CD-HApt@DOX nanoparticles. In vitro release assays verified pH-sensitive DOX release. MSN-BM/CD-HApt@DOX (relative DOX concentration, 3.6 μg/mL) underwent HER2-mediated endocytosis and was more cytotoxic to HER2-positive SKBR3 cells than HER2-negative MCF7 cells. MSN-BM/CD-HApt@DOX also exhibited better uptake and stronger growth inhibition in SKBR3 cells than the control MSN-BM/CD-NCApt@DOX functionalized with a scrambled nucleotide sequence on CD. Overall, intracellular delivery of DOX and the biotherapeutic agent HApt resulted in synergistic cytotoxic effects in HER2-positive cancer cells in comparison to either DOX or HApt alone. Conclusion: MSN-BM/CD-HApt@DOX enables HER2-mediated targeting and biotherapeutic effects as well as pH-responsive DOX drug release, resulting in synergistic cytotoxic effects in HER2-overexpressing cells in vitro. This novel nanocarrier could potentially enable specific targeting to improve the efficacy of chemotherapy for HER2-positive cancer."}

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{"project":"Goldhamster2_Cellosaurus","denotations":[{"id":"T1","span":{"begin":0,"end":1},"obj":"CVCL_6479|Finite_cell_line|Mus musculus"},{"id":"T2","span":{"begin":46,"end":55},"obj":"CVCL_C410|Hybridoma|Mus musculus"},{"id":"T3","span":{"begin":180,"end":186},"obj":"CVCL_E025|Induced_pluripotent_stem_cell|Homo sapiens"},{"id":"T4","span":{"begin":229,"end":230},"obj":"CVCL_6479|Finite_cell_line|Mus musculus"},{"id":"T5","span":{"begin":544,"end":546},"obj":"CVCL_5M23|Cancer_cell_line|Mesocricetus auratus"},{"id":"T6","span":{"begin":594,"end":595},"obj":"CVCL_6479|Finite_cell_line|Mus musculus"},{"id":"T7","span":{"begin":687,"end":690},"obj":"CVCL_9882|Cancer_cell_line|Homo sapiens"},{"id":"T8","span":{"begin":744,"end":750},"obj":"CVCL_E025|Induced_pluripotent_stem_cell|Homo sapiens"},{"id":"T9","span":{"begin":775,"end":777},"obj":"CVCL_5M23|Cancer_cell_line|Mesocricetus 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sapiens"},{"id":"T20","span":{"begin":1058,"end":1060},"obj":"CVCL_S926|Spontaneously_immortalized_cell_line|Lates calcarifer"},{"id":"T21","span":{"begin":1203,"end":1204},"obj":"CVCL_6479|Finite_cell_line|Mus musculus"},{"id":"T22","span":{"begin":1249,"end":1250},"obj":"CVCL_6479|Finite_cell_line|Mus musculus"},{"id":"T23","span":{"begin":1359,"end":1361},"obj":"CVCL_4203|Spontaneously_immortalized_cell_line|Lithobates catesbeiana"},{"id":"T24","span":{"begin":1362,"end":1364},"obj":"CVCL_ZD54|Transformed_cell_line|Homo sapiens"},{"id":"T25","span":{"begin":1371,"end":1374},"obj":"CVCL_E844|Transformed_cell_line|Homo sapiens"},{"id":"T26","span":{"begin":1421,"end":1424},"obj":"CVCL_9882|Cancer_cell_line|Homo sapiens"},{"id":"T27","span":{"begin":1425,"end":1427},"obj":"CVCL_E481|Transformed_cell_line|Homo sapiens"},{"id":"T28","span":{"begin":1425,"end":1427},"obj":"CVCL_S926|Spontaneously_immortalized_cell_line|Lates calcarifer"},{"id":"T29","span":{"begin":1428,"end":1430},"obj":"CVCL_5731|Spontaneously_immortalized_cell_line|Mus musculus"},{"id":"T30","span":{"begin":1428,"end":1430},"obj":"CVCL_W955|Cancer_cell_line|Homo sapiens"},{"id":"T31","span":{"begin":1514,"end":1517},"obj":"CVCL_9882|Cancer_cell_line|Homo sapiens"},{"id":"T32","span":{"begin":1518,"end":1520},"obj":"CVCL_E481|Transformed_cell_line|Homo sapiens"},{"id":"T33","span":{"begin":1518,"end":1520},"obj":"CVCL_S926|Spontaneously_immortalized_cell_line|Lates calcarifer"},{"id":"T34","span":{"begin":1521,"end":1523},"obj":"CVCL_5731|Spontaneously_immortalized_cell_line|Mus musculus"},{"id":"T35","span":{"begin":1521,"end":1523},"obj":"CVCL_W955|Cancer_cell_line|Homo sapiens"},{"id":"T36","span":{"begin":1569,"end":1571},"obj":"CVCL_F566|Transformed_cell_line|Homo sapiens"},{"id":"T37","span":{"begin":1569,"end":1571},"obj":"CVCL_W799|Cancer_cell_line|Homo sapiens"},{"id":"T38","span":{"begin":1649,"end":1654},"obj":"CVCL_0033|Cancer_cell_line|Homo sapiens"},{"id":"T39","span":{"begin":1680,"end":1684},"obj":"CVCL_0031|Cancer_cell_line|Homo sapiens"},{"id":"T40","span":{"begin":1692,"end":1695},"obj":"CVCL_9882|Cancer_cell_line|Homo sapiens"},{"id":"T41","span":{"begin":1696,"end":1698},"obj":"CVCL_E481|Transformed_cell_line|Homo sapiens"},{"id":"T42","span":{"begin":1696,"end":1698},"obj":"CVCL_S926|Spontaneously_immortalized_cell_line|Lates calcarifer"},{"id":"T43","span":{"begin":1699,"end":1701},"obj":"CVCL_5731|Spontaneously_immortalized_cell_line|Mus musculus"},{"id":"T44","span":{"begin":1699,"end":1701},"obj":"CVCL_W955|Cancer_cell_line|Homo sapiens"},{"id":"T45","span":{"begin":1774,"end":1779},"obj":"CVCL_0033|Cancer_cell_line|Homo sapiens"},{"id":"T46","span":{"begin":1803,"end":1806},"obj":"CVCL_9882|Cancer_cell_line|Homo sapiens"},{"id":"T47","span":{"begin":1807,"end":1809},"obj":"CVCL_E481|Transformed_cell_line|Homo sapiens"},{"id":"T48","span":{"begin":1807,"end":1809},"obj":"CVCL_S926|Spontaneously_immortalized_cell_line|Lates calcarifer"},{"id":"T49","span":{"begin":1810,"end":1812},"obj":"CVCL_5731|Spontaneously_immortalized_cell_line|Mus musculus"},{"id":"T50","span":{"begin":1810,"end":1812},"obj":"CVCL_W955|Cancer_cell_line|Homo sapiens"},{"id":"T51","span":{"begin":1843,"end":1844},"obj":"CVCL_6479|Finite_cell_line|Mus musculus"},{"id":"T52","span":{"begin":1878,"end":1880},"obj":"CVCL_5731|Spontaneously_immortalized_cell_line|Mus musculus"},{"id":"T53","span":{"begin":1878,"end":1880},"obj":"CVCL_W955|Cancer_cell_line|Homo sapiens"},{"id":"T54","span":{"begin":2014,"end":2020},"obj":"CVCL_E025|Induced_pluripotent_stem_cell|Homo sapiens"},{"id":"T55","span":{"begin":2082,"end":2085},"obj":"CVCL_9882|Cancer_cell_line|Homo sapiens"},{"id":"T56","span":{"begin":2086,"end":2088},"obj":"CVCL_E481|Transformed_cell_line|Homo sapiens"},{"id":"T57","span":{"begin":2086,"end":2088},"obj":"CVCL_S926|Spontaneously_immortalized_cell_line|Lates calcarifer"},{"id":"T58","span":{"begin":2089,"end":2091},"obj":"CVCL_5731|Spontaneously_immortalized_cell_line|Mus musculus"},{"id":"T59","span":{"begin":2089,"end":2091},"obj":"CVCL_W955|Cancer_cell_line|Homo sapiens"},{"id":"T60","span":{"begin":2410,"end":2416},"obj":"CVCL_E025|Induced_pluripotent_stem_cell|Homo sapiens"}],"text":"A dual-functional HER2 aptamer-conjugated, pH-activated mesoporous silica nanocarrier-based drug delivery system provides in vitro synergistic cytotoxicity in HER2-positive breast cancer cells.\nPurpose: As well as functioning as a ligand that is selectively internalized by cells overexpressing human epidermal growth factor receptor-2 (HER2), HApt can exert cytotoxic effects by inducing cross-linking and subsequent translocation of HER2 to cytoplasmic vesicles, such downregulation of HER2 inhibits cell proliferation and induces apoptosis. We aimed to exploit the potential of HApt as both a targeting agent and antagonist to maximize the efficacy of mesoporous silica nanoparticle (MSN)-based drug release systems for HER2-positive breast cancer. Materials and methods: We fabricated novel HApt aptamer-functionalized pH-sensitive β-cyclodextrin (β-CD)-capped doxorubicin (DOX)-loaded mesoporous silica nanoparticles (termed MSN-BM/CD-HApt@DOX) for targeted delivery and selective targeting of HER2-positive cells. MSN-functionalized benzimidazole (MSN-BM) was used to load and achieve pH stimuli-responsive release of the chemotherapeutic agent doxorubicin (DOX). β-cyclodextrin was introduced as a gatekeeper for encapsulated DOX and HApt as a selective HER2-targeting moiety and biotherapeutic agent. Results: Physical and chemical characterizations (FT-IR, XRD, TEM and BET) confirmed successful construction of MSN-BM/CD-HApt@DOX nanoparticles. In vitro release assays verified pH-sensitive DOX release. MSN-BM/CD-HApt@DOX (relative DOX concentration, 3.6 μg/mL) underwent HER2-mediated endocytosis and was more cytotoxic to HER2-positive SKBR3 cells than HER2-negative MCF7 cells. MSN-BM/CD-HApt@DOX also exhibited better uptake and stronger growth inhibition in SKBR3 cells than the control MSN-BM/CD-NCApt@DOX functionalized with a scrambled nucleotide sequence on CD. Overall, intracellular delivery of DOX and the biotherapeutic agent HApt resulted in synergistic cytotoxic effects in HER2-positive cancer cells in comparison to either DOX or HApt alone. Conclusion: MSN-BM/CD-HApt@DOX enables HER2-mediated targeting and biotherapeutic effects as well as pH-responsive DOX drug release, resulting in synergistic cytotoxic effects in HER2-overexpressing cells in vitro. This novel nanocarrier could potentially enable specific targeting to improve the efficacy of chemotherapy for HER2-positive cancer."}