{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T17:26:21Z","timestamp":1777310781054,"version":"3.51.4"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T00:00:00Z","timestamp":1657497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:p>The inability of small molecule drugs to diffuse into tumor interstitium is responsible for the relatively low effectiveness of chemotherapy. Herein, a hydrogen sulfide (H<jats:sub>2<\/jats:sub>S) gas\u2013involved chemosensitization strategy is proposed for pancreatic cancer treatment by developing a tumor-specific lipase-responsive nanomedicine based on aptamer-conjugated DATS\/Dox co-loaded PCL-<jats:italic>b<\/jats:italic>-PEO micelle (DA\/D@Ms-A). After receptor-mediated endocytosis and subsequent digestion of PCL blocks by intracellular lipase, the nanomedicine releases Dox and DATS, which then react with intracellular glutathione to produce H<jats:sub>2<\/jats:sub>S. The cytotoxicity result indicates that H<jats:sub>2<\/jats:sub>S can enhance Dox chemotherapy efficiency owing to the synergetic therapeutic effect of Dox and H<jats:sub>2<\/jats:sub>S. Moreover, the nanomedicine is featured with well tumor penetration capability benefitting from the targeting ability of aptamers and high <jats:italic>in vivo<\/jats:italic> biocompatibility due to the high density of PEO and biodegradable PCL. The nanomedicine capable of synergetic gas-chemotherapy holds great potential for pancreatic cancer treatment.<\/jats:p>","DOI":"10.3389\/fbioe.2022.934151","type":"journal-article","created":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T07:34:08Z","timestamp":1657524848000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Tumor Cell-Specific and Lipase-Responsive Delivery of Hydrogen Sulfide for Sensitizing Chemotherapy of Pancreatic Cancer"],"prefix":"10.3389","volume":"10","author":[{"given":"Libing","family":"Tian","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Pei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaojun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kun","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuting","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yougen","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu-Feng","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lichan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1038\/424870a","article-title":"Biology's New Dimension","volume":"424","author":"Abbott","year":"2003","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1089\/ars.2017.7058","article-title":"A Review of Hydrogen Sulfide Synthesis, Metabolism, and Measurement: Is Modulation of Hydrogen Sulfide a Novel Therapeutic for Cancer?","volume":"31","author":"Cao","year":"2019","journal-title":"Antioxidants Redox Signal."},{"key":"B3","doi-asserted-by":"publisher","first-page":"4881","DOI":"10.1021\/acs.jmedchem.6b00184","article-title":"H2S-Donating Doxorubicins May Overcome Cardiotoxicity and Multidrug Resistance","volume":"59","author":"Chegaev","year":"2016","journal-title":"J. Med. Chem."},{"key":"B4","doi-asserted-by":"publisher","first-page":"10887","DOI":"10.1021\/acsnano.9b04954","article-title":"Gas-mediated Cancer Bioimaging and Therapy","volume":"13","author":"Chen","year":"2019","journal-title":"ACS Nano"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2174","DOI":"10.3748\/wjg.14.2174","article-title":"Detection of Apoptosis Induced by New Type Gosling Viral Enteritis Virus In Vitro through Fluorescein Annexin V-FITC\/PI Double Labeling","volume":"14","author":"Chen","year":"2008","journal-title":"Wjg"},{"key":"B6","doi-asserted-by":"publisher","first-page":"7671","DOI":"10.7150\/thno.45079","article-title":"ZnS@ZIF-8 Core-Shell Nanoparticles Incorporated with ICG and TPZ to Enable H2S-Amplified Synergistic Therapy","volume":"10","author":"Fang","year":"2020","journal-title":"Theranostics"},{"key":"B7","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1080\/14737140.2018.1428093","article-title":"A Look at the Progress of Treating Pancreatic Cancer over the Past 20 Years","volume":"18","author":"Goess","year":"2018","journal-title":"Expert Rev. Anticancer Ther."},{"key":"B8","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1042\/bj2240591","article-title":"Interactions of Sulphide and Other Ligands with Cytochrome C Oxidase. An Electron-Paramagnetic-Resonance Study","volume":"224","author":"Hill","year":"1984","journal-title":"Biochem. J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/S0140-6736(16)00141-0","article-title":"Pancreatic Cancer","volume":"388","author":"Kamisawa","year":"2016","journal-title":"Lancet"},{"key":"B10","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1089\/ars.2013.5308","article-title":"Anti-cancer Activity of New Designer Hydrogen Sulfide-Donating Hybrids","volume":"20","author":"Kashfi","year":"2014","journal-title":"Antioxidants Redox Signal."},{"key":"B11","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1021\/bm010168s","article-title":"Enzymatic Degradation of Block Copolymers Prepared from \u03b5-Caprolactone and Poly(ethylene Glycol)","volume":"3","author":"Li","year":"2002","journal-title":"Biomacromolecules"},{"key":"B12","doi-asserted-by":"publisher","first-page":"4196","DOI":"10.1021\/acs.orglett.5b01962","article-title":"Diallyl Trisulfide Is a Fast H2S Donor, but Diallyl Disulfide Is a Slow One: The Reaction Pathways and Intermediates of Glutathione with Polysulfides","volume":"17","author":"Liang","year":"2015","journal-title":"Org. Lett."},{"key":"B13","doi-asserted-by":"publisher","first-page":"10327","DOI":"10.1002\/anie.201104305","article-title":"Capture and Visualization of Hydrogen Sulfide by a Fluorescent Probe","volume":"50","author":"Liu","year":"2011","journal-title":"Angew. Chem. Int. Ed."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.21873\/anticanres.14133","article-title":"Pathogenesis and Treatment of Pancreatic Cancer Related Pain","volume":"40","author":"Lohse","year":"2020","journal-title":"Anticancer Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"16633","DOI":"10.1073\/pnas.0902952106","article-title":"No Facilitator Required for Membrane Transport of Hydrogen Sulfide","volume":"106","author":"Mathai","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B16","doi-asserted-by":"publisher","first-page":"15111","DOI":"10.1021\/ja508063s","article-title":"Why Can Hydrogen Sulfide Permeate Cell Membranes?","volume":"136","author":"Riahi","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"B17","doi-asserted-by":"publisher","first-page":"175883592091597","DOI":"10.1177\/1758835920915978","article-title":"Polymer Nanoparticle-Assisted Chemotherapy of Pancreatic Cancer","volume":"12","author":"Su","year":"2020","journal-title":"Ther. Adv. Med. Oncol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA A Cancer J. Clin."},{"key":"B19","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/nrd.2015.1","article-title":"Gasotransmitters in Cancer: from Pathophysiology to Experimental Therapy","volume":"15","author":"Szabo","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"B20","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1038\/nrd2425","article-title":"Hydrogen Sulphide and its Therapeutic Potential","volume":"6","author":"Szab\u00f3","year":"2007","journal-title":"Nat. Rev. Drug Discov."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2099","DOI":"10.1111\/bph.12369","article-title":"Regulation of Mitochondrial Bioenergetic Function by Hydrogen Sulfide. Part I. Biochemical and Physiological Mechanisms","volume":"171","author":"Szabo","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"173814","DOI":"10.1016\/j.ejphar.2020.173814","article-title":"Enhanced Targeting of 3D Pancreatic Cancer Spheroids by Aptamer-Conjugated Polymeric Micelles with Deep Tumor Penetration","volume":"894","author":"Tian","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"10760","DOI":"10.1021\/jacs.9b03720","article-title":"Elucidation and Structural Modeling of Cd71 as a Molecular Target for Cell-specific Aptamer Binding","volume":"141","author":"Wu","year":"2019","journal-title":"J. Am. Chem. Soc."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1903512","DOI":"10.1002\/advs.201903512","article-title":"FeS@BSA Nanoclusters to Enable H 2 S\u2010Amplified ROS\u2010Based Therapy with MRI Guidance","volume":"7","author":"Xie","year":"2020","journal-title":"Adv. Sci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.ctrv.2011.01.006","article-title":"Liposome Based Delivery Systems in Pancreatic Cancer Treatment: From Bench to Bedside","volume":"37","author":"Yang","year":"2011","journal-title":"Cancer Treat. Rev."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2007991","DOI":"10.1002\/adfm.202007991","article-title":"Photothermo\u2010Promoted Nanocatalysis Combined with H 2 S\u2010Mediated Respiration Inhibition for Efficient Cancer Therapy","volume":"31","author":"Yang","year":"2021","journal-title":"Adv. Funct. Mat."},{"key":"B27","doi-asserted-by":"publisher","first-page":"20200185","DOI":"10.1002\/VIW.20200185","article-title":"Novel Gas\u2010based Nanomedicines for Cancer Therapy","volume":"3","author":"Yao","year":"2022","journal-title":"View"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1801964","DOI":"10.1002\/adma.201801964","article-title":"Gas-generating Nanoplatforms: Material Chemistry, Multifunctionality, and Gas Therapy","volume":"30","author":"Yu","year":"2018","journal-title":"Adv. Mat."}],"container-title":["Frontiers in Bioengineering and Biotechnology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2022.934151\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T07:34:10Z","timestamp":1657524850000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2022.934151\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,11]]},"references-count":28,"alternative-id":["10.3389\/fbioe.2022.934151"],"URL":"https:\/\/doi.org\/10.3389\/fbioe.2022.934151","relation":{},"ISSN":["2296-4185"],"issn-type":[{"value":"2296-4185","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,11]]},"article-number":"934151"}}