Rapamycin-Loaded Lipid Nanocapsules Induce Selective Inhibition of the mTORC1-Signaling Pathway in Glioblastoma Cells
Inhibition of the PI3K/Akt/mTOR signaling pathway represents a potential issue for the treatment of cancer, including glioblastoma. As such, rapamycin that inhibits the mechanistic target of rapamycin (mTOR), the downstream effector of this signaling pathway, is of great interest. However, clinical...
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| Veröffentlicht in: | Frontiers in bioengineering and biotechnology 2021-02, Vol.8, p.602998-602998 |
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| creator | Séhédic, Delphine Roncali, Loris Djoudi, Amel Buchtova, Nela Avril, Sylvie Chérel, Michel Boury, Frank Lacoeuille, Franck Hindré, François Garcion, Emmanuel |
| description | Inhibition of the PI3K/Akt/mTOR signaling pathway represents a potential issue for the treatment of cancer, including glioblastoma. As such, rapamycin that inhibits the mechanistic target of rapamycin (mTOR), the downstream effector of this signaling pathway, is of great interest. However, clinical development of rapamycin has floundered due to the lack of a suitable formulation of delivery systems. In the present study, a novel method for the formulation of safe rapamycin nanocarriers is investigated. A phase inversion process was adapted to prepare lipid nanocapsules (LNCs) loaded with the lipophilic and temperature sensitive rapamycin. Rapamycin-loaded LNCs (LNC-rapa) are ~110 nm in diameter with a low polydispersity index ( |
| doi_str_mv | 10.3389/fbioe.2020.602998 |
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. Nevertheless, it demonstrated the selective inhibition of the phosphorylation of mTORC1 signaling pathway on Ser2448 at a concentration of 1 μM rapamycin in serum-free medium. Interestingly, cells cultivated in normoxia (21% O
) seem to be more sensitive to mTOR inhibition by rapamycin than those cultivated in hypoxia (0.4% O
). Finally, we also established that mTOR phosphorylation inhibition by LNC-rapa induced a negative feedback through the activation of Akt phosphorylation. This phenomenon was more noticeable after stabilization of HIF-1α in hypoxia.</description><identifier>ISSN: 2296-4185</identifier><identifier>EISSN: 2296-4185</identifier><identifier>DOI: 10.3389/fbioe.2020.602998</identifier><identifier>PMID: 33718332</identifier><language>eng</language><publisher>Switzerland: Frontiers</publisher><subject>Akt ; Bioengineering and Biotechnology ; Cancer ; Cellular Biology ; hypoxia ; Life Sciences ; mTOR ; nanoparticles ; Pharmaceutical sciences ; radiation ; rapamycin</subject><ispartof>Frontiers in bioengineering and biotechnology, 2021-02, Vol.8, p.602998-602998</ispartof><rights>Copyright © 2021 Séhédic, Roncali, Djoudi, Buchtova, Avril, Chérel, Boury, Lacoeuille, Hindré and Garcion.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>Copyright © 2021 Séhédic, Roncali, Djoudi, Buchtova, Avril, Chérel, Boury, Lacoeuille, Hindré and Garcion. 2021 Séhédic, Roncali, Djoudi, Buchtova, Avril, Chérel, Boury, Lacoeuille, Hindré and Garcion</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c502t-e271902289f7b7304772671503cc65d56e28a87d4a2916f9829804a1921b6e443</citedby><cites>FETCH-LOGICAL-c502t-e271902289f7b7304772671503cc65d56e28a87d4a2916f9829804a1921b6e443</cites><orcidid>0000-0002-7070-7664 ; 0000-0002-3457-3988 ; 0000-0003-0887-272X ; 0000-0003-0574-6752</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947795/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947795/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,27926,27927,53793,53795</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33718332$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://inserm.hal.science/inserm-03374695$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Séhédic, Delphine</creatorcontrib><creatorcontrib>Roncali, Loris</creatorcontrib><creatorcontrib>Djoudi, Amel</creatorcontrib><creatorcontrib>Buchtova, Nela</creatorcontrib><creatorcontrib>Avril, Sylvie</creatorcontrib><creatorcontrib>Chérel, Michel</creatorcontrib><creatorcontrib>Boury, Frank</creatorcontrib><creatorcontrib>Lacoeuille, Franck</creatorcontrib><creatorcontrib>Hindré, François</creatorcontrib><creatorcontrib>Garcion, Emmanuel</creatorcontrib><title>Rapamycin-Loaded Lipid Nanocapsules Induce Selective Inhibition of the mTORC1-Signaling Pathway in Glioblastoma Cells</title><title>Frontiers in bioengineering and biotechnology</title><addtitle>Front Bioeng Biotechnol</addtitle><description>Inhibition of the PI3K/Akt/mTOR signaling pathway represents a potential issue for the treatment of cancer, including glioblastoma. As such, rapamycin that inhibits the mechanistic target of rapamycin (mTOR), the downstream effector of this signaling pathway, is of great interest. However, clinical development of rapamycin has floundered due to the lack of a suitable formulation of delivery systems. In the present study, a novel method for the formulation of safe rapamycin nanocarriers is investigated. A phase inversion process was adapted to prepare lipid nanocapsules (LNCs) loaded with the lipophilic and temperature sensitive rapamycin. Rapamycin-loaded LNCs (LNC-rapa) are ~110 nm in diameter with a low polydispersity index (<0.05) and the zeta potential of about -5 mV. The encapsulation efficiency, determined by spectrophotometry conjugated with filtration/exclusion, was found to be about 69%, which represents 0.6 wt% of loading capacity. Western blot analysis showed that LNC-rapa do not act synergistically with X-ray beam radiation in U87MG glioblastoma model
. Nevertheless, it demonstrated the selective inhibition of the phosphorylation of mTORC1 signaling pathway on Ser2448 at a concentration of 1 μM rapamycin in serum-free medium. Interestingly, cells cultivated in normoxia (21% O
) seem to be more sensitive to mTOR inhibition by rapamycin than those cultivated in hypoxia (0.4% O
). Finally, we also established that mTOR phosphorylation inhibition by LNC-rapa induced a negative feedback through the activation of Akt phosphorylation. This phenomenon was more noticeable after stabilization of HIF-1α in hypoxia.</description><subject>Akt</subject><subject>Bioengineering and Biotechnology</subject><subject>Cancer</subject><subject>Cellular Biology</subject><subject>hypoxia</subject><subject>Life Sciences</subject><subject>mTOR</subject><subject>nanoparticles</subject><subject>Pharmaceutical sciences</subject><subject>radiation</subject><subject>rapamycin</subject><issn>2296-4185</issn><issn>2296-4185</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNpdks1u1DAUhSMEolXpA7BBXrIgg3_i2N4gVaPSjhRR1Ja1dWM7E1eJPcTJoHl7Mk2pWla27j3ns699suwjwSvGpPra1D66FcUUr0pMlZJvslNKVZkXRPK3L_Yn2XlKDxhjQrngkr7PThgTRDJGT7PpFnbQH4wPeRXBOosqv_MW_YAQDezS1LmENsFOxqE71zkz-r2bC62v_ehjQLFBY-tQf39zuyb5nd8G6HzYop8wtn_ggHxAV52PdQdpjD2gteu69CF710CX3PnTepb9-n55v77Oq5urzfqiyg3HdMwdFURhSqVqRC0YLoSgpSAcM2NKbnnpqAQpbAFUkbJRkiqJCyCKkrp0RcHOss3CtREe9G7wPQwHHcHrx0IcthqG0ZvOaWEkIQQbYRpWFGCVZFbWzAhluRBGzKxvC2s31b2zxoVxgO4V9HUn-FZv414LNd9b8RnwZQG0_9muLyrtQ3JDr_H8M0Wp-J7M8s9P5w3x9-TSqHufzPx6EFyckqYck0JIQo9SskjNEFMaXPOMJ1gfw6Ifw6KPYdFLWGbPp5fjPDv-RYP9BQg2umg</recordid><startdate>20210225</startdate><enddate>20210225</enddate><creator>Séhédic, Delphine</creator><creator>Roncali, Loris</creator><creator>Djoudi, Amel</creator><creator>Buchtova, Nela</creator><creator>Avril, Sylvie</creator><creator>Chérel, Michel</creator><creator>Boury, Frank</creator><creator>Lacoeuille, Franck</creator><creator>Hindré, François</creator><creator>Garcion, Emmanuel</creator><general>Frontiers</general><general>Frontiers Media S.A</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-7070-7664</orcidid><orcidid>https://orcid.org/0000-0002-3457-3988</orcidid><orcidid>https://orcid.org/0000-0003-0887-272X</orcidid><orcidid>https://orcid.org/0000-0003-0574-6752</orcidid></search><sort><creationdate>20210225</creationdate><title>Rapamycin-Loaded Lipid Nanocapsules Induce Selective Inhibition of the mTORC1-Signaling Pathway in Glioblastoma Cells</title><author>Séhédic, Delphine ; Roncali, Loris ; Djoudi, Amel ; Buchtova, Nela ; Avril, Sylvie ; Chérel, Michel ; Boury, Frank ; Lacoeuille, Franck ; Hindré, François ; Garcion, Emmanuel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c502t-e271902289f7b7304772671503cc65d56e28a87d4a2916f9829804a1921b6e443</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Akt</topic><topic>Bioengineering and Biotechnology</topic><topic>Cancer</topic><topic>Cellular Biology</topic><topic>hypoxia</topic><topic>Life Sciences</topic><topic>mTOR</topic><topic>nanoparticles</topic><topic>Pharmaceutical sciences</topic><topic>radiation</topic><topic>rapamycin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Séhédic, Delphine</creatorcontrib><creatorcontrib>Roncali, Loris</creatorcontrib><creatorcontrib>Djoudi, Amel</creatorcontrib><creatorcontrib>Buchtova, Nela</creatorcontrib><creatorcontrib>Avril, Sylvie</creatorcontrib><creatorcontrib>Chérel, Michel</creatorcontrib><creatorcontrib>Boury, Frank</creatorcontrib><creatorcontrib>Lacoeuille, Franck</creatorcontrib><creatorcontrib>Hindré, François</creatorcontrib><creatorcontrib>Garcion, Emmanuel</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Frontiers in bioengineering and biotechnology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Séhédic, Delphine</au><au>Roncali, Loris</au><au>Djoudi, Amel</au><au>Buchtova, Nela</au><au>Avril, Sylvie</au><au>Chérel, Michel</au><au>Boury, Frank</au><au>Lacoeuille, Franck</au><au>Hindré, François</au><au>Garcion, Emmanuel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rapamycin-Loaded Lipid Nanocapsules Induce Selective Inhibition of the mTORC1-Signaling Pathway in Glioblastoma Cells</atitle><jtitle>Frontiers in bioengineering and biotechnology</jtitle><addtitle>Front Bioeng Biotechnol</addtitle><date>2021-02-25</date><risdate>2021</risdate><volume>8</volume><spage>602998</spage><epage>602998</epage><pages>602998-602998</pages><issn>2296-4185</issn><eissn>2296-4185</eissn><abstract>Inhibition of the PI3K/Akt/mTOR signaling pathway represents a potential issue for the treatment of cancer, including glioblastoma. 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. Nevertheless, it demonstrated the selective inhibition of the phosphorylation of mTORC1 signaling pathway on Ser2448 at a concentration of 1 μM rapamycin in serum-free medium. Interestingly, cells cultivated in normoxia (21% O
) seem to be more sensitive to mTOR inhibition by rapamycin than those cultivated in hypoxia (0.4% O
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| subjects | Akt Bioengineering and Biotechnology Cancer Cellular Biology hypoxia Life Sciences mTOR nanoparticles Pharmaceutical sciences radiation rapamycin |
| title | Rapamycin-Loaded Lipid Nanocapsules Induce Selective Inhibition of the mTORC1-Signaling Pathway in Glioblastoma Cells |
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