Mitochondria-Targeting Polymer Micelles in Stepwise Response Releasing Gemcitabine and Destroying the Mitochondria and Nucleus for Combined Antitumor Chemotherapy

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-<i<b</i<-(BS-AA)<sub<n</sub< (P1), untargeted pH/ROS dual-responsive copolymer mPEG2k-<i<b</i<-(BS-AA)<sub<n</sub< (P2), pH single-responsive copolymer (mPEG2k-<i<b</i<-(AH-AA)<sub<n</sub< (P3), ROS single-responsive copolymer mPEG2k-<i<b</i<-(SA-TG)<sub<n</sub< (P4), and non-responsive copolymer mPEG-<i<b</i<-PCL (P5) were constructed. pH/ROS-responsive properties were characterized by proton nuclear magnetic resonance (<sup<1</sup<H 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. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Shanming Zhang [verfasserIn] Fen Zheng [verfasserIn] Kaige Liu [verfasserIn] Shengke Liu [verfasserIn] Tonghu Xiao [verfasserIn] Yabin Zhu [verfasserIn] Long Xu [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	mitochondria-targeted pH/ROS dual-responsive acetal thioether TPP

Übergeordnetes Werk:	In: International Journal of Molecular Sciences - MDPI AG, 2003, 23(2022), 20, p 12624
Übergeordnetes Werk:	volume:23 ; year:2022 ; number:20, p 12624

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.3390/ijms232012624

Katalog-ID:	DOAJ084111402

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allfields	10.3390/ijms232012624 doi (DE-627)DOAJ084111402 (DE-599)DOAJ9ebb5bfff25a44e8b964c226f0d0f4a8 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Shanming Zhang verfasserin aut Mitochondria-Targeting Polymer Micelles in Stepwise Response Releasing Gemcitabine and Destroying the Mitochondria and Nucleus for Combined Antitumor Chemotherapy 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-<i<b</i<-(BS-AA)<sub<n</sub< (P1), untargeted pH/ROS dual-responsive copolymer mPEG2k-<i<b</i<-(BS-AA)<sub<n</sub< (P2), pH single-responsive copolymer (mPEG2k-<i<b</i<-(AH-AA)<sub<n</sub< (P3), ROS single-responsive copolymer mPEG2k-<i<b</i<-(SA-TG)<sub<n</sub< (P4), and non-responsive copolymer mPEG-<i<b</i<-PCL (P5) were constructed. pH/ROS-responsive properties were characterized by proton nuclear magnetic resonance (<sup<1</sup<H 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. mitochondria-targeted pH/ROS dual-responsive acetal thioether TPP Biology (General) Chemistry Fen Zheng verfasserin aut Kaige Liu verfasserin aut Shengke Liu verfasserin aut Tonghu Xiao verfasserin aut Yabin Zhu verfasserin aut Long Xu verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 20, p 12624 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:20, p 12624 https://doi.org/10.3390/ijms232012624 kostenfrei https://doaj.org/article/9ebb5bfff25a44e8b964c226f0d0f4a8 kostenfrei https://www.mdpi.com/1422-0067/23/20/12624 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2022 20, p 12624
spelling	10.3390/ijms232012624 doi (DE-627)DOAJ084111402 (DE-599)DOAJ9ebb5bfff25a44e8b964c226f0d0f4a8 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Shanming Zhang verfasserin aut Mitochondria-Targeting Polymer Micelles in Stepwise Response Releasing Gemcitabine and Destroying the Mitochondria and Nucleus for Combined Antitumor Chemotherapy 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-<i<b</i<-(BS-AA)<sub<n</sub< (P1), untargeted pH/ROS dual-responsive copolymer mPEG2k-<i<b</i<-(BS-AA)<sub<n</sub< (P2), pH single-responsive copolymer (mPEG2k-<i<b</i<-(AH-AA)<sub<n</sub< (P3), ROS single-responsive copolymer mPEG2k-<i<b</i<-(SA-TG)<sub<n</sub< (P4), and non-responsive copolymer mPEG-<i<b</i<-PCL (P5) were constructed. pH/ROS-responsive properties were characterized by proton nuclear magnetic resonance (<sup<1</sup<H 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. mitochondria-targeted pH/ROS dual-responsive acetal thioether TPP Biology (General) Chemistry Fen Zheng verfasserin aut Kaige Liu verfasserin aut Shengke Liu verfasserin aut Tonghu Xiao verfasserin aut Yabin Zhu verfasserin aut Long Xu verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 20, p 12624 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:20, p 12624 https://doi.org/10.3390/ijms232012624 kostenfrei https://doaj.org/article/9ebb5bfff25a44e8b964c226f0d0f4a8 kostenfrei https://www.mdpi.com/1422-0067/23/20/12624 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2022 20, p 12624
allfields_unstemmed	10.3390/ijms232012624 doi (DE-627)DOAJ084111402 (DE-599)DOAJ9ebb5bfff25a44e8b964c226f0d0f4a8 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Shanming Zhang verfasserin aut Mitochondria-Targeting Polymer Micelles in Stepwise Response Releasing Gemcitabine and Destroying the Mitochondria and Nucleus for Combined Antitumor Chemotherapy 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-<i<b</i<-(BS-AA)<sub<n</sub< (P1), untargeted pH/ROS dual-responsive copolymer mPEG2k-<i<b</i<-(BS-AA)<sub<n</sub< (P2), pH single-responsive copolymer (mPEG2k-<i<b</i<-(AH-AA)<sub<n</sub< (P3), ROS single-responsive copolymer mPEG2k-<i<b</i<-(SA-TG)<sub<n</sub< (P4), and non-responsive copolymer mPEG-<i<b</i<-PCL (P5) were constructed. pH/ROS-responsive properties were characterized by proton nuclear magnetic resonance (<sup<1</sup<H 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. mitochondria-targeted pH/ROS dual-responsive acetal thioether TPP Biology (General) Chemistry Fen Zheng verfasserin aut Kaige Liu verfasserin aut Shengke Liu verfasserin aut Tonghu Xiao verfasserin aut Yabin Zhu verfasserin aut Long Xu verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 20, p 12624 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:20, p 12624 https://doi.org/10.3390/ijms232012624 kostenfrei https://doaj.org/article/9ebb5bfff25a44e8b964c226f0d0f4a8 kostenfrei https://www.mdpi.com/1422-0067/23/20/12624 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2022 20, p 12624
allfieldsGer	10.3390/ijms232012624 doi (DE-627)DOAJ084111402 (DE-599)DOAJ9ebb5bfff25a44e8b964c226f0d0f4a8 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Shanming Zhang verfasserin aut Mitochondria-Targeting Polymer Micelles in Stepwise Response Releasing Gemcitabine and Destroying the Mitochondria and Nucleus for Combined Antitumor Chemotherapy 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-<i<b</i<-(BS-AA)<sub<n</sub< (P1), untargeted pH/ROS dual-responsive copolymer mPEG2k-<i<b</i<-(BS-AA)<sub<n</sub< (P2), pH single-responsive copolymer (mPEG2k-<i<b</i<-(AH-AA)<sub<n</sub< (P3), ROS single-responsive copolymer mPEG2k-<i<b</i<-(SA-TG)<sub<n</sub< (P4), and non-responsive copolymer mPEG-<i<b</i<-PCL (P5) were constructed. pH/ROS-responsive properties were characterized by proton nuclear magnetic resonance (<sup<1</sup<H 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. mitochondria-targeted pH/ROS dual-responsive acetal thioether TPP Biology (General) Chemistry Fen Zheng verfasserin aut Kaige Liu verfasserin aut Shengke Liu verfasserin aut Tonghu Xiao verfasserin aut Yabin Zhu verfasserin aut Long Xu verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 20, p 12624 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:20, p 12624 https://doi.org/10.3390/ijms232012624 kostenfrei https://doaj.org/article/9ebb5bfff25a44e8b964c226f0d0f4a8 kostenfrei https://www.mdpi.com/1422-0067/23/20/12624 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2022 20, p 12624
allfieldsSound	10.3390/ijms232012624 doi (DE-627)DOAJ084111402 (DE-599)DOAJ9ebb5bfff25a44e8b964c226f0d0f4a8 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Shanming Zhang verfasserin aut Mitochondria-Targeting Polymer Micelles in Stepwise Response Releasing Gemcitabine and Destroying the Mitochondria and Nucleus for Combined Antitumor Chemotherapy 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-<i<b</i<-(BS-AA)<sub<n</sub< (P1), untargeted pH/ROS dual-responsive copolymer mPEG2k-<i<b</i<-(BS-AA)<sub<n</sub< (P2), pH single-responsive copolymer (mPEG2k-<i<b</i<-(AH-AA)<sub<n</sub< (P3), ROS single-responsive copolymer mPEG2k-<i<b</i<-(SA-TG)<sub<n</sub< (P4), and non-responsive copolymer mPEG-<i<b</i<-PCL (P5) were constructed. pH/ROS-responsive properties were characterized by proton nuclear magnetic resonance (<sup<1</sup<H 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. mitochondria-targeted pH/ROS dual-responsive acetal thioether TPP Biology (General) Chemistry Fen Zheng verfasserin aut Kaige Liu verfasserin aut Shengke Liu verfasserin aut Tonghu Xiao verfasserin aut Yabin Zhu verfasserin aut Long Xu verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 20, p 12624 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:20, p 12624 https://doi.org/10.3390/ijms232012624 kostenfrei https://doaj.org/article/9ebb5bfff25a44e8b964c226f0d0f4a8 kostenfrei https://www.mdpi.com/1422-0067/23/20/12624 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2022 20, p 12624
language	English
source	In International Journal of Molecular Sciences 23(2022), 20, p 12624 volume:23 year:2022 number:20, p 12624
sourceStr	In International Journal of Molecular Sciences 23(2022), 20, p 12624 volume:23 year:2022 number:20, p 12624
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	mitochondria-targeted pH/ROS dual-responsive acetal thioether TPP Biology (General) Chemistry
isfreeaccess_bool	true
container_title	International Journal of Molecular Sciences
authorswithroles_txt_mv	Shanming Zhang @@aut@@ Fen Zheng @@aut@@ Kaige Liu @@aut@@ Shengke Liu @@aut@@ Tonghu Xiao @@aut@@ Yabin Zhu @@aut@@ Long Xu @@aut@@
publishDateDaySort_date	2022-01-01T00:00:00Z
hierarchy_top_id	316340715
id	DOAJ084111402
language_de	englisch
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callnumber-first	Q - Science
author	Shanming Zhang
spellingShingle	Shanming Zhang misc QH301-705.5 misc QD1-999 misc mitochondria-targeted misc pH/ROS dual-responsive misc acetal misc thioether misc TPP misc Biology (General) misc Chemistry Mitochondria-Targeting Polymer Micelles in Stepwise Response Releasing Gemcitabine and Destroying the Mitochondria and Nucleus for Combined Antitumor Chemotherapy
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topic_title	QH301-705.5 QD1-999 Mitochondria-Targeting Polymer Micelles in Stepwise Response Releasing Gemcitabine and Destroying the Mitochondria and Nucleus for Combined Antitumor Chemotherapy mitochondria-targeted pH/ROS dual-responsive acetal thioether TPP
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title	Mitochondria-Targeting Polymer Micelles in Stepwise Response Releasing Gemcitabine and Destroying the Mitochondria and Nucleus for Combined Antitumor Chemotherapy
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title_full	Mitochondria-Targeting Polymer Micelles in Stepwise Response Releasing Gemcitabine and Destroying the Mitochondria and Nucleus for Combined Antitumor Chemotherapy
author_sort	Shanming Zhang
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author_browse	Shanming Zhang Fen Zheng Kaige Liu Shengke Liu Tonghu Xiao Yabin Zhu Long Xu
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title_sort	mitochondria-targeting polymer micelles in stepwise response releasing gemcitabine and destroying the mitochondria and nucleus for combined antitumor chemotherapy
callnumber	QH301-705.5
title_auth	Mitochondria-Targeting Polymer Micelles in Stepwise Response Releasing Gemcitabine and Destroying the Mitochondria and Nucleus for Combined Antitumor Chemotherapy
abstract	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-<i<b</i<-(BS-AA)<sub<n</sub< (P1), untargeted pH/ROS dual-responsive copolymer mPEG2k-<i<b</i<-(BS-AA)<sub<n</sub< (P2), pH single-responsive copolymer (mPEG2k-<i<b</i<-(AH-AA)<sub<n</sub< (P3), ROS single-responsive copolymer mPEG2k-<i<b</i<-(SA-TG)<sub<n</sub< (P4), and non-responsive copolymer mPEG-<i<b</i<-PCL (P5) were constructed. pH/ROS-responsive properties were characterized by proton nuclear magnetic resonance (<sup<1</sup<H 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.
abstractGer	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-<i<b</i<-(BS-AA)<sub<n</sub< (P1), untargeted pH/ROS dual-responsive copolymer mPEG2k-<i<b</i<-(BS-AA)<sub<n</sub< (P2), pH single-responsive copolymer (mPEG2k-<i<b</i<-(AH-AA)<sub<n</sub< (P3), ROS single-responsive copolymer mPEG2k-<i<b</i<-(SA-TG)<sub<n</sub< (P4), and non-responsive copolymer mPEG-<i<b</i<-PCL (P5) were constructed. pH/ROS-responsive properties were characterized by proton nuclear magnetic resonance (<sup<1</sup<H 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.
abstract_unstemmed	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-<i<b</i<-(BS-AA)<sub<n</sub< (P1), untargeted pH/ROS dual-responsive copolymer mPEG2k-<i<b</i<-(BS-AA)<sub<n</sub< (P2), pH single-responsive copolymer (mPEG2k-<i<b</i<-(AH-AA)<sub<n</sub< (P3), ROS single-responsive copolymer mPEG2k-<i<b</i<-(SA-TG)<sub<n</sub< (P4), and non-responsive copolymer mPEG-<i<b</i<-PCL (P5) were constructed. pH/ROS-responsive properties were characterized by proton nuclear magnetic resonance (<sup<1</sup<H 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.
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title_short	Mitochondria-Targeting Polymer Micelles in Stepwise Response Releasing Gemcitabine and Destroying the Mitochondria and Nucleus for Combined Antitumor Chemotherapy
url	https://doi.org/10.3390/ijms232012624 https://doaj.org/article/9ebb5bfff25a44e8b964c226f0d0f4a8 https://www.mdpi.com/1422-0067/23/20/12624 https://doaj.org/toc/1661-6596 https://doaj.org/toc/1422-0067
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