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These esters were further conjugated to thiolated polyethylene glycols (PEGs), yielding compounds with enhanced water solubility, pendant thiol groups and with variation in the number of methylene groups between the ester and thioether moieties. Hydrogels were subsequently formed via conjugate addition reactions using multi-arm PEG macromers, specifically 8-arm PEG acrylates or vinyl sulphones, alongside thiolated PEG crosslinkers. The primary focus was to elucidate the impact of structural modifications surrounding the thioether ester linker on drug release kinetics. In vitro release studies demonstrated zero-order Ra elution over 7\u201319 days, modulated by gel architecture. Notably, Ra incorporated via \u03b1-thioether ester bonds exhibited significantly faster release than their \u03b2-thioether ester counterparts, with release rate increases of 11% and 31%, respectively, across the gel assemblies examined. This behavior was attributed to the electron-withdrawing effect of the adjacent thioether group, which enhanced ester hydrolysis. Additionally, creating a hydrogel more prone to swelling and degradation (by using the PEG acrylate multi-arm instead of the PEG vinyl sulphone equivalent) increased the overall drug release rate due to higher water uptake within the gel matrix. An alternative strategy involved Ra-based crosslinking, where Ra, di-functionalized with IAA, acted as a crosslinker for the PEG thiol multi-arm molecules. This assembly exhibited a biphasic release profile, initially mimicking the linear zero-order release of Ra mono-iodoacetic ester crosslinked with PEG acrylates, followed by an exponential burst phase. These findings provide critical insights into hydrogel design strategies for tailoring drug release kinetics, paving the way for advanced controlled drug delivery applications.<\/jats:p>","DOI":"10.1177\/08853282251410673","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T14:11:54Z","timestamp":1767708714000},"page":"29-42","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineered zero-order drug release from degradable PEG hydrogels \u2013 A rapamycin case study"],"prefix":"10.1177","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8370-9637","authenticated-orcid":false,"given":"Lage","family":"Ahrenstedt","sequence":"first","affiliation":[{"name":"University of Cape Town"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4200-1538","authenticated-orcid":false,"given":"Anel","family":"Oosthuysen","sequence":"additional","affiliation":[{"name":"University of Cape Town"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9502-4109","authenticated-orcid":false,"given":"Peter","family":"Zilla","sequence":"additional","affiliation":[{"name":"University of Cape Town"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0380-4393","authenticated-orcid":false,"given":"Jaco","family":"Theron","sequence":"additional","affiliation":[{"name":"University of Cape Town"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deon","family":"Bezuidenhout","sequence":"additional","affiliation":[{"name":"University of Cape Town"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/jam.14126"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.119.315185"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00117-3"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.01520"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2016.00104"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.08.031"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1158\/1940-6207.CAPR-20-0383"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/ctr.12361"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.3390\/ph14030217"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2019.02.016"},{"issue":"3","key":"e_1_3_5_12_2","first-page":"317","article-title":"Systemic rapamycin without loading dose for restenosis prevention after coronary bare metal stent implantation","volume":"75","author":"Stojkovic S","year":"2010","unstructured":"Stojkovic S, Ostojic M, Nedeljkovic M, et al. 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