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Call\u2014","doi-asserted-by":"publisher","award":["LA\/P\/0045\/2020","UIDB\/00511\/2020","UIDP\/00511\/2020","NORTE-01-0145-FEDER-000054","EXPL\/NAN-MAT\/0209\/2021","CEECIND\/01741\/2021","CEECINST\/00049\/2018","SFRH\/BD\/129312\/2017","COVID\/BD\/151869\/2021"],"award-info":[{"award-number":["LA\/P\/0045\/2020","UIDB\/00511\/2020","UIDP\/00511\/2020","NORTE-01-0145-FEDER-000054","EXPL\/NAN-MAT\/0209\/2021","CEECIND\/01741\/2021","CEECINST\/00049\/2018","SFRH\/BD\/129312\/2017","COVID\/BD\/151869\/2021"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Membranes"],"abstract":"<jats:p>Bortezomib (BTZ) is a potent proteasome inhibitor currently being used to treat multiple myeloma. However, its high toxicity and resistance to therapy severely limit the treatment outcomes. Drug\u2013membrane interactions have a crucial role in drugs\u2019 behavior in vivo, affecting their bioavailability and pharmacological activity. Additionally, drugs\u2019 toxicity often occurs due to their effects on the cell membranes. Therefore, studying BTZ\u2019s interactions with cell membranes may explain the limitations of its therapy. Due to the cell membranes\u2019 complexity, lipid vesicles were proposed here as biomembrane models, focusing on the membrane\u2019s main constituents. Two models with distinct composition and complexity were used, one composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and the other containing DMPC, cholesterol (Chol), and sphingomyelin (SM). BTZ\u2019s interactions with the models were evaluated regarding the drugs\u2019 lipophilicity, preferential location, and effects on the membrane\u2019s physical state. The studies were conducted at different pH values (7.4 and 6.5) to mimic the normal blood circulation and the intestinal environment, respectively. BTZ revealed a high affinity for the membranes, which proved to be dependent on the drug-ionization state and the membrane complexity. Furthermore, BTZ\u2019s interactions with the cell membranes was proven to induce changes in the membrane fluidity. This may be associated with its resistance to therapy, since the activity of efflux transmembrane proteins is dependent on the membrane\u2019s fluidity.<\/jats:p>","DOI":"10.3390\/membranes12090823","type":"journal-article","created":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T00:22:48Z","timestamp":1661300568000},"page":"823","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Interaction of Bortezomib with Cell Membranes Regulates Its Toxicity and Resistance to Therapy"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2428-7520","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Ramalho","sequence":"first","affiliation":[{"name":"LEPABE\u2014Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"},{"name":"ALiCE\u2014Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6918-8775","authenticated-orcid":false,"given":"St\u00e9phanie","family":"Andrade","sequence":"additional","affiliation":[{"name":"LEPABE\u2014Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"},{"name":"ALiCE\u2014Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9841-3967","authenticated-orcid":false,"given":"Joana Ang\u00e9lica","family":"Loureiro","sequence":"additional","affiliation":[{"name":"LEPABE\u2014Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"},{"name":"ALiCE\u2014Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8505-3432","authenticated-orcid":false,"given":"Maria Carmo","family":"Pereira","sequence":"additional","affiliation":[{"name":"LEPABE\u2014Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"},{"name":"ALiCE\u2014Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ria, R., and Vacca, A. 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