Carcinoma–Astrocyte Gap Junction Interruption by a Dual-Targeted Biomimetic Liposomal System to Attenuate Chemoresistance and Treat Brain Metastasis
Brain metastasis contributes substantially to the morbidity and mortality of various malignancies and is characterized by high chemoresistance. Intracellular communication between carcinoma cells and astrocytes through gap junctions, which are assembled mainly by the connexin 43 protein, has been sh...
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| Veröffentlicht in: | ACS nano 2024-12, Vol.18 (50), p.34107-34125 |
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| creator | Cheng, Yunlong Xu, Minjun Wu, Jing Qian, Kang Yang, Peng Zhou, Lingling Meng, Ran Li, Yixian Wang, Tianying Sheng, Dongyu Wei, Yan Zhang, Qizhi |
| description | Brain metastasis contributes substantially to the morbidity and mortality of various malignancies and is characterized by high chemoresistance. Intracellular communication between carcinoma cells and astrocytes through gap junctions, which are assembled mainly by the connexin 43 protein, has been shown to play a vital role in this process. However, effectively blocking the gap junctions between the two cell types remains extremely challenging because of insufficient drug delivery to the target site. Herein, we designed a connexin blocker-carbenoxolone (CBX)-loaded biomimetic liposomal system with artificial liposomes fused with brain metastatic cell and reactive astrocyte membranes (LAsomes) to block gap junctions and attenuate chemoresistance. LAsomes effectively penetrated the blood–brain barrier via semaphorin 4D (SEMA 4D)Plexin B1 interactions and actively migrated to their source cells via homotypic recognition. Consequently, LAsomes effectively inhibited material transfer and Ca2+ flow from metastatic cells to astrocytes via gap junctions, thereby markedly increasing the sensitivity of metastatic tumor cells to chemotherapy. These results reveal that closing the gap junctions may be a promising therapeutic strategy for intractable brain metastasis. |
| doi_str_mv | 10.1021/acsnano.4c09996 |
| format | Article |
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Intracellular communication between carcinoma cells and astrocytes through gap junctions, which are assembled mainly by the connexin 43 protein, has been shown to play a vital role in this process. However, effectively blocking the gap junctions between the two cell types remains extremely challenging because of insufficient drug delivery to the target site. Herein, we designed a connexin blocker-carbenoxolone (CBX)-loaded biomimetic liposomal system with artificial liposomes fused with brain metastatic cell and reactive astrocyte membranes (LAsomes) to block gap junctions and attenuate chemoresistance. LAsomes effectively penetrated the blood–brain barrier via semaphorin 4D (SEMA 4D)Plexin B1 interactions and actively migrated to their source cells via homotypic recognition. Consequently, LAsomes effectively inhibited material transfer and Ca2+ flow from metastatic cells to astrocytes via gap junctions, thereby markedly increasing the sensitivity of metastatic tumor cells to chemotherapy. These results reveal that closing the gap junctions may be a promising therapeutic strategy for intractable brain metastasis.</description><identifier>ISSN: 1936-0851</identifier><identifier>ISSN: 1936-086X</identifier><identifier>EISSN: 1936-086X</identifier><identifier>DOI: 10.1021/acsnano.4c09996</identifier><identifier>PMID: 39626120</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Astrocytes - drug effects ; Astrocytes - metabolism ; Astrocytes - pathology ; Biomimetic Materials - chemistry ; Biomimetic Materials - pharmacology ; Blood-Brain Barrier - drug effects ; Blood-Brain Barrier - metabolism ; Brain Neoplasms - drug therapy ; Brain Neoplasms - metabolism ; Brain Neoplasms - pathology ; Brain Neoplasms - secondary ; Carbenoxolone - chemistry ; Carbenoxolone - pharmacology ; Cell Line, Tumor ; Drug Resistance, Neoplasm - drug effects ; Gap Junctions - drug effects ; Gap Junctions - metabolism ; Humans ; Liposomes - chemistry ; Mice</subject><ispartof>ACS nano, 2024-12, Vol.18 (50), p.34107-34125</ispartof><rights>2024 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-a217t-4b930709654ea6aaec17fecac4f5f10d9f8022c0ff2b8e45ae26e45ff43409083</cites><orcidid>0000-0002-8544-609X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acsnano.4c09996$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acsnano.4c09996$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27075,27923,27924,56737,56787</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39626120$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cheng, Yunlong</creatorcontrib><creatorcontrib>Xu, Minjun</creatorcontrib><creatorcontrib>Wu, Jing</creatorcontrib><creatorcontrib>Qian, Kang</creatorcontrib><creatorcontrib>Yang, Peng</creatorcontrib><creatorcontrib>Zhou, Lingling</creatorcontrib><creatorcontrib>Meng, Ran</creatorcontrib><creatorcontrib>Li, Yixian</creatorcontrib><creatorcontrib>Wang, Tianying</creatorcontrib><creatorcontrib>Sheng, Dongyu</creatorcontrib><creatorcontrib>Wei, Yan</creatorcontrib><creatorcontrib>Zhang, Qizhi</creatorcontrib><title>Carcinoma–Astrocyte Gap Junction Interruption by a Dual-Targeted Biomimetic Liposomal System to Attenuate Chemoresistance and Treat Brain Metastasis</title><title>ACS nano</title><addtitle>ACS Nano</addtitle><description>Brain metastasis contributes substantially to the morbidity and mortality of various malignancies and is characterized by high chemoresistance. Intracellular communication between carcinoma cells and astrocytes through gap junctions, which are assembled mainly by the connexin 43 protein, has been shown to play a vital role in this process. However, effectively blocking the gap junctions between the two cell types remains extremely challenging because of insufficient drug delivery to the target site. Herein, we designed a connexin blocker-carbenoxolone (CBX)-loaded biomimetic liposomal system with artificial liposomes fused with brain metastatic cell and reactive astrocyte membranes (LAsomes) to block gap junctions and attenuate chemoresistance. LAsomes effectively penetrated the blood–brain barrier via semaphorin 4D (SEMA 4D)Plexin B1 interactions and actively migrated to their source cells via homotypic recognition. Consequently, LAsomes effectively inhibited material transfer and Ca2+ flow from metastatic cells to astrocytes via gap junctions, thereby markedly increasing the sensitivity of metastatic tumor cells to chemotherapy. These results reveal that closing the gap junctions may be a promising therapeutic strategy for intractable brain metastasis.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Astrocytes - drug effects</subject><subject>Astrocytes - metabolism</subject><subject>Astrocytes - pathology</subject><subject>Biomimetic Materials - chemistry</subject><subject>Biomimetic Materials - pharmacology</subject><subject>Blood-Brain Barrier - drug effects</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Brain Neoplasms - drug therapy</subject><subject>Brain Neoplasms - metabolism</subject><subject>Brain Neoplasms - pathology</subject><subject>Brain Neoplasms - secondary</subject><subject>Carbenoxolone - chemistry</subject><subject>Carbenoxolone - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Gap Junctions - drug effects</subject><subject>Gap Junctions - metabolism</subject><subject>Humans</subject><subject>Liposomes - chemistry</subject><subject>Mice</subject><issn>1936-0851</issn><issn>1936-086X</issn><issn>1936-086X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc9O3DAQh60KVP60596Qj0hVwHYSJz4uS0upFnHoInGLZr3j1iixg-0c9tZ3qNQH7JPgsgs3TjOj-eaT7B8hnzg740zwc9DRgfNnlWZKKfmOHHJVyoK18n7vta_5ATmK8YGxumkb-Z4clEoKyQU7JH_nELR1foB_v__MYgpebxLSKxjp98npZL2j1y5hCNP4PKw2FOjlBH2xhPATE67phfWDHTBZTRd29DHLevpjExMONHk6SwndBNk6_4WDDxhtTOA0UnBrugwIiV4EsI7eYIK8yvsPZN9AH_Hjrh6Tu69flvNvxeL26no-WxQgeJOKaqVK1jAl6wpBAqDmjUENujK14WytTMuE0MwYsWqxqgGFzMWYqqyYYm15TE633jH4xwlj6gYbNfY9OPRT7EqeOVFt0fMtqoOPMaDpxmAHCJuOs-5_GN0ujG4XRr442cmn1YDrV_7l9zPweQvky-7BT8Hlt76pewIhopn9</recordid><startdate>20241217</startdate><enddate>20241217</enddate><creator>Cheng, Yunlong</creator><creator>Xu, Minjun</creator><creator>Wu, Jing</creator><creator>Qian, Kang</creator><creator>Yang, Peng</creator><creator>Zhou, Lingling</creator><creator>Meng, Ran</creator><creator>Li, Yixian</creator><creator>Wang, Tianying</creator><creator>Sheng, Dongyu</creator><creator>Wei, Yan</creator><creator>Zhang, Qizhi</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><orcidid>https://orcid.org/0000-0002-8544-609X</orcidid></search><sort><creationdate>20241217</creationdate><title>Carcinoma–Astrocyte Gap Junction Interruption by a Dual-Targeted Biomimetic Liposomal System to Attenuate Chemoresistance and Treat Brain Metastasis</title><author>Cheng, Yunlong ; 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Intracellular communication between carcinoma cells and astrocytes through gap junctions, which are assembled mainly by the connexin 43 protein, has been shown to play a vital role in this process. However, effectively blocking the gap junctions between the two cell types remains extremely challenging because of insufficient drug delivery to the target site. Herein, we designed a connexin blocker-carbenoxolone (CBX)-loaded biomimetic liposomal system with artificial liposomes fused with brain metastatic cell and reactive astrocyte membranes (LAsomes) to block gap junctions and attenuate chemoresistance. LAsomes effectively penetrated the blood–brain barrier via semaphorin 4D (SEMA 4D)Plexin B1 interactions and actively migrated to their source cells via homotypic recognition. 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| subjects | Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Astrocytes - drug effects Astrocytes - metabolism Astrocytes - pathology Biomimetic Materials - chemistry Biomimetic Materials - pharmacology Blood-Brain Barrier - drug effects Blood-Brain Barrier - metabolism Brain Neoplasms - drug therapy Brain Neoplasms - metabolism Brain Neoplasms - pathology Brain Neoplasms - secondary Carbenoxolone - chemistry Carbenoxolone - pharmacology Cell Line, Tumor Drug Resistance, Neoplasm - drug effects Gap Junctions - drug effects Gap Junctions - metabolism Humans Liposomes - chemistry Mice |
| title | Carcinoma–Astrocyte Gap Junction Interruption by a Dual-Targeted Biomimetic Liposomal System to Attenuate Chemoresistance and Treat Brain Metastasis |
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