{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T16:04:57Z","timestamp":1784909097553,"version":"3.55.0"},"reference-count":37,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2018,11,8]],"date-time":"2018-11-08T00:00:00Z","timestamp":1541635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["51273156; 51373130"],"award-info":[{"award-number":["51273156; 51373130"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Training Programs of Innovation and Entrepreneurship for Undergraduates","award":["20171049720004"],"award-info":[{"award-number":["20171049720004"]}]},{"name":"Crohn\u2019s &amp; Colitis Foundation of America Career Award","award":["No. 348137"],"award-info":[{"award-number":["No. 348137"]}]},{"DOI":"10.13039\/100001797","name":"PhRMA Foundation","doi-asserted-by":"publisher","award":["No. RSGTMT17"],"award-info":[{"award-number":["No. RSGTMT17"]}],"id":[{"id":"10.13039\/100001797","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>For enhanced intracellular accumulation of 6-mercaptopurine (6-MP) in leukemia, a folate receptor-targeted and glutathione (GSH)-responsive polymeric prodrug nanoparticle was made. The nanoparticles were prepared by conjugating 6-MP to carboxymethyl chitosan via a GSH-sensitive carbonyl vinyl sulfide linkage, ultrasonic self-assembly and surface decoration with folate. The TEM graphs shows that the as-synthesized nanoparticles are spherical with a particle size of 170~220 nm. In vitro drug release of nanoparticles demonstrated acceptable stability in PBS containing 20 \u03bcM GSH at pH 7.4. However, the cumulative drug release rate of the samples containing 20 mM and 10 mM GSH medium reached 78.9% and 64.8%, respectively, in pH 5.0 at 20 h. This indicated that this nano-sized system is highly sensitive to GSH. The inhibition ratio of folate-modified nanoparticles compared to unmodified nanoparticles was higher in cancer cells (human promyelocytic leukemia cells, HL-60) while their cytotoxicity was lower in normal cells (mouse fibroblast cell lines, L929). Furthermore, in vitro cancer cell incubation studies confirmed that folate-modified nanoparticles therapeutics were significantly more effective than unmodified nanoparticles therapeutics. Our results suggest that folate receptor-targeting and GSH-stimulation can significantly elevate tumour intracellular drug release. Therefore, folate-modified nanoparticles containing chemoradiotherapy is a potential treatment for leukemia therapy.<\/jats:p>","DOI":"10.3390\/md16110439","type":"journal-article","created":{"date-parts":[[2018,11,9]],"date-time":"2018-11-09T03:08:02Z","timestamp":1541732882000},"page":"439","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":114,"title":["Folate Receptor-Targeted and GSH-Responsive Carboxymethyl Chitosan Nanoparticles Containing Covalently Entrapped 6-Mercaptopurine for Enhanced Intracellular Drug Delivery in Leukemia"],"prefix":"10.3390","volume":"16","author":[{"given":"Xuan","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhong","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Davoudi","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50011, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8657-7489","authenticated-orcid":false,"given":"Hua","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingru","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiong","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihua","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuxiang","family":"Yu","sequence":"additional","affiliation":[{"name":"Hubei Provincial Key Laboratory of Antiviral Drugs, Wuhan East Lake High-Tech Development Zone, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghui","family":"Xiong","sequence":"additional","affiliation":[{"name":"Hubei Provincial Key Laboratory of Antiviral Drugs, Wuhan East Lake High-Tech Development Zone, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50011, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,11,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1080\/09205063.2016.1238128","article-title":"Glutathione-dependent micelles based on carboxymethyl chitosan for delivery of doxorubicin","volume":"27","author":"Zhang","year":"2016","journal-title":"J. Biomater. Sci. Polym. Ed."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.3109\/03639045.2012.694588","article-title":"Sulfobutylether-\u03b2-cyclodextrin\/chitosan nanoparticles enhance the oral permeability and bioavailability of docetaxel","volume":"39","author":"Wu","year":"2013","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1016\/j.jconrel.2013.10.012","article-title":"Multifunctional nanoparticles for targeted delivery of immune activating and cancer therapeutic agents","volume":"172","author":"Jia","year":"2013","journal-title":"J. Control. Release"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.2217\/nnm-2017-0189","article-title":"Efficient induction of apoptosis in cancer cells by paclitaxel-loaded selenium nanoparticles","volume":"12","author":"Bidkar","year":"2017","journal-title":"Nanomedicine"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9485","DOI":"10.1021\/nn302317j","article-title":"Probing of the assembly structure and dynamics within nanoparticles during interaction with blood proteins","volume":"6","author":"Li","year":"2012","journal-title":"ACS Nano"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1515\/bmt-2014-0192","article-title":"The possibility of using magnetic nanoparticles to increase the therapeutic efficiency of Herceptin antibody","volume":"60","author":"Rasaneh","year":"2015","journal-title":"Biomed. Tech."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1166\/jbn.2017.2407","article-title":"Synthesis and in vitro characterization of carboxymethyl chitosan-CBA-doxorubicin conjugate nanoparticles as pH-sensitive drug delivery systems","volume":"13","author":"Hu","year":"2017","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1021\/acs.molpharmaceut.6b00738","article-title":"Optimization of curcumin-loaded PEG-PLGA nanoparticles by GSH functionalization: Investigation of the internalization pathway in neuronal cells","volume":"14","author":"Paka","year":"2016","journal-title":"Mol. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.msec.2016.12.067","article-title":"Preparation and characterization of DOX loaded keratin nanoparticles for pH\/GSH dual responsive release","volume":"73","author":"Li","year":"2017","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4576","DOI":"10.1016\/j.biomaterials.2012.02.059","article-title":"The accumulation of dual pH and temperature responsive micelles in tumors","volume":"33","author":"Chen","year":"2012","journal-title":"Biomaterials"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/S1369-7021(12)70195-5","article-title":"Intracellular drug release nanosystems","volume":"15","author":"Meng","year":"2012","journal-title":"Mater. Today"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.jconrel.2011.01.030","article-title":"Glutathione-responsive nano-vehicles as a promising platform for targeted intracellular drug and gene delivery","volume":"152","author":"Cheng","year":"2011","journal-title":"J. Control. Release"},{"key":"ref_13","first-page":"3550","article-title":"Rapidly disassembling nanomicelles with disulfide-linked PEG shells for glutathione-mediated intracellular drug delivery","volume":"47","author":"Wen","year":"2011","journal-title":"ChemComm"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.carbpol.2017.03.083","article-title":"Folic acid functionalized reduction-responsive magnetic chitosan nanocapsules for targeted delivery and triggered release of drugs","volume":"168","author":"Zhong","year":"2017","journal-title":"Carbohydr. Polym."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10404","DOI":"10.1039\/C7NR03592F","article-title":"Overcoming multidrug resistance using folate receptor-targeted and pH-responsive polymeric nanogels containing covalently entrapped doxorubicin","volume":"9","author":"Chen","year":"2017","journal-title":"Nanoscale"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.ijpharm.2012.06.043","article-title":"Preparation, characterization and in vitro release study of a glutathione-dependent polymeric prodrug Cis-3-(9H-purin-6-ylthio)-acrylic acid-graft-carboxymethyl chitosan","volume":"436","author":"Gong","year":"2012","journal-title":"Int. J. Pharm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.1016\/j.carbpol.2010.10.069","article-title":"Preparation, characterization, and in vitro drug release behavior of 6-mercaptopurine-carboxymethyl chitosan","volume":"83","author":"Zheng","year":"2011","journal-title":"Carbohydr. Polym."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1166\/jbn.2016.2279","article-title":"Redox sensitive shell and core crosslinked hyaluronic acid nanocarriers for tumor-targeted drug delivery","volume":"12","author":"Zheng","year":"2016","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6811","DOI":"10.1021\/jm100509v","article-title":"Folate-targeted therapies for cancer","volume":"53","author":"Xia","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.powtec.2012.11.003","article-title":"Surface modification and paclitaxel drug delivery of folic acid modified polyethylene glycol functionalized hydroxyapatite nanoparticles","volume":"235","author":"Venkatasubbu","year":"2013","journal-title":"Powder Technol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.msec.2017.08.026","article-title":"Folic acid grafted and tertiary amino based pH-responsive pentablock polymeric micelles for targeting anticancer drug delivery","volume":"82","author":"Chen","year":"2018","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.jddst.2017.10.025","article-title":"Camptothecin loaded graphene oxide nanoparticle functionalized with polyethylene glycol and folic acid for anticancer drug delivery","volume":"43","author":"Deb","year":"2018","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1021\/ar7000815","article-title":"Discovery and development of folic-acid-based receptor targeting for imaging and therapy of cancer and inflammatory diseases","volume":"41","author":"Low","year":"2007","journal-title":"Acc. Chem. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/S2221-1691(11)60005-1","article-title":"Nitric oxide mediated Staphylococcus aureus pathogenesis and protective role of nanoconjugated vancomycin","volume":"1","author":"Chakraborty","year":"2011","journal-title":"Asian Pac. J. Trop. Biomed."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.cbpa.2009.03.022","article-title":"Folate-targeted therapeutic and imaging agents for cancer","volume":"13","author":"Low","year":"2009","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10985","DOI":"10.1002\/ange.201701366","article-title":"Smart Human-Serum-Albumin\u2013As2O3 Nanodrug with Self-Amplified Folate Receptor-Targeting Ability for Chronic Myeloid Leukemia Treatment","volume":"129","author":"Peng","year":"2017","journal-title":"Angew. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.nantod.2012.12.003","article-title":"Degradable polymeric nanocapsule for efficient intracellular delivery of a high molecular weight tumor-selective protein complex","volume":"8","author":"Zhao","year":"2013","journal-title":"Nano Today"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.carbpol.2017.01.023","article-title":"Construction and in vitro evaluation of enzyme nanoreactors based on carboxymethyl chitosan for arginine deprivation in cancer therapy","volume":"162","author":"Zeng","year":"2017","journal-title":"Carbohydr. Polym."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2758","DOI":"10.1016\/j.biomaterials.2013.01.005","article-title":"In vitro antitumor activity of methotrexate via pH-sensitive chitosan nanoparticles","volume":"34","author":"Nogueira","year":"2013","journal-title":"Biomaterials"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1080\/03639045.2017.1371738","article-title":"Development of chitosan\/gelatin\/keratin composite containing hydrocortisone sodium succinate as a buccal mucoadhesive patch to treat desquamative gingivitis","volume":"44","author":"Davoudi","year":"2018","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1166\/jbn.2015.1904","article-title":"Simultaneous effect of thiolation and carboxylation of chitosan particles towards mucoadhesive oral insulin delivery applications: An in vitro and in vivo evaluation","volume":"11","author":"Rekha","year":"2015","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"723","DOI":"10.2217\/nnm.14.8","article-title":"Design of chitosan-based nanoformulations for efficient intracellular release of active compounds","volume":"9","author":"Du","year":"2014","journal-title":"Nanomedicine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1016\/j.msec.2017.03.198","article-title":"An overview of carboxymethyl derivatives of chitosan: Their use as biomaterials and drug delivery systems","volume":"77","author":"Chorilli","year":"2017","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S2221-1691(12)60044-6","article-title":"Biocompatibility of folate-modified chitosan nanoparticles","volume":"2","author":"Chakraborty","year":"2012","journal-title":"Asian Pac. J. Trop. Biomed."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.carbpol.2012.07.076","article-title":"Biomedical applications of carboxymethyl chitosans","volume":"91","author":"Upadhyaya","year":"2013","journal-title":"Carbohydr. Polym."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Turbanova, E., Orlova, N., Ratsino, E., and Sokolov, L. (1981). Reaction of Alkyltrifluoromethyldiacetylenes with Mercaptopurines. Chemischer Informationsdienst, 12.","DOI":"10.1002\/chin.198135269"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1002\/jbm.a.36305","article-title":"Intestinal organoids containing poly (lactic-co-glycolic acid) nanoparticles for the treatment of inflammatory bowel diseases","volume":"106","author":"Davoudi","year":"2018","journal-title":"J. Biomed. Mater. Res. B"}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/16\/11\/439\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:28:40Z","timestamp":1760196520000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/16\/11\/439"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,8]]},"references-count":37,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2018,11]]}},"alternative-id":["md16110439"],"URL":"https:\/\/doi.org\/10.3390\/md16110439","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,8]]}}}