Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide

Nature Chemistry
Yueqin ZhengBinghe Wang

Abstract

Controlled activation is a critical component in prodrug development. Here we report a concentration-sensitive platform approach for bioorthogonal prodrug activation by taking advantage of reaction kinetics. Using two 'click and release' systems, we demonstrate enrichment and prodrug activation specifically in mitochondria to demonstrate the principle of the approach. In both cases, the payload (doxorubicin or carbon monoxide) was released inside the mitochondrial matrix following the enrichment-initiated click reaction. Furthermore, mitochondria-targeted delivery yielded substantial augmentation of functional biological and therapeutic effects in vitro and in vivo when compared to controls, which did not result in enrichment. This method is thus a platform for targeted drug delivery that is amenable to conjugation with a variety of molecules and is not limited to cell-surface delivery. Taken together, these two 'click and release' pairs clearly demonstrate the concept of enrichment-triggered drug release and the critical feasibility of treating clinically relevant diseases such as acute liver injury and cancer.

References

Jul 1, 1997·Journal of Pharmaceutical Sciences·D ShanB Wang
Feb 9, 2002·Circulation Research·Roberto MotterliniColin J Green
Apr 17, 2003·Proceedings of the National Academy of Sciences of the United States of America·Robin A J SmithMichael P Murphy
Jul 5, 2003·Circulation Research·James E ClarkRoberto Motterlini
Dec 6, 2003·The Journal of Experimental Medicine·Brian S ZuckerbraunLeo E Otterbein
Oct 4, 2006·Annual Review of Pharmacology and Toxicology·Michael P Murphy, Robin A J Smith
Mar 6, 2008·Expert Opinion on Drug Delivery·Xiaobin ZhaoRobert J Lee
Sep 19, 2008·Journal of the American Chemical Society·Melissa L BlackmanJoseph M Fox
Dec 5, 2008·Bioconjugate Chemistry·Neal K DevarajScott A Hilderbrand
Feb 17, 2010·Journal of the American Chemical Society·Takashi MuraseMakoto Fujita
Sep 3, 2010·Nature Reviews. Drug Discovery·Roberto Motterlini, Leo E Otterbein
Mar 25, 2011·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Kaori KuramitsuLeo E Otterbein
Apr 1, 2010·Oman Medical Journal·Anil K Philip, Betty Philip
Dec 14, 2011·Chemical Communications : Chem Comm·Weixuan ChenBinghe Wang
Apr 27, 2012·Biochemistry Research International·Cláudia S F QueirogaHelena L A Vieira
Apr 30, 2013·International Journal of Pharmaceutics·Abdullah Al-NahainSung Young Park
Nov 28, 2013·Angewandte Chemie·Ron M VersteegenMarc S Robillard
Dec 7, 2013·Therapeutic Delivery·Xi HeChen Jiang
May 9, 2014·Organic & Biomolecular Chemistry·Danzhu WangBinghe Wang
May 24, 2014·Dalton Transactions : an International Journal of Inorganic Chemistry·Christoph NagelUlrich Schatzschneider
Nov 5, 2014·Nature Chemical Biology·Jie LiPeng R Chen
Nov 8, 2014·Chemical Communications : Chem Comm·Danzhu WangBinghe Wang
Nov 14, 2014·Topics in Current Chemistry·Andrew J Wiemer, David F Wiemer
Feb 19, 2015·Frontiers in Physiology·Nils Schallner, Leo E Otterbein
Jan 9, 2016·Journal of the American Chemical Society·Jeffrey C KernRobert M Garbaccio
Jan 12, 2016·Biomacromolecules·Kristi S Anseth, Harm-Anton Klok
Jan 23, 2016·Nature Chemistry·Vijay ChudasamaStephen Caddick
Apr 12, 2016·Cellular & Molecular Immunology·Mark W RobinsonCliona O'Farrelly
Apr 27, 2016·Antimicrobial Agents and Chemotherapy·Mareike Klinger-StrobelAlexander Schiller
Jun 17, 2016·Bioconjugate Chemistry·Raffaella RossinMarc S Robillard
Oct 25, 2016·International Journal of Pharmaceutics·Wei JinKun Cheng
Sep 14, 2016·Annual Review of Pharmacology and Toxicology·Justin R Hamilton, JoAnn Trejo
Oct 22, 2016·Nature Chemistry·Ji LuoAlexander Deiters
Dec 9, 2016·Angewandte Chemie·Ester Jiménez-MorenoGonçalo J L Bernardes
Jan 12, 2017·Chemical Communications : Chem Comm·Andrea K SteigerMichael D Pluth
Jan 13, 2017·American Journal of Physiology. Cell Physiology·Roberto Motterlini, Roberta Foresti
Jan 21, 2017·Advanced Science·Gurusamy SaravanakumarWon Jong Kim
Jan 31, 2017·Organic Letters·Xingyue JiBinghe Wang
May 26, 2017·Chemistry : a European Journal·Zhixiang PanBinghe Wang
Nov 10, 2017·Journal of Inflammation·Matthew J BradleyThomas A Davis

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Citations

Feb 7, 2019·Chemical Society Reviews·Xingyue JiBinghe Wang
Mar 15, 2019·Chemical Communications : Chem Comm·Dongqing WangYi Hu
Apr 4, 2019·Dalton Transactions : an International Journal of Inorganic Chemistry·André L AmorimRosely A Peralta
Jun 13, 2019·Nucleic Acids Research·Kazumitsu OnizukaFumi Nagatsugi
Aug 6, 2019·Chemical Communications : Chem Comm·Yu GengYouqing Shen
May 11, 2019·Current Topics in Medicinal Chemistry·Gang LiuJia Zhou
Jun 12, 2020·Organic & Biomolecular Chemistry·Jessica M FairhallAllan B Gamble
Dec 11, 2019·Medicinal Research Reviews·Xiaoxiao YangBinghe Wang
Aug 18, 2020·Medicinal Research Reviews·Xiaoxiao YangBinghe Wang
Jul 4, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Arduino A MangoniPaula A C Gomes
Oct 20, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jianghua LiGuangli Yu
Feb 13, 2019·Chembiochem : a European Journal of Chemical Biology·Xinqi ZhouCliff I Stains
Feb 29, 2020·Chemical Science·Julian TuRaphael M Franzini
May 23, 2020·Science Advances·Jin MengQianjun He
May 16, 2019·Chemical Communications : Chem Comm·Yong LiBo Tang
Feb 23, 2020·International Journal of Molecular Sciences·Nadège BellanceRodrigue Rossignol
Sep 14, 2019·Israel Journal of Chemistry·Tatiana Soboleva, Lisa M Berreau
Aug 21, 2020·ChemistryOpen·Youshan Li, Hua Fu
Jan 30, 2019·Chembiochem : a European Journal of Chemical Biology·Julian TuRaphael M Franzini
Sep 10, 2020·Angewandte Chemie·Siyue TaoJinming Hu
Dec 4, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yayue WangPing Feng
Mar 2, 2021·Acta Pharmaceutica Sinica. B·Dominik BakalarzMarcin Magierowski
Oct 23, 2020·Chemical Reviews·Christopher P HopperBinghe Wang
Jan 6, 2021·Chemical Reviews·Titas DebRaphael M Franzini
Apr 23, 2021·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Wei HaYan-Ping Shi
Jul 10, 2021·Bioorganic & Medicinal Chemistry·Ladie Kimberly De La CruzBinghe Wang
Jul 9, 2021·ACS Central Science·Jie WangPeng R Chen

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Methods Mentioned

BETA
confocal microscopy
enzyme-linked immunosorbent assay
ELISA
NMR

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