Designing synergistic crystallization inhibitors: Bile salt derivatives of cellulose with enhanced hydrophilicity

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dc.contributor.authorNovo, Diana C.en
dc.contributor.authorGao, Chengzheen
dc.contributor.authorQi, Qingqingen
dc.contributor.authorMosquera-Giraldo, Laura I.en
dc.contributor.authorSpiering, Glenn A.en
dc.contributor.authorMoore, Robert B.en
dc.contributor.authorTaylor, Lynne S.en
dc.contributor.authorEdgar, Kevin J.en
dc.date.accessioned2022-08-02T18:36:21Zen
dc.date.available2022-08-02T18:36:21Zen
dc.date.issued2022-09-15en
dc.date.updated2022-08-02T18:05:17Zen
dc.description.abstractCrystallization inhibitors in amorphous solid dispersions (ASD) enable metastable supersaturated drug solutions that persist for a physiologically relevant time. Olefin cross-metathesis (CM) has successfully provided multifunctional cellulose-based derivatives as candidate ASD matrix polymers. In proof of concept studies, we prepared hydrophobic bile salt/cellulose adducts by CM with naturally occurring bile salts. We hypothesized that increased hydrophilicity would enhance the ability of these conjugates to maximize bioactive supersaturation. Their selective preparation presents a significant synthetic challenge, given polysaccharide reactivity and polysaccharide and bile salt complexity. We prepared such derivatives using a more hydrophilic hydroxypropyl cellulose (HPC) backbone, employing a pent-4-enyl tether (Pen) for appending bile acids. We probed structure-property relationships by varying the nature and degree of substitution of the bile acid substituent (lithocholic or deoxycholic acid). These conjugates are indeed synergistic inhibitors, as demonstrated with the fast-crystallizing prostate cancer drug, enzalutamide. The lithocholic acid methyl ester derivative, AcrMLC-PenHHPCPen (0.64), increased induction time 68 fold vs. drug alone.en
dc.description.versionAccepted versionen
dc.format.mimetypeapplication/pdfen
dc.identifier119680 (Article number)en
dc.identifier.doihttps://doi.org/10.1016/j.carbpol.2022.119680en
dc.identifier.eissn1879-1344en
dc.identifier.issn0144-8617en
dc.identifier.orcidEdgar, Kevin [0000-0002-9459-9477]en
dc.identifier.otherS0144-8617(22)00585-9 (PII)en
dc.identifier.pmid35725174en
dc.identifier.urihttp://hdl.handle.net/10919/111428en
dc.identifier.volume292en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/35725174en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectAmorphous solid dispersionen
dc.subjectBile-saltsen
dc.subjectCelluloseen
dc.subjectChemoselectivityen
dc.subjectEnzalutamideen
dc.subjectOlefin cross-metathesisen
dc.subjectUrologic Diseasesen
dc.subjectCanceren
dc.subject.meshHumansen
dc.subject.meshBile Acids and Saltsen
dc.subject.meshCelluloseen
dc.subject.meshCrystallizationen
dc.subject.meshSolubilityen
dc.subject.meshMaleen
dc.subject.meshHydrophobic and Hydrophilic Interactionsen
dc.titleDesigning synergistic crystallization inhibitors: Bile salt derivatives of cellulose with enhanced hydrophilicityen
dc.title.serialCarbohydrate Polymersen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherJournal Articleen
dcterms.dateAccepted2022-05-28en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Natural Resources & Environmenten
pubs.organisational-group/Virginia Tech/Natural Resources & Environment/Sustainable Biomaterialsen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Natural Resources & Environment/CNRE T&R Facultyen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciences/Durelle Scotten

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