{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T13:04:54Z","timestamp":1765976694048,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,6,22]],"date-time":"2023-06-22T00:00:00Z","timestamp":1687392000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Ultrasound-based engineering of carrier-free nanodrugs by supramolecular self-assembly has recently emerged as an innovative and environmentally friendly synthetic approach. By applying high-frequency sound waves (490 kHz) in aqueous solutions, the transformation of small chemotherapeutic and antibiotic drug molecules into carrier-free nanodrugs with anticancer and antimicrobial activities was recently achieved. The transformation of the antibiotic drug molecules, i.e., doxycycline, into stable nanodrugs (~130 nm) with selective anticancer activity was achieved without requiring organic solvents, chemical agents, or surfactants. The obtained nanodrug exhibited reactive oxygen species (ROS)-mediated cytotoxicity on human breast cancer (MDA-MB 231 cells) but a negligible antiproliferative effect on healthy fibroblast cells. Imaging by super-resolution microscopy (STORM) provided insights into the intracellular trafficking and endosomal escape of the nanodrugs. Overall, these findings suggest that small antibiotic drugs can be transformed into chemotherapeutic nanodrugs with high selectivity against cancer cells.<\/jats:p>","DOI":"10.3390\/molecules28134927","type":"journal-article","created":{"date-parts":[[2023,6,23]],"date-time":"2023-06-23T02:34:07Z","timestamp":1687487647000},"page":"4927","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Ultrasonic Transformation of Antibiotic Molecules into a Selective Chemotherapeutic Nanodrug"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8716-1648","authenticated-orcid":false,"given":"Haiyan","family":"Zhu","sequence":"first","affiliation":[{"name":"School of Chemistry, The University of Melbourne, Parkville, Melbourne, VIC 3010, Australia"},{"name":"School of Science, RMIT University, Melbourne, VIC 3000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sukhvir Kaur","family":"Bhangu","sequence":"additional","affiliation":[{"name":"School of Science, RMIT University, Melbourne, VIC 3000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8442-1499","authenticated-orcid":false,"given":"Muthupandian","family":"Ashokkumar","sequence":"additional","affiliation":[{"name":"School of Chemistry, The University of Melbourne, Parkville, Melbourne, VIC 3010, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Cavalieri","sequence":"additional","affiliation":[{"name":"School of Science, RMIT University, Melbourne, VIC 3000, Australia"},{"name":"Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.4137\/CPath.S31563","article-title":"Diversity of breast carcinoma: Histological subtypes and clinical relevance","volume":"8","author":"Makki","year":"2015","journal-title":"Clin. Med. Insights Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1146\/annurev.pu.17.050196.000403","article-title":"Epidemiology and prevention of breast cancer","volume":"17","author":"Kelsey","year":"1996","journal-title":"Annu. Rev. Public Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/ng879","article-title":"Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations","volume":"31","author":"Ouweland","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5837","DOI":"10.1038\/sj.onc.1209875","article-title":"Pathology and gene expression of hereditary breast tumors associated with BRCA1, BRCA2 and CHEK2 gene mutations","volume":"25","author":"Honrado","year":"2006","journal-title":"Oncogene"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.ejca.2006.01.009","article-title":"Endometriosis as a model for inflammation\u2013hormone interactions in ovarian and breast cancers","volume":"42","author":"Ness","year":"2006","journal-title":"Eur. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ja\u0142brzykowska, K., Chrzanowska, A., Roszkowski, P., and Struga, M. (2022). The New Face of a Well-Known Antibiotic: A Review of the Anticancer Activity of Enoxacin and Its Derivatives. Cancers, 14.","DOI":"10.3390\/cancers14133056"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Alshaman, R., Alattar, A., El-Sayed, R.M., Gardouh, A.R., Elshaer, R.E., Elkazaz, A.Y., Eladl, M.A., El-Sherbiny, M., Farag, N.E., and Hamdan, A.M. (2022). Formulation and characterization of doxycycline-loaded polymeric nanoparticles for testing antitumor\/antiangiogenic action in experimental colon cancer in mice. Nanomaterials, 12.","DOI":"10.3390\/nano12050857"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"174593","DOI":"10.1016\/j.ejphar.2021.174593","article-title":"A Brief look at antitumor effects of doxycycline in the treatment of colorectal cancer and combination therapies","volume":"916","author":"Ghasemi","year":"2022","journal-title":"Eur. J. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1016\/j.bmcl.2019.04.045","article-title":"Doxycycline, salinomycin, monensin and ivermectin repositioned as cancer drugs","volume":"29","author":"Markowska","year":"2019","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_10","first-page":"3995","article-title":"Doxycycline induces apoptosis in PANC-1 pancreatic cancer cells","volume":"29","author":"Son","year":"2009","journal-title":"Anticancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1002\/der2.49","article-title":"Treating acne with the tetracycline class of antibiotics: A review","volume":"2","author":"Graber","year":"2021","journal-title":"Dermatol. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1016\/j.eurpolymj.2013.04.033","article-title":"Designing polymeric microparticles for biomedical and industrial applications","volume":"49","author":"Campos","year":"2013","journal-title":"Eur. Polym. J."},{"key":"ref_13","first-page":"2035","article-title":"Safety and efficacy review of doxycycline","volume":"1","author":"Holmes","year":"2009","journal-title":"Clin. Medicine. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1097\/00007691-198206000-00001","article-title":"Doxycycline","volume":"4","author":"Cunha","year":"1982","journal-title":"Ther. Drug Monit."},{"key":"ref_15","unstructured":"Eisen, D.P. (2017). Kucers\u2019 the Use of Antibiotics, CRC Press."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.biopha.2013.03.001","article-title":"Nanoparticle and liposome formulations of doxycycline: Transport properties through Caco-2 cell line and effects on matrix metalloproteinase secretion","volume":"67","author":"Yilmaz","year":"2013","journal-title":"Biomed. Pharmacother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.msec.2017.08.012","article-title":"Hybrid nanofibers based on poly-caprolactone\/gelatin\/hydroxyapatite nanoparticles-loaded Doxycycline: Effective anti-tumoral and antibacterial activity","volume":"83","author":"Scheuermann","year":"2018","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1007\/s00284-020-02058-4","article-title":"Novel biosynthesis of copper nanoparticles using Zingiber and Allium sp. with synergic effect of doxycycline for anticancer and bactericidal activity","volume":"77","author":"Yaqub","year":"2020","journal-title":"Curr. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Gardouh, A.R., Attia, M.A., Enan, E.T., Elbahaie, A.M., Fouad, R.A., El-Shafey, M., Youssef, A.M., Alomar, S.Y., Ali, Z.A.-E., and Zaitone, S.A. (2020). Synthesis and antitumor activity of doxycycline polymeric nanoparticles: Effect on tumor apoptosis in solid ehrlich carcinoma. Molecules, 25.","DOI":"10.3390\/molecules25143230"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12302","DOI":"10.1002\/anie.201706771","article-title":"Sono-RAFT Polymerization in Aqueous Medium","volume":"56","author":"McKenzie","year":"2017","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Baral, A., Bhangu, S.K., Cimino, R., Pelin, J.N., Alves, W.A., Chattopadhyay, S., Ashokkumar, M., and Cavalieri, F. (2020). Sono-Assembly of the [Arg-Phe] 4 Octapeptide into Biofunctional Nanoparticles. Nanomaterials, 10.","DOI":"10.3390\/nano10091772"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1021\/acsmacrolett.9b00576","article-title":"Sono-polymerization of poly (ethylene glycol)-based nanoparticles for targeted drug delivery","volume":"8","author":"Gao","year":"2019","journal-title":"ACS Macro Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ultsonch.2004.01.037","article-title":"Using sonochemistry for the fabrication of nanomaterials","volume":"11","author":"Gedanken","year":"2004","journal-title":"Ultrason. Sonochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.eurpolymj.2018.06.004","article-title":"Ultrasound promoted synthesis and properties of chitosan nanocomposites containing carbon nanotubes and silver nanoparticles","volume":"105","author":"Bibi","year":"2018","journal-title":"Eur. Polym. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.1021\/la804278w","article-title":"Novel one-pot synthesis of magnetite latex nanoparticles by ultrasound irradiation","volume":"25","author":"Teo","year":"2009","journal-title":"Langmuir"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1800353","DOI":"10.1002\/macp.201800353","article-title":"Ultrasound-Assisted Synthesis of Cross-Linked Poly (ethylene glycol) Nanostructures with Hydrophobic Core and Hydrophilic Shell","volume":"219","author":"Zhu","year":"2018","journal-title":"Macromol. Chem. Phys."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2107964","DOI":"10.1002\/adma.202107964","article-title":"Transforming the chemical structure and bio-nano activity of doxorubicin by ultrasound for selective killing of cancer cells","volume":"34","author":"Bhangu","year":"2022","journal-title":"Adv. Mater."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"106029","DOI":"10.1016\/j.ultsonch.2022.106029","article-title":"Sonosynthesis of nanobiotics with antimicrobial and antioxidant properties","volume":"86","author":"Zhu","year":"2022","journal-title":"Ultrason. Sonochem."},{"key":"ref_29","first-page":"4117","article-title":"Induction of mitochondrial dysfunction and oxidative damage by antibiotic drug doxycycline enhances the responsiveness of glioblastoma to chemotherapy","volume":"23","author":"Tan","year":"2017","journal-title":"Med. Sci. Monit. Int. Med. J. Exp. Clin. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1111\/j.1600-0854.2009.00961.x","article-title":"Transferrin-directed internalization and cycling of transferrin receptor 2","volume":"10","author":"Chen","year":"2009","journal-title":"Traffic"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.clim.2006.06.006","article-title":"The transferrin receptor part II: Targeted delivery of therapeutic agents into cancer cells","volume":"121","author":"Daniels","year":"2006","journal-title":"Clin. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"11306","DOI":"10.1021\/ja1043177","article-title":"The complex role of multivalency in nanoparticles targeting the transferrin receptor for cancer therapies","volume":"132","author":"Wang","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1080\/09205063.2012.690282","article-title":"Modeling the proton sponge hypothesis: Examining proton sponge effectiveness for enhancing intracellular gene delivery through multiscale modeling","volume":"24","author":"Freeman","year":"2013","journal-title":"J. Biomater. Sci. Polym. Ed."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1002\/(SICI)1097-0290(20000120)67:2<217::AID-BIT11>3.0.CO;2-Q","article-title":"Design of imidazole-containing endosomolytic biopolymers for gene delivery","volume":"67","author":"Pack","year":"2000","journal-title":"Biotechnol. Bioeng."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.tcb.2013.08.003","article-title":"Mitochondria: Gatekeepers of response to chemotherapy","volume":"23","author":"Sarosiek","year":"2013","journal-title":"Trends Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Mitra, S., Nguyen, L.N., Akter, M., Park, G., Choi, E.H., and Kaushik, N.K. (2019). Impact of ROS generated by chemical, physical, and plasma techniques on cancer attenuation. Cancers, 11.","DOI":"10.3390\/cancers11071030"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.ccr.2006.08.015","article-title":"Reactive oxygen species in cancer cells: Live by the sword, die by the sword","volume":"10","author":"Schumacker","year":"2006","journal-title":"Cancer Cell"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/13\/4927\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:58:54Z","timestamp":1760126334000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/13\/4927"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,22]]},"references-count":37,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["molecules28134927"],"URL":"https:\/\/doi.org\/10.3390\/molecules28134927","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2023,6,22]]}}}