{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T17:12:31Z","timestamp":1774458751065,"version":"3.50.1"},"reference-count":56,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T00:00:00Z","timestamp":1669161600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"U.S. National Science Foundation","doi-asserted-by":"publisher","award":["DMR-1609914"],"award-info":[{"award-number":["DMR-1609914"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Delivery of chemotherapeutics to cancer cells using polymeric micelles is a promising strategy for cancer treatment. However, limited stability of micelles, premature drug release and off-target effect are the major obstacles that restrict the utilization of polymeric micelles as effective drug delivery systems. In this work, we addressed these issues through the innovative design of targeted pH-sensitive crosslinked polymeric micelles for chemotherapeutic delivery. A well-defined triblock copolymer, poly(ethylene glycol)-b-poly(2-hydroxyethyl methacrylate)-b-poly(butyl acrylate) (PEG-b-PHEMA-b-PBA), was synthesized by living radical polymerization, and then modified by using 4-pentenoic anhydride to incorporate pendant crosslinkable alkene groups in the middle block. The resulting copolymer underwent self-assembly in aqueous solution to form non-crosslinked micelles (NCMs). Subsequently, intramicellar thiol\u2013ene crosslinking was performed by using 1,4-butanediol bis(3-mercaptopropionate) to give crosslinked micelles (CMs) with pH-sensitive crosslinks. The targeted CM (cRGD-DOX10-CM5) was readily prepared by using tumor-targeting ligand cyclo(Arg-Gly-Asp-D-Phe-Cys) (cRGD) together with the 1,4-butanediol bis(3-mercaptopropionate) during the crosslinking step. The study of cumulative DOX release revealed the pH-sensitive feature of drug release from these CMs. An in vitro MTT assay revealed that NCMs and CMs are biocompatible with MCF 10A cells, and the samples exhibited significant therapeutic efficiency as compared to free DOX. Cellular uptake studies confirmed higher uptake of cRGD-DOX10-CM5 by MCF 10A cancer cells via cRGD-receptor-mediated endocytosis as compared to the corresponding analogues without cRGD. These results indicate that such pH-responsive crosslinked PEG-b-PHEMA-b-PBA-based micelles are therapeutically effective against cancer cells and hold remarkable promise to act as smart drug delivery systems for cancer therapy.<\/jats:p>","DOI":"10.3390\/molecules27238153","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T03:24:09Z","timestamp":1669260249000},"page":"8153","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Well-Defined pH-Sensitive Self-Assembled Triblock Copolymer-Based Crosslinked Micelles for Efficient Cancer Chemotherapy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3181-4635","authenticated-orcid":false,"given":"Mohamed Alaa","family":"Mohamed","sequence":"first","affiliation":[{"name":"Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA"},{"name":"Chemistry Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ajay","family":"Singh","sequence":"additional","affiliation":[{"name":"Institute for Lasers, Photonics and Biophotonics, Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paras N.","family":"Prasad","sequence":"additional","affiliation":[{"name":"Institute for Lasers, Photonics and Biophotonics, Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chong","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/nrc1566","article-title":"Cancer nanotechnology: Opportunities and challenges","volume":"5","author":"Ferrari","year":"2005","journal-title":"Nat. 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