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Minimizing initial \u201cburst\u201d can also be important, especially with drugs causing systemic toxicity. Both goals are challenging with small hydrophilic molecules. The delivery of molecules such as the ultrapotent local anesthetic tetrodotoxin (TTX) exemplifies both challenges. Toxicity can be mitigated by conjugating TTX to polymers with ester bonds, but the slow ester hydrolysis can result in subtherapeutic TTX release. Here, we developed a prodrug strategy, based on dynamic covalent chemistry utilizing a reversible reaction between the diol TTX and phenylboronic acids. These polymeric prodrugs exhibited TTX encapsulation efficiencies exceeding 90\u2009% and the resulting polymeric nanoparticles showed a range of TTX release rates. In vivo injection of the TTX polymeric prodrugs at the sciatic nerve reduced TTX systemic toxicity and produced nerve block lasting 9.7\u00b12.0\u2005h, in comparison to 1.6\u00b10.6\u2005h from free TTX. This approach could also be used to co\u2010deliver the diol dexamethasone, which prolonged nerve block to 21.8\u00b15.1\u2005h. This work emphasized the usefulness of dynamic covalent chemistry for depot\u2010type drug delivery systems with slow and effective drug release kinetics.<\/jats:p>","DOI":"10.1002\/anie.202406158","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T17:24:40Z","timestamp":1718645080000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Polymeric Prodrugs using Dynamic Covalent Chemistry for Prolonged Local Anesthesia"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2485-7514","authenticated-orcid":false,"given":"Tianrui","family":"Xue","sequence":"first","affiliation":[{"name":"Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital Harvard Medical School  Boston, Massachusetts 02115 United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8186-2435","authenticated-orcid":false,"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital Harvard Medical School  Boston, Massachusetts 02115 United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Torre","sequence":"additional","affiliation":[{"name":"Department of Pathology Brigham and Women's Hospital Harvard Medical School  Boston, Massachusetts 02115 United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachelle","family":"Shao","sequence":"additional","affiliation":[{"name":"Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital Harvard Medical School  Boston, Massachusetts 02115 United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyuan","family":"Han","sequence":"additional","affiliation":[{"name":"Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital Harvard Medical School  Boston, Massachusetts 02115 United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuanglong","family":"Chen","sequence":"additional","affiliation":[{"name":"Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital Harvard Medical School  Boston, Massachusetts 02115 United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Lee","sequence":"additional","affiliation":[{"name":"Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital Harvard Medical School  Boston, Massachusetts 02115 United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5369-5932","authenticated-orcid":false,"given":"Daniel S.","family":"Kohane","sequence":"additional","affiliation":[{"name":"Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology Boston Children's Hospital Harvard Medical School  Boston, Massachusetts 02115 United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,17]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-3659(01)00248-6"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2014.05.029"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-817909-3.00001-7"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/263797a0"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-409X(98)00027-1"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2011.07.057"},{"key":"e_1_2_7_7_1","volume":"8","author":"Li Q.","year":"2020","journal-title":"Front. 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