PMID- 34762396 OWN - NLM STAT- MEDLINE DCOM- 20220314 LR - 20230601 IS - 1526-4602 (Electronic) IS - 1525-7797 (Print) IS - 1525-7797 (Linking) VI - 23 IP - 1 DP - 2022 Jan 10 TI - Thioether-Based Polymeric Micelles with Fine-Tuned Oxidation Sensitivities for Chemotherapeutic Drug Delivery. PG - 77-88 LID - 10.1021/acs.biomac.1c01010 [doi] AB - Oxidation-sensitive drug delivery systems (DDSs) have attracted attention due to the potential to improve efficacy and safety of chemotherapeutics. These systems are designed to release the payload in response to oxidative stress conditions, which are associated with many types of cancer. Despite extensive research on the development of oxidation-sensitive DDS, the lack of selectivity toward cancer cells over healthy cells remains a challenge. Here, we report the design and characterization of polymeric micelles containing thioether groups with varying oxidation sensitivities within the micellar core, which become hydrophilic upon thioether oxidation, leading to destabilization of the micellar structure. We first used the thioether model compounds, 3-methylthiopropylamide (TPAM), thiomorpholine amide (TMAM), and 4-(methylthio)benzylamide (TPhAM) to investigate the effect of the chemical structures of the thioethers on the oxidation by hydrogen peroxide (H(2)O(2)). TPAM shows the fastest oxidation, followed by TMAM and TPhAM, showing that the oxidation reaction of thioethers can be modulated by changing the substituent groups bound to the sulfur atom. We next prepared micelles containing these different thioether groups within the core (TP, TM, and TPh micelles). The micelles containing the thioether groups with a higher oxidation sensitivity were destabilized by H(2)O(2) at a lower concentration. Micelle destabilization was also tested in human liver cancer (HepG2) cells and human umbilical vein endothelial cells (HUVECs). The TP micelles having the highest oxidation sensitivity were destabilized in both HepG2 cells and HUVECs, while the TPh micelles, which showed the lowest reactivity toward H(2)O(2), were stable in these cell lines. The TM micelles possessing a moderate oxidation sensitivity were destabilized in HepG2 cells but were stable in HUVECs. Furthermore, the micelles were loaded with doxorubicin (Dox) to evaluate their potential in drug delivery applications. Among the micelles, the TM micelles loaded with Dox showed the enhanced relative toxicity in HepG2 cells over HUVECs. Therefore, our approach to fine-tune the oxidation sensitivity of the micelles has potential for improving therapeutic efficacy and safety of drugs in cancer treatment. FAU - van der Vlies, Andre J AU - van der Vlies AJ AD - Department of Materials Science and Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, United States. FAU - Xu, Jiayi AU - Xu J AUID- ORCID: 0000-0003-1763-6251 AD - Tim Taylor Department of Chemical Engineering, Kansas State University, Manhattan, Kansas 66506, United States. FAU - Ghasemi, Masoud AU - Ghasemi M AD - Department of Chemical Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, United States. FAU - Bator, Carol AU - Bator C AD - Huck Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, United States. FAU - Bell, Amanda AU - Bell A AD - Tim Taylor Department of Chemical Engineering, Kansas State University, Manhattan, Kansas 66506, United States. FAU - Rosoff-Verbit, Brett AU - Rosoff-Verbit B AD - Department of Materials Science and Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, United States. FAU - Liu, Bin AU - Liu B AUID- ORCID: 0000-0001-7890-7612 AD - Tim Taylor Department of Chemical Engineering, Kansas State University, Manhattan, Kansas 66506, United States. FAU - Gomez, Enrique D AU - Gomez ED AUID- ORCID: 0000-0001-8942-4480 AD - Department of Materials Science and Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, United States. AD - Department of Chemical Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, United States. AD - Materials Research Institute, The Pennsylvania State University, University Park, Pennsylvania 16802, United States. FAU - Hasegawa, Urara AU - Hasegawa U AUID- ORCID: 0000-0002-4189-7630 AD - Department of Materials Science and Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, United States. AD - Tim Taylor Department of Chemical Engineering, Kansas State University, Manhattan, Kansas 66506, United States. LA - eng GR - P20 GM103638/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20211111 PL - United States TA - Biomacromolecules JT - Biomacromolecules JID - 100892849 RN - 0 (Drug Carriers) RN - 0 (Micelles) RN - 0 (Sulfides) RN - 80168379AG (Doxorubicin) RN - BBX060AN9V (Hydrogen Peroxide) SB - IM MH - Cell Survival MH - Doxorubicin/chemistry MH - Drug Carriers/chemistry MH - Drug Delivery Systems MH - Drug Liberation MH - Endothelial Cells/metabolism MH - Humans MH - *Hydrogen Peroxide/chemistry MH - Hydrogen-Ion Concentration MH - *Micelles MH - Sulfides/pharmacology PMC - PMC10232214 MID - NIHMS1895269 EDAT- 2021/11/12 06:00 MHDA- 2022/03/15 06:00 PMCR- 2023/05/31 CRDT- 2021/11/11 17:09 PHST- 2021/11/12 06:00 [pubmed] PHST- 2022/03/15 06:00 [medline] PHST- 2021/11/11 17:09 [entrez] PHST- 2023/05/31 00:00 [pmc-release] AID - 10.1021/acs.biomac.1c01010 [doi] PST - ppublish SO - Biomacromolecules. 2022 Jan 10;23(1):77-88. doi: 10.1021/acs.biomac.1c01010. Epub 2021 Nov 11.