{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T22:28:33Z","timestamp":1790893713483,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T00:00:00Z","timestamp":1666224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Nature Science Foundation of China","doi-asserted-by":"publisher","award":["22105109"],"award-info":[{"award-number":["22105109"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Nature Science Foundation of China","doi-asserted-by":"publisher","award":["LQ21E030001"],"award-info":[{"award-number":["LQ21E030001"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["22105109"],"award-info":[{"award-number":["22105109"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LQ21E030001"],"award-info":[{"award-number":["LQ21E030001"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"name":"K.C. Wong Magna Fund in Ningbo University","award":["22105109"],"award-info":[{"award-number":["22105109"]}]},{"name":"K.C. Wong Magna Fund in Ningbo University","award":["LQ21E030001"],"award-info":[{"award-number":["LQ21E030001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mitochondrial DNA and nuclear DNA are essential genetic material which play an important role in maintaining normal metabolism, survival, and proliferation of cells. Constructing a mitochondria-targeting stimuli-responsive nano-drug delivery system releasing chemotherapeutic agents in a stepwise response manner and destroying mitochondrial DNA and nuclear DNA simultaneously is an effective way to improve the anti-tumor effect of chemotherapeutic agents. In this study, a new mitochondria-targeting pH\/ROS dual-responsive block copolymer TPP-PEG2k-b-(BS-AA)n (P1), untargeted pH\/ROS dual-responsive copolymer mPEG2k-b-(BS-AA)n (P2), pH single-responsive copolymer (mPEG2k-b-(AH-AA)n (P3), ROS single-responsive copolymer mPEG2k-b-(SA-TG)n (P4), and non-responsive copolymer mPEG-b-PCL (P5) were constructed. pH\/ROS-responsive properties were characterized by proton nuclear magnetic resonance (1H NMR) and dynamic light scattering (DLS). Anticancer chemotherapeutic agent gemcitabine (GEM) or fluorescent substance Nile Red (NR) were loaded in the polymer micelles. Results of the mitochondrial colocalization experiment indicate that (5-carboxypentyl)(triphenyl)phosphonium bromide (TPP)-functionalized P1 micelles could be efficiently targeted and located in mitochondria. Results of the cellular uptake experiment showed that pH\/ROS dual-responsive GEM-loaded P1 and P2 micelles have faster internalized and entry nucleus rates than single-responsive or non-responsive GEM-loaded micelles. The in vitro release experiment suggests pH\/ROS dual-responsive GEM\/P1 and GEM\/P2 micelles have higher cumulative release than single-responsive GEM\/P3 and GEM\/P4 micelles. The in vitro cytotoxic experiment shows that the mitochondria-targeted dual-responsive GEM\/P1 micelles had the lowest IC50 values, and the cytotoxic effect of dual-responsive GEM\/P2 micelles was superior to the single-responsive and non-responsive drug-loaded micelles.<\/jats:p>","DOI":"10.3390\/ijms232012624","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T22:49:46Z","timestamp":1666306186000},"page":"12624","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Mitochondria-Targeting Polymer Micelles in Stepwise Response Releasing Gemcitabine and Destroying the Mitochondria and Nucleus for Combined Antitumor Chemotherapy"],"prefix":"10.3390","volume":"23","author":[{"given":"Shanming","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fen","family":"Zheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaige","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengke","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8557-0699","authenticated-orcid":false,"given":"Tonghu","family":"Xiao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yabin","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Medicine, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0510-420X","authenticated-orcid":false,"given":"Long","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis of Zhejiang Province, School of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2101432","DOI":"10.1002\/adfm.202101432","article-title":"A traceable, sequential multistage-targeting nanoparticles combining chemo\/chemodynamic therapy for enhancing antitumor efficacy","volume":"31","author":"Wang","year":"2021","journal-title":"Adv. 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