PMID- 36538847 OWN - NLM STAT- MEDLINE DCOM- 20230124 LR - 20230201 IS - 1878-5905 (Electronic) IS - 0142-9612 (Linking) VI - 293 DP - 2023 Feb TI - A novel ROS-activable self-immolative prodrug for tumor-specific amplification of oxidative stress and enhancing chemotherapy of mitoxantrone. PG - 121954 LID - S0142-9612(22)00594-4 [pii] LID - 10.1016/j.biomaterials.2022.121954 [doi] AB - Reactive oxygen species (ROS) as well-known endogenous stimuli has been widely used to activate drug delivery systems (DDSs) for tumor-specific therapy. Unfortunately, endogenous ROS in the tumor microenvironment (TME) is not enough to achieve effective therapeutic efficacy and cancer cells have adapted to high oxidative stress by upregulating glutathione (GSH) level. Herein, we devised a novel ROS-activable self-immolative prodrug CASDB with both GSH-depletion ability and ROS self-supply competence. Then, an stimuli-responsive nanoplatform integrating CASDB with clinical chemotherapeutics mitoxantrone (MTO) and PLGA was fabricated (denoted as CMPs) through nanoprecipitation method. The CMPs could achieve desired accumulation at tumor tissues through enhanced permeability and retention (EPR) effects. Then the accumulated CMPs could induce tumor cell apoptosis efficiently. Especially, ROS in tumor sites could trigger the immolation of CASDB to generate CA and quinone methide (QM). Then CA and QM cooperatively promoted damage of mitochondria due to oxidative stress and led to cancer cells more sensitive to MTO. Accordingly, MTO could perturb cellular microenvironment of cancer cells then promote the degradation of CASDB. The experiment results demonstrated that CMPs were ideal for desirable synergetic tumor-specific anticancer therapy with negligible systemic toxicity. The half-maximal inhibitory concentrations (IC50) value of CMPs was 6.53 muM, while the IC50 values of MTO was 14.76 muM. And the CMPs group showed the strongest tumor suppressor effect with the tumor sizes increased to 1.2-fold (Control group: 20.6-fold, MTO only: 3.0-fold). This study should be inspirational for designing efficient prodrugs to overcome the handicaps of traditional chemotherapy. CI - Copyright (c) 2022. Published by Elsevier Ltd. FAU - Zhang, Hongjie AU - Zhang H AD - CAS Key Lab of Soft Matter Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui, PR China; State Key Laboratory of Fire Science, University of Science and Technology of China, 443 Huangshan Road, Hefei, Anhui, PR China. FAU - Chen, Weijian AU - Chen W AD - CAS Key Lab of Soft Matter Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui, PR China; State Key Laboratory of Fire Science, University of Science and Technology of China, 443 Huangshan Road, Hefei, Anhui, PR China. FAU - Wang, Jing AU - Wang J AD - Department of Thyroid and Breast Surgery, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui, PR China. FAU - Du, Wenxiang AU - Du W AD - CAS Key Lab of Soft Matter Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui, PR China; State Key Laboratory of Fire Science, University of Science and Technology of China, 443 Huangshan Road, Hefei, Anhui, PR China. FAU - Wang, Bibo AU - Wang B AD - CAS Key Lab of Soft Matter Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui, PR China; State Key Laboratory of Fire Science, University of Science and Technology of China, 443 Huangshan Road, Hefei, Anhui, PR China. FAU - Song, Lei AU - Song L AD - CAS Key Lab of Soft Matter Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui, PR China; State Key Laboratory of Fire Science, University of Science and Technology of China, 443 Huangshan Road, Hefei, Anhui, PR China. Electronic address: leisong@ustc.edu.cn. FAU - Hu, Yuan AU - Hu Y AD - CAS Key Lab of Soft Matter Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui, PR China; State Key Laboratory of Fire Science, University of Science and Technology of China, 443 Huangshan Road, Hefei, Anhui, PR China. Electronic address: yuanhu@ustc.edu.cn. FAU - Ma, Xiaopeng AU - Ma X AD - Department of Thyroid and Breast Surgery, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui, PR China. Electronic address: XiaopengMa@fsyy.ustc.edu.cn. LA - eng PT - Journal Article DEP - 20221209 PL - Netherlands TA - Biomaterials JT - Biomaterials JID - 8100316 RN - BZ114NVM5P (Mitoxantrone) RN - 0 (Prodrugs) RN - 0 (Reactive Oxygen Species) SB - IM MH - Mitoxantrone/pharmacology MH - *Prodrugs/pharmacology/therapeutic use MH - Reactive Oxygen Species/metabolism MH - Cell Line, Tumor MH - Oxidative Stress MH - *Nanoparticles OTO - NOTNLM OT - Enhanced chemotherapy OT - Mitoxantrone OT - Reactive oxygen species OT - Self-amplifying OT - "Win-win" drug delivery system COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/12/21 06:00 MHDA- 2023/01/25 06:00 CRDT- 2022/12/20 18:04 PHST- 2022/07/30 00:00 [received] PHST- 2022/12/05 00:00 [revised] PHST- 2022/12/09 00:00 [accepted] PHST- 2022/12/21 06:00 [pubmed] PHST- 2023/01/25 06:00 [medline] PHST- 2022/12/20 18:04 [entrez] AID - S0142-9612(22)00594-4 [pii] AID - 10.1016/j.biomaterials.2022.121954 [doi] PST - ppublish SO - Biomaterials. 2023 Feb;293:121954. doi: 10.1016/j.biomaterials.2022.121954. Epub 2022 Dec 9.