{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T05:00:38Z","timestamp":1785042038842,"version":"3.55.0"},"reference-count":44,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In this study, a pH-responsive chondroitin sulfate\u2013methotrexate (MTX) polymeric prodrug was synthesized through Schiff base formation between oxidized chondroitin sulfate and MTX. The resulting amphiphilic conjugate exhibited a conjugation degree of 184 mg MTX per g conjugate and spontaneously self-assembled into stable nanoparticles (CSMXPs) with a mean diameter of 120 \u00b1 10 nm, a polydispersity index of 0.24, and a critical aggregation concentration of 4.7 \u00d7 10\u22124 mg mL\u22121. Drug release studies demonstrated a marked pH-dependent behavior, with complete MTX release after 24 h at pH 5.0 and a sustained release profile under physiological conditions. The release mechanism followed reversible first-order kinetics and was accelerated by acid-catalyzed hydrolysis of the imine linkage. Biological evaluation revealed enhanced therapeutic selectivity of CSMXPs compared with free MTX. At 36 \u03bcM MTX-equivalent concentration, CSMXPs reduced HeLa cell viability to 37%, while maintaining MCF-10A viability above 88%, whereas free MTX decreased viability in both cell lines (51% and 65%, respectively). Fluorescence confocal microscopy confirmed efficient nanoparticle uptake by cancer cells. These findings demonstrate that CSMXPs represent a promising self-assembling nanoprodrug platform for selective and targeted cancer therapy.<\/jats:p>","DOI":"10.3390\/molecules31152578","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T07:36:13Z","timestamp":1784878573000},"page":"2578","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chondroitin Sulfate-Based Self-Assembling Nanoprodrug for Controlled Methotrexate Delivery in Cancer Therapy"],"prefix":"10.3390","volume":"31","author":[{"given":"Ludovica","family":"Scorzafave","sequence":"first","affiliation":[{"name":"Department of Pharmacy Health and Nutritional Science, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Pellegrino","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Health and Nutritional Science, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9592-1333","authenticated-orcid":false,"given":"Giuseppe","family":"Cirillo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Health and Nutritional Science, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Fiore","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Health and Nutritional Science, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7252-7340","authenticated-orcid":false,"given":"Roberta","family":"Pino","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Health and Nutritional Science, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7513-3495","authenticated-orcid":false,"given":"Diana","family":"Amantea","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Health and Nutritional Science, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4373-6232","authenticated-orcid":false,"given":"Antonella","family":"Leggio","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Health and Nutritional Science, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5961-1963","authenticated-orcid":false,"given":"Fiore Pasquale","family":"Nicoletta","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Health and Nutritional Science, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9548-0446","authenticated-orcid":false,"given":"Francesca","family":"Iemma","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Health and Nutritional Science, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2026-0152","authenticated-orcid":false,"given":"Manuela","family":"Curcio","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Health and Nutritional Science, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Jornada, D.H., Dos Santos Fernandes, G.F., Chiba, D.E., De Melo, T.R.F., Dos Santos, J.L., and Chung, M.C. 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