{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T18:29:15Z","timestamp":1780511355400,"version":"3.54.1"},"reference-count":40,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T00:00:00Z","timestamp":1740614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Research, Innovation and Digitization","award":["PNRR-III-C9-2022-I8-291"],"award-info":[{"award-number":["PNRR-III-C9-2022-I8-291"]}]},{"name":"Ministry of Research, Innovation and Digitization","award":["760081\/23.05.2023"],"award-info":[{"award-number":["760081\/23.05.2023"]}]},{"name":"Ministry of Research, Innovation and Digitization","award":["4716\/25.02.2021"],"award-info":[{"award-number":["4716\/25.02.2021"]}]},{"name":"\u201cGrigore T. Popa\u201d University of Medicine and Pharmacy of Iasi","award":["PNRR-III-C9-2022-I8-291"],"award-info":[{"award-number":["PNRR-III-C9-2022-I8-291"]}]},{"name":"\u201cGrigore T. Popa\u201d University of Medicine and Pharmacy of Iasi","award":["760081\/23.05.2023"],"award-info":[{"award-number":["760081\/23.05.2023"]}]},{"name":"\u201cGrigore T. Popa\u201d University of Medicine and Pharmacy of Iasi","award":["4716\/25.02.2021"],"award-info":[{"award-number":["4716\/25.02.2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Objectives: This work aimed to develop and investigate liposomes incorporating Rhein (Lip-Rh) into the liposomal membrane to enhance the compound\u2019s water solubility and oral bioavailability. Methods: Liposomes were produced by the thin lipid film technique, with a phosphatidylcholine-to-cholesterol molar ratio of 5:1, dissolved in chloroform and methanol, and thereafter hydrated with ultrapure water and subjected to sonication. The resultant liposomes were studied from a physicochemical perspective using DLS, zeta potential, STEM, UV\u2013Vis, and fluorescence spectroscopies, while oral bioavailability was assessed by fluorescence imaging. Additionally, cell viability assays were performed on tumour cells (MCF-7) in comparison to normal cells (HGFs). Results: The resultant nanoparticles exhibited relatively uniform sizes and narrow size distribution. In vivo fluorescence imaging studies performed on Wistar rats demonstrated significantly enhanced oral bioavailability for Lip-Rh, with rapid absorption into the bloodstream observed one hour after administration, in contrast to the free compound dissolved in vegetable oil. Cell viability assays demonstrated higher cytotoxicity of Lip-Rh towards MCF-7 cells compared to HGF cells, highlighting the selective therapeutic potential of the product. Moreover, we determined that the optimal dose of Rhein per kilogram of body weight, when encapsulated in liposomes, is approximately 2.5 times less than when Rhein is delivered in its unencapsulated form. Conclusions: Lip-Rh is a promising candidate for oncological treatments, presenting three key advantages: increased cytotoxicity towards tumour cells, protection of normal tissues, and the practicality of oral delivery. Additional investigation is required to explore its application in anticancer therapy, whether as monotherapy or as a complementary treatment.<\/jats:p>","DOI":"10.3390\/pharmaceutics17030307","type":"journal-article","created":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T03:37:57Z","timestamp":1740627477000},"page":"307","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Fluorescent Rhein-Loaded Liposomes for In Vivo Biodistribution Study"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4585-4116","authenticated-orcid":false,"given":"Silviu Iulian","family":"Filipiuc","sequence":"first","affiliation":[{"name":"Centre of Advanced Research in Bionanoconjugates and Biopolymers, \u201cPetru Poni\u201d Institute of Macromolecular Chemistry, 700487 Iasi, Romania"},{"name":"Advanced Center for Research and Development in Experimental Medicine \u201cProf. Ostin C. Mungiu\u201d, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5581-4624","authenticated-orcid":false,"given":"Natalia","family":"Simionescu","sequence":"additional","affiliation":[{"name":"Centre of Advanced Research in Bionanoconjugates and Biopolymers, \u201cPetru Poni\u201d Institute of Macromolecular Chemistry, 700487 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4440-9628","authenticated-orcid":false,"given":"Gabriela Dumitri\u021ba","family":"Stanciu","sequence":"additional","affiliation":[{"name":"Advanced Center for Research and Development in Experimental Medicine \u201cProf. Ostin C. Mungiu\u201d, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4340-4756","authenticated-orcid":false,"given":"Adina","family":"Coroaba","sequence":"additional","affiliation":[{"name":"Centre of Advanced Research in Bionanoconjugates and Biopolymers, \u201cPetru Poni\u201d Institute of Macromolecular Chemistry, 700487 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6629-6460","authenticated-orcid":false,"given":"Narcisa Laura","family":"Marangoci","sequence":"additional","affiliation":[{"name":"Centre of Advanced Research in Bionanoconjugates and Biopolymers, \u201cPetru Poni\u201d Institute of Macromolecular Chemistry, 700487 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2131-5322","authenticated-orcid":false,"given":"Leontina Elena","family":"Filipiuc","sequence":"additional","affiliation":[{"name":"Advanced Center for Research and Development in Experimental Medicine \u201cProf. Ostin C. Mungiu\u201d, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4021-982X","authenticated-orcid":false,"given":"Mariana","family":"Pinteala","sequence":"additional","affiliation":[{"name":"Centre of Advanced Research in Bionanoconjugates and Biopolymers, \u201cPetru Poni\u201d Institute of Macromolecular Chemistry, 700487 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7563-1267","authenticated-orcid":false,"given":"Cristina Mariana","family":"Uritu","sequence":"additional","affiliation":[{"name":"Centre of Advanced Research in Bionanoconjugates and Biopolymers, \u201cPetru Poni\u201d Institute of Macromolecular Chemistry, 700487 Iasi, Romania"},{"name":"Advanced Center for Research and Development in Experimental Medicine \u201cProf. Ostin C. Mungiu\u201d, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9868-1999","authenticated-orcid":false,"given":"Bogdan Ionel","family":"Tamba","sequence":"additional","affiliation":[{"name":"Advanced Center for Research and Development in Experimental Medicine \u201cProf. Ostin C. Mungiu\u201d, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1002\/ptr.7429","article-title":"Anti-inflammatory Effect of Rhein on Ulcerative Colitis via Inhibiting PI3K\/Akt\/mTOR Signaling Pathway and Regulating Gut Microbiota","volume":"36","author":"Dong","year":"2022","journal-title":"Phytother. Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Folliero, V., Dell\u2019Annunziata, F., Roscetto, E., Amato, A., Gasparro, R., Zannella, C., Casolaro, V., Filippis, A.D., Catania, M.R., and Franci, G. (2022). Rhein: A Novel Antibacterial Compound against Streptococcus Mutans Infection. Microbiol. Res., 261.","DOI":"10.1016\/j.micres.2022.127062"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Deng, T., Du, J., Yin, Y., Cao, B., Wang, Z., Zhang, Z., Yang, M., and Han, J. (2023). Rhein for Treating Diabetes Mellitus: A Pharmacological and Mechanistic Overview. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1106260"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Fu, Y., Yang, L., Liu, L., Kong, L., Sun, H., Sun, Y., Yin, F., Yan, G., and Wang, X. (2024). Rhein: An Updated Review Concerning Its Biological Activity, Pharmacokinetics, Structure Optimization, and Future Pharmaceutical Applications. Pharmaceuticals, 17.","DOI":"10.3390\/ph17121665"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"952504","DOI":"10.1155\/2012\/952504","article-title":"Rhein Induces Apoptosis in Human Breast Cancer Cells","volume":"2012","author":"Chang","year":"2012","journal-title":"Evid. -Based Complement. Altern. Med."},{"key":"ref_6","first-page":"379","article-title":"The Role of Ca+2 on Rhein-Induced Apoptosis in Human Cervical Cancer Ca Ski Cells","volume":"27","author":"Ip","year":"2007","journal-title":"Anticancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhang, H., Yi, J.-K., Huang, H., Park, S., Park, S., Kwon, W., Kim, E., Jang, S., Kim, S.-Y., and Choi, S.-K. (2021). Rhein Suppresses Colorectal Cancer Cell Growth by Inhibiting the mTOR Pathway In Vitro and In Vivo. Cancers, 13.","DOI":"10.3390\/cancers13092176"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.2147\/CMAR.S171517","article-title":"Rhein Shows Potent Efficacy against Non-Small-Cell Lung Cancer through Inhibiting the STAT3 Pathway","volume":"11","author":"Yang","year":"2019","journal-title":"Cancer Manag. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s13046-018-1015-9","article-title":"Rhein Sensitizes Human Pancreatic Cancer Cells to EGFR Inhibitors by Inhibiting STAT3 Pathway","volume":"38","author":"Yang","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s13659-020-00272-y","article-title":"Anti-Inflammatory Effects and Mechanisms of Rhein, an Anthraquinone Compound, and Its Applications in Treating Arthritis: A Review","volume":"10","author":"Wang","year":"2020","journal-title":"Nat. Prod. Bioprospecting"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1053\/joca.1998.0201","article-title":"eAnti-Interleukin-1 Effects of Diacerein and Rhein in Human Osteoarthritic Synovial Tissue and Cartilage Cultures","volume":"7","author":"Yaron","year":"1999","journal-title":"Osteoarthr. Cartil."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.6026\/97320630081195","article-title":"Anti Hyperglycaemic Study of Natural Inhibitors for Insulin Receptor","volume":"8","author":"Chatterjee","year":"2012","journal-title":"Bioinformation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"374936","DOI":"10.1155\/2012\/374936","article-title":"Rhein Reduces Fat Weight in Db\/Db Mouse and Prevents Diet-Induced Obesity in C57Bl\/6 Mouse through the Inhibition of PPAR \u03b3 Signaling","volume":"2012","author":"Zhang","year":"2012","journal-title":"PPAR Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Dell\u2019Annunziata, F., Folliero, V., Palma, F., Crudele, V., Finamore, E., Sanna, G., Manzin, A., Filippis, A.D., Galdiero, M., and Franci, G. (2022). Anthraquinone Rhein Exhibits Antibacterial Activity against Staphylococcus Aureus. Appl. Sci., 12.","DOI":"10.3390\/app12178691"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"110019","DOI":"10.1016\/j.fsi.2024.110019","article-title":"Antiviral Effects of Rhein on Largemouth Bass Ranavirus (LMBRaV)","volume":"155","author":"Chen","year":"2024","journal-title":"Fish Shellfish Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Liu, J., Ding, D., Liu, F., and Chen, Y. (2022). Rhein Inhibits the Progression of Chemoresistant Lung Cancer Cell Lines via the Stat3\/Snail\/MMP2\/MMP9 Pathway. BioMed Res. Int., 2022.","DOI":"10.1155\/2022\/7184871"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Liu, P., Chen, G., and Zhang, J. (2022). A Review of Liposomes as a Drug Delivery System: Current Status of Approved Products, Regulatory Environments, and Future Perspectives. Molecules, 27.","DOI":"10.3390\/molecules27041372"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lombardo, D., and Kiselev, M.A. (2022). Methods of Liposomes Preparation: Formation and Control Factors of Versatile Nanocarriers for Biomedical and Nanomedicine Application. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14030543"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1166\/jbn.2014.1690","article-title":"Heparin-Anthranoid Conjugates Associated with Nanomagnetite Particles and Their Cytotoxic Effect on Cancer Cells","volume":"10","author":"Uritu","year":"2014","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.2147\/DDDT.S81320","article-title":"Preparation, Characterization, and in Vivo Study of Rhein-Loaded Poly(Lactic-Co-Glycolic Acid) Nanoparticles for Oral Delivery","volume":"9","author":"Gu","year":"2015","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_21","first-page":"217","article-title":"Mathematical Modelling of the Release Profile of Anthraquinone-Derived Drugs Encapsulated on Magnetite Nanoparticles","volume":"58","author":"Bacaita","year":"2013","journal-title":"Rev. Roum. De Chim."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2460666","DOI":"10.1080\/10717544.2025.2460666","article-title":"Exploring the Effects of Cannabidiol Encapsulation in Liposomes on Their Physicochemical Properties and Biocompatibility","volume":"32","author":"Jurgelane","year":"2025","journal-title":"Drug Deliv."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Voicu, G., Mocanu, C.A., Safciuc, F., Anghelache, M., Deleanu, M., Cecoltan, S., Pinteala, M., Uritu, C.M., Droc, I., and Simionescu, M. (2023). Nanocarriers of shRNA-Runx2 Directed to Collagen IV as a Nanotherapeutic System to Target Calcific Aortic Valve Disease. Mater. Today Bio, 20.","DOI":"10.1016\/j.mtbio.2023.100620"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"125806","DOI":"10.1016\/j.colsurfa.2020.125806","article-title":"Transferrin-Functionalized Liposomes for Docetaxel Delivery to Prostate Cancer Cells","volume":"611","author":"Eloy","year":"2021","journal-title":"Colloids Surf. A Physicochem. Eng. Asp."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"104984","DOI":"10.1016\/j.supflu.2020.104984","article-title":"Sustainable Technologies for Liposome Preparation","volume":"165","author":"Maja","year":"2020","journal-title":"J. Supercrit. Fluids"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Yu, B., Lee, R.J., and Lee, L.J. (2009). Microfluidic Methods for Production of Liposomes. Methods in Enzymology, Elsevier.","DOI":"10.1016\/S0076-6879(09)65007-2"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Aden, S., Snoj, T., and Anderluh, G. (2021). The Use of Giant Unilamellar Vesicles to Study Functional Properties of Pore-Forming Toxins. Methods in Enzymology, Elsevier.","DOI":"10.1016\/bs.mie.2021.01.016"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kannavou, M., Natsaridis, E., and Missirlis, A. (2024). Liposomes for Drug Delivery by Localized Routes of Administration. Liposomes in Drug Delivery, Academic Press.","DOI":"10.1016\/B978-0-443-15491-1.00025-0"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.jconrel.2019.04.025","article-title":"Liposomes Used as a Vaccine Adjuvant-Delivery System: From Basics to Clinical Immunization","volume":"303","author":"Wang","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Cipollaro, L., Trucillo, P., Bragazzi, N.L., Porta, G.D., Reverchon, E., and Maffulli, N. (2020). Liposomes for Intra-Articular Analgesic Drug Delivery in Orthopedics: State-of-Art and Future Perspectives. Insights from a Systematic Mini-Review of the Literature. Medicina, 56.","DOI":"10.3390\/medicina56090423"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"101509","DOI":"10.1016\/j.jddst.2020.101509","article-title":"Recent Advances in Inhalable Liposomes for Treatment of Pulmonary Diseases: Concept to Clinical Stance","volume":"56","author":"Mehta","year":"2020","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1080\/08982104.2024.2341139","article-title":"Liposomes in the Cosmetics: Present and Outlook","volume":"34","author":"Huang","year":"2024","journal-title":"J. Liposome Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/0005-2736(93)90115-G","article-title":"Subcutaneous Administration of Liposomes: A Comparison with the Intravenous and Intraperitoneal Routes of Injection","volume":"1150","author":"Allen","year":"1993","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Biomembr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"102757","DOI":"10.1016\/j.cis.2022.102757","article-title":"Liposomes as Biocompatible and Smart Delivery Systems\u2014The Current State","volume":"309","author":"Dymek","year":"2022","journal-title":"Adv. Colloid Interface Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12599","DOI":"10.1074\/jbc.RA119.009683","article-title":"Nanoscale Dynamics of Cholesterol in the Cell Membrane","volume":"294","author":"Pinkwart","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1590\/S0100-879X1999000200006","article-title":"Liposomes: From Biophysics to the Design of Peptide Vaccines","volume":"32","year":"1999","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1529\/biophysj.106.096362","article-title":"Solution pH Alters Mechanical and Electrical Properties of Phosphatidylcholine Membranes: Relation between Interfacial Electrostatics, Intramembrane Potential, and Bending Elasticity","volume":"92","author":"Zhou","year":"2007","journal-title":"Biophys. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/978-1-4939-7352-1_8","article-title":"Imaging of Liposomes by Transmission Electron Microscopy","volume":"Volume 1682","author":"McNeil","year":"2018","journal-title":"Characterization of Nanoparticles Intended for Drug Delivery"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1097\/CAD.0b013e3283182913","article-title":"Rhein Lysinate Suppresses the Growth of Breast Cancer Cells and Potentiates the Inhibitory Effect of Taxol in Athymic Mice","volume":"20","author":"Lin","year":"2009","journal-title":"Anti-Cancer Drugs"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"10665","DOI":"10.7150\/thno.43528","article-title":"Rhein Modulates Host Purine Metabolism in Intestine through Gut Microbiota and Ameliorates Experimental Colitis","volume":"10","author":"Wu","year":"2020","journal-title":"Theranostics"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/3\/307\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:43:04Z","timestamp":1760028184000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/3\/307"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,27]]},"references-count":40,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["pharmaceutics17030307"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17030307","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,27]]}}}