{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T11:38:53Z","timestamp":1790163533347,"version":"4.1.0"},"reference-count":32,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2019,9,10]],"date-time":"2019-09-10T00:00:00Z","timestamp":1568073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LR17H180001, LY19H180002"],"award-info":[{"award-number":["LR17H180001, LY19H180002"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["51433005"],"award-info":[{"award-number":["51433005"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tumorous metastasis is a difficult challenge to resolve for researchers and for clinicians. Targeted delivery of antitumor drugs towards tumor cells\u2019 nuclei can be a practical approach to resolving this issue. This work describes an efficient nuclear-targeting delivery system prepared from trans-activating transcriptional activator (TAT) peptide-functionalized graphene nanocarriers. The TAT peptide, originally observed in a human immunodeficiency virus 1 (HIV-1), was incorporated with graphene via an edge-functionalized ball-milling method developed by the author\u2019s research group. High tumor-targeting capability of the resulting nanocarrier was realized by the strong affinity between TAT and the nuclei of cancer cells, along with the enhanced permeability and retention (EPR) effect of two-dimensional graphene nanosheets. Subsequently, a common antitumor drug, mitomycin C (MMC), was covalently linked to the TAT-functionalized graphene (TG) to form a nuclear-targeted nanodrug MMC-TG. The presence of nanomaterials inside the nuclei of ocular choroidal melanoma (OCM-1) cells was shown using transmission electron microscopy (TEM) and confocal laser scanning microscopy. In vitro results from a Transwell co-culture system showed that most of the MMC-TG nanodrugs were delivered in a targeted manner to the tumorous OCM-1 cells, while a very small amount of MMC-TG was delivered in a non-targeted manner to normal human retinal pigment epithelial (ARPE-19) cells. TEM results further confirmed that apoptosis of OCM-1 cells was started from the lysis of nuclear substances, followed by the disappearance of nuclear membrane and cytoplasm. This suggests that the as-synthesized MMC-TG is a promising nuclear-target nanodrugfor resolution of tumorous metastasis issues at the headstream.<\/jats:p>","DOI":"10.3390\/ijms20184454","type":"journal-article","created":{"date-parts":[[2019,9,10]],"date-time":"2019-09-10T10:52:26Z","timestamp":1568112746000},"page":"4454","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["The Use of TAT Peptide-Functionalized Graphene as a Highly Nuclear-Targeting Carrier System for Suppression of Choroidal Melanoma"],"prefix":"10.3390","volume":"20","author":[{"given":"Suyan","family":"Shan","sequence":"first","affiliation":[{"name":"Laboratory of Nanoscale Biosensing and Bioimaging, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, 270 Xueyuanxi Road, Wenzhou 325027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujuan","family":"Jia","sequence":"additional","affiliation":[{"name":"Laboratory of Nanoscale Biosensing and Bioimaging, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, 270 Xueyuanxi Road, Wenzhou 325027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Lawson","sequence":"additional","affiliation":[{"name":"ARC Center of Excellence for Nanoscale Bio Photonics, Macquarie University, Sydney, NSW 2109, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Yan","sequence":"additional","affiliation":[{"name":"Laboratory of Nanoscale Biosensing and Bioimaging, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, 270 Xueyuanxi Road, Wenzhou 325027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mimi","family":"Lin","sequence":"additional","affiliation":[{"name":"Laboratory of Nanoscale Biosensing and Bioimaging, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, 270 Xueyuanxi Road, Wenzhou 325027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6932-583X","authenticated-orcid":false,"given":"Yong","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory of Nanoscale Biosensing and Bioimaging, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, 270 Xueyuanxi Road, Wenzhou 325027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/S0039-6257(00)00210-1","article-title":"Chemotherapy for eye cancer","volume":"45","author":"Wilson","year":"2001","journal-title":"Surv. Ophthalmol."},{"key":"ref_2","first-page":"865","article-title":"Enoxacin-loaded poly lactic-co-glycolic acid coating on porous magnesium scaffold as a drug delivery system antibacterial properties and inhibition of osteoclastic bone resorption","volume":"3","author":"Li","year":"2016","journal-title":"Adv. Mater. Interfaces"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3190","DOI":"10.1039\/C4TB00015C","article-title":"Graphene quantum dots conjugated albumin nanoparticles for targeted drug delivery and imaging of pancreatic cancer","volume":"2","author":"Nigam","year":"2014","journal-title":"J. Mater. Chem. B"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3250","DOI":"10.1021\/am500325w","article-title":"Up-conversion nanoparticle assembled mesoporous silica composites: Synthesis, plasmon-enhanced luminescence, and near-infrared light triggered drug release","volume":"6","author":"Niu","year":"2014","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.drudis.2016.10.001","article-title":"Nanoporous metal organic frameworks as hybrid polymer-metal composites for drug delivery and biomedical applications","volume":"22","author":"Beg","year":"2017","journal-title":"Drug Discov. Today"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"123","DOI":"10.4155\/fmc.14.140","article-title":"Molecularly imprinted polymeric micro-and nano-particles for the targeted delivery of active molecules","volume":"7","author":"Ma","year":"2015","journal-title":"Future Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2575","DOI":"10.3109\/10717544.2015.1035466","article-title":"Prodrug-based nano-drug delivery system for co-encapsulate paclitaxel and carboplatin for lung cancer treatment","volume":"23","author":"Zhang","year":"2016","journal-title":"Drug Deliv."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1016\/j.ejca.2015.07.013","article-title":"Uveal melanoma UK national guidelines","volume":"51","author":"Nathan","year":"2015","journal-title":"Eur. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Castet, F., Garcia-Mulero, S., Sanz-Pamplona, R., Cuellar, A., Casanovas, O., Caminal, J., and Piulats, J. (2019). Uveal melanoma, angiogenesis and immunotherapy, is there any hope?. Cancers, 11.","DOI":"10.3390\/cancers11060834"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/eye.2016.275","article-title":"Uveal melanoma: Relatively rare but deadly cancer","volume":"31","author":"Kaliki","year":"2017","journal-title":"Eye"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.preteyeres.2018.03.004","article-title":"Ocular treatment of choroidal melanoma in relation to the outcome of metastatic death\u2014A personal view","volume":"66","author":"Damato","year":"2018","journal-title":"Prog. Retin Eye Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1800377","DOI":"10.1002\/adhm.201800377","article-title":"A transferrin triggered pathway for highly targeted delivery of graphene-based nanodrugs to treat choroidal melanoma","volume":"7","author":"Zhao","year":"2018","journal-title":"Adv. Healthc. Mater."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1039\/C5PY00047E","article-title":"Graphene oxide complex as a pH-sensitive antitumor drug","volume":"6","author":"Cheng","year":"2015","journal-title":"Polym. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1126\/science.1095833","article-title":"Drug delivery systems: Entering the mainstream","volume":"303","author":"Allen","year":"2004","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jconrel.2018.06.023","article-title":"Cell penetrating peptides in ocular drug delivery: State of the art","volume":"284","author":"Pescina","year":"2018","journal-title":"J. Control Release"},{"key":"ref_16","first-page":"123","article-title":"The TAT protein transport system: Intriguing questions and conundrums","volume":"365","author":"Shruthi","year":"2018","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8367","DOI":"10.1039\/c2jm30961k","article-title":"Electroactive and biocompatible hydroxyl- functionalized graphene by ball milling","volume":"22","author":"Yan","year":"2012","journal-title":"J. Mater. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6834","DOI":"10.1021\/acsami.5b12843","article-title":"Aligned nanofibers from polypyrrole\/graphene as electrodes for regeneration of optic nerve via electrical stimulation","volume":"8","author":"Yan","year":"2016","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5375","DOI":"10.1016\/j.biomaterials.2005.01.050","article-title":"Biodegradable dextran-based microspheres for delivery of anticancer drug mitomycin C","volume":"26","author":"Cheung","year":"2005","journal-title":"Biomaterials"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1600590","DOI":"10.1002\/admi.201600590","article-title":"Optical biosensors based on nitrogen-doped graphene functionalized with magnetic nanoparticles","volume":"3","author":"Zhang","year":"2016","journal-title":"Adv. Mater. Interfaces"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1021\/nl025856b","article-title":"Carbon nanotubols from mechanochemical reaction","volume":"3","author":"Pan","year":"2003","journal-title":"Nano Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1166\/jbn.2018.2597","article-title":"Hydroxyl-functional groups on graphene trigger the targeted delivery of antitumor drugs","volume":"14","author":"Lin","year":"2018","journal-title":"J. Biomed. Nanotechol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zheng, Z., Huang, L., Yan, L., Yuan, F., Wang, L., Wang, K., Lawson, T., Lin, M., and Liu, Y. (2019). Polyaniline functionalized graphene nanoelectrodes for the regeneration of PC12 cells via electrical stimulation. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20082013"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1002\/dev.21472","article-title":"Anticipatory eye movements and long-term memory in early infancy","volume":"58","author":"Adler","year":"2016","journal-title":"Dev. Psychobiol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kit, D., Katz, L., Sullivan, B., Synder, K., Ballar, D., and Hayhoe, M. (2014). Eye movements, visual search and scene memory, in an immersive virtual environment. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0094362"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1002\/bjs.9189","article-title":"Systematic review and meta-analysis of liver resection for metastatic melanoma","volume":"100","author":"Aubin","year":"2005","journal-title":"Brit. J. Surg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.jconrel.2010.08.027","article-title":"To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery","volume":"148","author":"Danhier","year":"2010","journal-title":"J. Control. Release"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1002\/smll.201101613","article-title":"Engineered redox-responsive PEG detachment mechanism in PEGylated nano-graphene oxide for intracellular drug delivery","volume":"8","author":"Wen","year":"2012","journal-title":"Small"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2040","DOI":"10.1111\/j.1349-7006.2009.01297.x","article-title":"Curcumin reduced the side effects of mitomycin C by inhibiting GRP58-mediated DNA cross-linking in MCF-7 breast cancer xenografts","volume":"100","author":"Zhou","year":"2009","journal-title":"Cancer Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"321","DOI":"10.2165\/00003495-200666030-00005","article-title":"Mitomycin-Clinical applications in ophthalmic practice","volume":"66","author":"Abraham","year":"2006","journal-title":"Drugs"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0002-9394(03)00207-1","article-title":"Inrumescent cataract after topical mitomycin-C for conjunctival malignant melanoma","volume":"136","author":"Sacu","year":"2003","journal-title":"Am. J. Ophthalmol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"419","DOI":"10.2217\/fon.12.191","article-title":"Repetitive chemoembolization of hypovascular liver metastases from the most common primary sites","volume":"9","author":"Farshid","year":"2013","journal-title":"Future Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/18\/4454\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:18:19Z","timestamp":1760188699000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/18\/4454"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,10]]},"references-count":32,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2019,9]]}},"alternative-id":["ijms20184454"],"URL":"https:\/\/doi.org\/10.3390\/ijms20184454","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,10]]}}}