{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:16:18Z","timestamp":1760058978137,"version":"build-2065373602"},"reference-count":26,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,11]],"date-time":"2025-05-11T00:00:00Z","timestamp":1746921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"DOR (University of Padova)","award":["PSR2023"],"award-info":[{"award-number":["PSR2023"]}]},{"name":"Universit\u00e0 degli Studi di Milano","award":["PSR2023"],"award-info":[{"award-number":["PSR2023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Cannabigerol (CBG) is a non-psychoactive phytocannabinoid with significant therapeutic potential, showing emerging applications in drug delivery. This study aimed to develop and evaluate CBG-conjugated nanoparticles (NPs) incorporating tubulin-targeting drugs to enhance anticancer activity. Methods: CBG was conjugated with N-desacetylthiocolchicine, paclitaxel, and camptothecin using sebacic acid and 4,4\u2032-dithiodibutyric acid as linkers, and nanoparticles were obtained. The NPs were characterized by their stability and size (hydrodynamic diameters &lt; 90 nm). Their antiproliferative activity was assessed in three human tumor cell lines and non-tumorigenic cells. Their cellular uptake and mechanisms of action were investigated via confocal microscopy and cell cycle analysis. Results: The chemical composition of the linkers significantly influenced the antiproliferative effect, with the NPs containing 4,4\u2032-dithiodibutyric acid demonstrating higher activity. Notably, NP3b, formulated with this linker, exhibited up to an 80-fold increase in antiproliferative potency compared to its sebacic acid counterpart (NP3a). In mesothelioma cells (MSTO-211H), NP3b displayed significantly higher cytotoxicity than in non-tumorigenic mesothelial cells (MeT-5A), indicating selectivity for cancer cells. Further analysis in glioblastoma cells confirmed that the NPs retained the microtubule-disrupting effects of their parent drugs. Conclusions: These findings highlight the potential of CBG-based NPs as versatile nanomedicine platforms for targeted cancer therapy. This study underscores the importance of linker chemistry in modulating therapeutic efficacy and supports the development of multifunctional drug delivery systems.<\/jats:p>","DOI":"10.3390\/pharmaceutics17050636","type":"journal-article","created":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T12:18:06Z","timestamp":1747052286000},"page":"636","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Self-Assembled Cannabigerol-Based Nanoparticles: Design, Synthesis, and Antiproliferative Activity"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9111-9768","authenticated-orcid":false,"given":"Arianna","family":"Amenta","sequence":"first","affiliation":[{"name":"Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Nordio","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via F. Marzolo 5, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Piazzola","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via F. Marzolo 5, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2370-9333","authenticated-orcid":false,"given":"Maria Luisa","family":"Di Paolo","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Padova, via G. Colombo 3, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4428-5833","authenticated-orcid":false,"given":"Fabio","family":"Milani","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Giacomini","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5881-7142","authenticated-orcid":false,"given":"Andrea","family":"Citarella","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Umberto","family":"Ciriello","sequence":"additional","affiliation":[{"name":"LINNEA SA, 6595 Riazzino, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Paladino","sequence":"additional","affiliation":[{"name":"LINNEA SA, 6595 Riazzino, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2325-3583","authenticated-orcid":false,"given":"Sara","family":"Pellegrino","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science, University of Milan, Via Golgi 19, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Silvestri","sequence":"additional","affiliation":[{"name":"Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1819-4483","authenticated-orcid":false,"given":"Valerio","family":"Fasano","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9828-9388","authenticated-orcid":false,"given":"Lisa","family":"Dalla Via","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via F. Marzolo 5, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6180-9581","authenticated-orcid":false,"given":"Daniele","family":"Passarella","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3591","DOI":"10.1021\/nn100869j","article-title":"Directed self-assembly of nanoparticles","volume":"4","author":"Grzelczak","year":"2010","journal-title":"ACS Nano"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1016\/j.drudis.2016.06.018","article-title":"Self-assembly drug conjugates for anticancer treatment","volume":"21","author":"Fumagalli","year":"2016","journal-title":"Drug Discov. Today"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4816","DOI":"10.1021\/acsbiomaterials.0c00883","article-title":"Self-Assembled Organic Nanomaterials for Drug Delivery, Bioimaging, and Cancer Therapy","volume":"6","author":"Zhang","year":"2020","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"43510","DOI":"10.1021\/acsomega.2c04098","article-title":"Natural Small-Molecule-Based Carrier-Free Self-Assembly Library Originated from Traditional Chinese Herbal Medicine","volume":"7","author":"Lin","year":"2022","journal-title":"ACS Omega"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2456","DOI":"10.1001\/jama.2015.6358","article-title":"Cannabinoids for Medical Use: A Systematic Review and Meta-analysis","volume":"313","author":"Whiting","year":"2015","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.2217\/nnm-2020-0221","article-title":"Challenges of cannabinoid delivery: How can nanomedicine help?","volume":"15","author":"Onaivi","year":"2020","journal-title":"Nanomedicine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1007\/s11101-021-09794-w","article-title":"Cannabigerol: A bibliometric overview and review of research on an important phytocannabinoid","volume":"21","author":"Anokwuru","year":"2022","journal-title":"Phytochem. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Li, S., Li, W., Malhi, N.K., Huang, J., Li, Q., Zhou, Z., Wang, R., Peng, J., Yin, T., and Wang, H. (2024). Cannabigerol (CBG): A Comprehensive Review of Its Molecular Mechanisms and Therapeutic Potential. Molecules, 29.","DOI":"10.3390\/molecules29225471"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Filipiuc, L.E., Ababei, D.C., Alexa-Stratulat, T., Pricope, C.V., Bild, V., Stefanescu, R., Stanciu, G.D., and Tamba, B.-I. (2021). Major Phytocannabinoids and Their Related Compounds: Should We Only Search for Drugs That Act on Cannabinoid Receptors?. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13111823"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Monou, P.K., Mamaligka, A.M., Tzimtzimis, E.K., Tzetzis, D., Vergkizi-Nikolakaki, S., Vizirianakis, I.S., Andriotis, E.G., Eleftheriadis, G.K., and Fatouros, D.G. (2022). Fabrication and Preliminary In Vitro Evaluation of 3D-Printed Alginate Films with Cannabidiol (CBD) and Cannabigerol (CBG) Nanoparticles for Potential Wound-Healing Applications. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14081637"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ejmech.2014.07.035","article-title":"New class of squalene-based releasable nanoassemblies of paclitaxel, podophyllotoxin, camptothecin and epothilone A","volume":"85","author":"Borrelli","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1002\/cplu.201402239","article-title":"Self-Assembled Squalene-based Fluorescent Heteronanoparticles","volume":"80","author":"Borrelli","year":"2015","journal-title":"ChemPlusChem"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1021\/acsmedchemlett.7b00262","article-title":"Heteronanoparticles by self-Assembly of Doxorubicin and Cyclopamine Conjugates","volume":"8","author":"Fumagalli","year":"2017","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1021\/acsmedchemlett.9b00668","article-title":"New Class of Betulinic Acid-Based Nanoassemblies of Cabazitaxel, Podophyllotoxin, and Thiocolchicine","volume":"11","author":"Colombo","year":"2020","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1021\/acsmedchemlett.4c00190","article-title":"Nicotinic Acid Derivatives As Novel Noncompetitive \u03b1-Amylase and \u03b1-Glucosidase Inhibitors for Type 2 Diabetes Treatment","volume":"15","author":"Citarella","year":"2024","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Antoniou, A.I., Nordio, G., Di Paolo, M.L., Colombo, E., Gaffuri, B., Polito, L., Amenta, A., Seneci, P., Dalla Via, L., and Perdicchia, D. (2023). 2-Hydroxyoleic Acid as a Self-Assembly Inducer for Anti-Cancer Drug-Centered Nanoparticles. Pharmaceuticals, 16.","DOI":"10.3390\/ph16050722"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"S54","DOI":"10.21037\/tcr.2016.06.12","article-title":"Microtubule targeting agents in glioma","volume":"5","author":"Calinescu","year":"2016","journal-title":"Transl. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Jastrz\u0105b, A., Jarocka-Karpowicz, I., and Skrzydlewska, E. (2022). The Origin and Biomedical Relevance of Cannabigerol. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147929"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Perez, E., Fernandez, J.R., Fitzgerald, C., Rouzard, K., Tamura, M., and Savile, C. (2022). In Vitro and Clinical Evaluation of Cannabigerol (CBG) Produced via Yeast Biosynthesis: A Cannabinoid with a Broad Range of Anti-Inflammatory and Skin Health-Boosting Properties. Molecules, 27.","DOI":"10.3390\/molecules27020491"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1039\/D4MD00517A","article-title":"A novel, glutathione-activated prodrug of pimasertib loaded in liposomes for targeted cancer therapy","volume":"16","author":"Amenta","year":"2024","journal-title":"RSC Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chan, J.Z., and Duncan, R.E. (2021). Regulatory Effects of Cannabidiol on Mitochondrial Functions: A Review. Cells, 10.","DOI":"10.3390\/cells10051251"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lah, T.T., Novak, M., Pena Almidon, M.A., Marinelli, O., \u017dvar Ba\u0161kovi\u010d, B., Majc, B., Mlinar, M., Bo\u0161njak, R., Breznik, B., and Zomer, R. (2021). Cannabigerol Is a Potential Therapeutic Agent in a Novel Combined Therapy for Glioblastoma. Cells, 10.","DOI":"10.3390\/cells10020340"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2787","DOI":"10.1093\/carcin\/bgu205","article-title":"Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid","volume":"35","author":"Borrelli","year":"2014","journal-title":"Carcinogenesis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3336516","DOI":"10.1155\/2022\/3336516","article-title":"Pharmacological Aspects and Biological Effects of Cannabigerol and Its Synthetic Derivatives","volume":"2022","author":"Calapai","year":"2022","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Colvin, E.K., Hudson, A.L., Anderson, L.L., Kumar, R.P., McGregor, I.S., Howell, V.M., and Arnold, J.C. (2022). An Examination of the Anti-Cancer Properties of Plant Cannabinoids in Preclinical Models of Mesothelioma. Cancers, 14.","DOI":"10.3390\/cancers14153813"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.jconrel.2018.04.019","article-title":"The effect of linkers on the self-assembling and anti-tumor efficacy of disulfide-linked doxorubicin drug-drug conjugate nanoparticles","volume":"279","author":"Wang","year":"2018","journal-title":"J. Control. 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