Novo, Diana C.Gao, ChengzheQi, QingqingMosquera-Giraldo, Laura I.Spiering, Glenn A.Moore, Robert B.Taylor, Lynne S.Edgar, Kevin J.2022-08-022022-08-022022-09-150144-8617S0144-8617(22)00585-9 (PII)http://hdl.handle.net/10919/111428Crystallization 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.application/pdfenIn CopyrightAmorphous solid dispersionBile-saltsCelluloseChemoselectivityEnzalutamideOlefin cross-metathesisUrologic DiseasesCancerHumansBile Acids and SaltsCelluloseCrystallizationSolubilityMaleHydrophobic and Hydrophilic InteractionsArticle - Refereed2022-08-02https://doi.org/10.1016/j.carbpol.2022.119680292Edgar, Kevin [0000-0002-9459-9477]357251741879-1344