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In the design, two different oligo(ethylene glycol)\u2010based spacers are linked through a ferulate residue to the backbone hyaluronic acid (\n                    <jats:bold>HA<\/jats:bold>\n                    ) showing a medium molar mass value (i.e., Mw\u2009=\u2009270 kDa). The spacers are designed to differ in the sensitivity to the hydrolytic conditions so that the chemical hydrolysis of ferulate ester bond in\n                    <jats:bold>12a<\/jats:bold>\n                    is assumed to produce the corresponding ferulic acid derivative\n                    <jats:bold>12b<\/jats:bold>\n                    . On the other hand, the same reaction in\n                    <jats:bold>13a<\/jats:bold>\n                    leading to ferulate derivative\n                    <jats:bold>13b<\/jats:bold>\n                    could be accompanied by the hydrolysis of the second ester bond with the release of the selective COX\u20102 inhibitor\n                    <jats:bold>7b<\/jats:bold>\n                    . The COX inhibitory activity of the newly synthesized compounds is evaluated in vitro, and macromolecular ester prodrugs\n                    <jats:bold>12a<\/jats:bold>\n                    and\n                    <jats:bold>13a<\/jats:bold>\n                    are found to be completely inactive together with hydrolysis product\n                    <jats:bold>12b<\/jats:bold>\n                    . Conversely, these in vitro studies reveal the intriguing COX\u20102 inhibitory activity and selectivity of ferulate derivative\n                    <jats:bold>13b<\/jats:bold>\n                    related to macromolecular ester prodrug\n                    <jats:bold>13a<\/jats:bold>\n                    . Therefore, to obtain information on the hydrolysis process in different environments, hydrolysis studies are performed on macromolecular ester prodrug\n                    <jats:bold>13a<\/jats:bold>\n                    by using\n                    <jats:sup>1<\/jats:sup>\n                    H NMR and UHPLC\u2010MS techniques. These studies show that severe hydrolytic conditions (i.e., aqueous NaOH solutions) promote the rapid release of potent and selective COX\u20102 inhibitor\n                    <jats:bold>7b<\/jats:bold>\n                    , whereas in ammonium acetate buffer the release is slower. Overall, these results lead to envision possible applications of the design approach to the development of macromolecular ester prodrugs of all the drug molecules bearing hydroxyl groups in their structures.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202500691","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T11:46:41Z","timestamp":1763466401000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Design, Synthesis, and Biological Characterization of Macromolecular Ester Prodrugs of a Selective Cyclooxygenase\u20102 Inhibitor"],"prefix":"10.1002","volume":"20","author":[{"given":"Mario","family":"Saletti","sequence":"first","affiliation":[{"name":"Dipartimento di Biotecnologie Chimica e Farmacia Universit\u00e0 degli Studi di Siena  Via Aldo Moro 2 53100 Siena Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1387-7875","authenticated-orcid":false,"given":"Marco","family":"Paolino","sequence":"additional","affiliation":[{"name":"Dipartimento di Biotecnologie Chimica e Farmacia Universit\u00e0 degli Studi di Siena  Via Aldo Moro 2 53100 Siena Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3811-744X","authenticated-orcid":false,"given":"Jacopo","family":"Venditti","sequence":"additional","affiliation":[{"name":"Dipartimento di Biotecnologie Chimica e Farmacia Universit\u00e0 degli Studi di Siena  Via Aldo Moro 2 53100 Siena Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8111-3776","authenticated-orcid":false,"given":"Germano","family":"Giuliani","sequence":"additional","affiliation":[{"name":"Dipartimento di Biotecnologie Chimica e Farmacia Universit\u00e0 degli Studi di Siena  Via Aldo Moro 2 53100 Siena Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3237-2584","authenticated-orcid":false,"given":"Antonietta","family":"Rossi","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia Scuola di Medicina e Chirurgia Universit\u00e0 di Napoli \u201cFederico II\u201d  Via D. 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