{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T07:43:30Z","timestamp":1781509410789,"version":"3.54.1"},"reference-count":55,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,7,10]],"date-time":"2020-07-10T00:00:00Z","timestamp":1594339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The use of controlled delivery therapy in colorectal cancer (CRC) reduces toxicity and side effects. Recently, we have suggested that the Frizzled 10 (FZD10) protein, a cell surface receptor belonging to the FZD protein family that is overexpressed in CRC cells, is a novel candidate for targeting and treatment of CRC. Here, the anticancer effect of novel immuno-liposomes loaded with 5-Fluorouracil (5-FU), decorated with an antibody against FZD10 (anti-FZD10\/5-FU\/LPs), was evaluated in vitro on two different CRC cell lines, namely metastatic CoLo-205 and nonmetastatic CaCo-2 cells, that were found to overexpress FZD10. The anti-FZD10\/5-FU\/LPs obtained were extensively characterized and their preclinical therapeutic efficacy was evaluated with the MTS cell proliferation assay based on reduction of tetrazolium compound, scratch test, Field Emission Scanning Electron Microscopes (FE-SEM) investigation and immunofluorescence analysis. The results highlighted that the cytotoxic activity of 5-FU was enhanced when encapsulated in the anti-FZD10 \/5-FU\/LPs at the lowest tested concentrations, as compared to the free 5-FU counterparts. The immuno-liposomes proposed herein possess a great potential for selective treatment of CRC because, in future clinical applications, they can be encapsulated in gastro-resistant capsules or suppositories for oral or rectal delivery, thereby successfully reaching the intestinal tract in a minimally invasive manner.<\/jats:p>","DOI":"10.3390\/pharmaceutics12070650","type":"journal-article","created":{"date-parts":[[2020,7,10]],"date-time":"2020-07-10T09:45:31Z","timestamp":1594374331000},"page":"650","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Effectiveness of a Controlled 5-FU Delivery Based on FZD10 Antibody-Conjugated Liposomes in Colorectal Cancer In vitro Models"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0812-4441","authenticated-orcid":false,"given":"Maria Principia","family":"Scavo","sequence":"first","affiliation":[{"name":"Personalized Medicine Laboratory, National Institute of Gastroenterology \u201cS. deBellis\u201d, Via Turi 26 Castellana Grotte, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Cutrignelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Drug Science, University of Bari, Via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2107-2762","authenticated-orcid":false,"given":"Nicoletta","family":"Depalo","sequence":"additional","affiliation":[{"name":"Institute for Chemical and Physical Processes (IPCF)-CNR SS Bari, Via Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Fanizza","sequence":"additional","affiliation":[{"name":"Institute for Chemical and Physical Processes (IPCF)-CNR SS Bari, Via Orabona 4, 70125 Bari, Italy"},{"name":"Department of Chemistry, University of Bari, Via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1266-638X","authenticated-orcid":false,"given":"Valentino","family":"Laquintana","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Drug Science, University of Bari, Via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7314-9736","authenticated-orcid":false,"given":"Giampietro","family":"Gasparini","sequence":"additional","affiliation":[{"name":"Oncology Unit, Hospital San Filippo Neri, 00135 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluigi","family":"Giannelli","sequence":"additional","affiliation":[{"name":"Scientific Direction, National Institute of Gastroenterology \u201cde Bellis\u201d, Via Turi 26 Castellana Grotte, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7756-7828","authenticated-orcid":false,"given":"Nunzio","family":"Denora","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Drug Science, University of Bari, Via E. Orabona 4, 70125 Bari, Italy"},{"name":"Institute for Chemical and Physical Processes (IPCF)-CNR SS Bari, Via Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,10]]},"reference":[{"key":"ref_1","unstructured":"Global Burden of Disease Cancer Collaboration, Fitzmaurice, C., Allen, C., Barber, R.M., Barregard, L., Bhutta, Z.A., Brenner, H., Dicker, D.J., Chimed-Orchir, O., and Dandona, R. (2017). Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability adjusted life-years for 32 cancer groups, 1990 to 2015. JAMA Oncol., 3, 524\u2013548."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.3390\/molecules13102340","article-title":"Novel strategies to improve the anticancer action of 5-fluorouracil by using drug delivery systems","volume":"13","author":"Arias","year":"2008","journal-title":"Molecules"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.3390\/molecules13081551","article-title":"5-Fluorouracil: Mechanisms of resistance and reversal strategies","volume":"13","author":"Zhang","year":"2008","journal-title":"Molecules"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"207","DOI":"10.3109\/02841869609098503","article-title":"Different intravenous administration techniques for 5-fluorouracil. Pharmacokinetics and pharmacodynamic effects","volume":"35","author":"Larsson","year":"1996","journal-title":"Acta. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nrd2614","article-title":"Nanoparticle therapeutics: An emerging treatment modality for cancer","volume":"7","author":"Davis","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.2217\/fon.13.146","article-title":"Liposomal chemotherapeutics","volume":"9","author":"Gentile","year":"2013","journal-title":"Future Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"146","DOI":"10.3109\/1061186X.2012.734311","article-title":"Design and development of liposomes for colon targeted drug delivery","volume":"21","author":"Gupta","year":"2013","journal-title":"J. Drug Target."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.ijpharm.2010.09.028","article-title":"Evaluation of liposomes coated with a pH responsive polymer","volume":"402","author":"Barea","year":"2010","journal-title":"Int. J. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.2147\/IJN.S125047","article-title":"Mechanism of hepatic targeting via oral administration of DSPE-PEG-cholic acid-modified nanoliposomes","volume":"12","author":"Li","year":"2017","journal-title":"Int. J. Nanomedicine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"845","DOI":"10.2217\/nnm-2016-0386","article-title":"PEGylated liposomes associate with Wnt3A protein and expand putative stem cells in human bone marrow populations","volume":"12","author":"Janeczek","year":"2017","journal-title":"Nanomedicine"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/j.biopha.2018.09.128","article-title":"A novel 5-Fluorouracil targeted delivery to colon cancer using folic acid conjugated liposomes","volume":"108","author":"Handali","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"138","DOI":"10.3389\/fphar.2014.00138","article-title":"Orally administered liposomal formulations for colon targeted drug delivered","volume":"5","author":"Hua","year":"2014","journal-title":"Front. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"85163","DOI":"10.18632\/oncotarget.13209","article-title":"Tumor specific delivery and therapy mediate by integrin \u03b26-target immunoliposomes for \u03b26-siRNA in colon carcinoma","volume":"7","author":"Song","year":"2016","journal-title":"Oncotarget"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s40495-016-0056-z","article-title":"Recent advances in immunoliposome-based cancer therapy","volume":"2","author":"Alavizadeh","year":"2016","journal-title":"Curr. Pharmacol. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Wong, S.C.C., He, C.W., Chan, C.M.L., Chan, A.K.C., Wong, H.T., Cheung, M.T., Luk, L.L.Y., Au, T.C.C., Chiu, M.K., and Ma, B.B.T. (2013). Clinical significance of frizzled homolog 3 protein in colorectal cancer patients. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079481"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1593\/neo.08320","article-title":"Frizzled-7 as a potential therapeutic target in colorectal cancer","volume":"10","author":"Ueno","year":"2008","journal-title":"Neoplasia"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zeng, C.M., Chen, Z., and Fu, L. (2018). Frizzled receptors as potential therapeutic targets in human cancers. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051543"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Scavo, M.P., Depalo, N., Rizzi, F., Ingrosso, C., Fanizza, E., Chieti, A., Messa, C., Denora, N., Laquintana, V., and Striccoli, M. (2019). FZD10 carried by exosomes sustains cancer cell proliferation. Cells, 8.","DOI":"10.3390\/cells8080777"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Scavo, M.P., Cigliano, A., Depalo, N., Fanizza, E., Bianco, M.G., Denora, N., Laquintana, V., Curri, M.L., Lorusso, D., and Lotesoriere, C. (2019). Frizzled-10 extracellular vesicles plasma concentration are associated with tumoral progression in patients with colorectal and gastric cancer. Int. J. Oncol.","DOI":"10.1155\/2019\/2715968"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Scavo, M.P., Depalo, N., Tutino, V., De Nunzio, V., Ingrosso, C., Rizzi, F., Notarnicola, M., Curri, M.L., and Giannelli, G. (2020). Exosomes for diagnosis and therapy in gastrointestinal cancers. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010367"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/j.1349-7006.2008.01052.x","article-title":"Inverse correlation of the up-regulation of FZD10 expression and the activation of beta-catenin in synchronous colorectal tumors","volume":"100","author":"Nagayama","year":"2009","journal-title":"Cancer Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6201","DOI":"10.1038\/sj.onc.1208780","article-title":"Therapeutic potential of antibodies against FZD10, a cell-surface protein; for synovial sarcomas","volume":"24","author":"Nagayama","year":"2005","journal-title":"Oncogene"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"824","DOI":"10.18632\/oncotarget.23159","article-title":"Frizzled-10 and cancer progression. Is it a new prognostic marker?","volume":"9","author":"Scavo","year":"2017","journal-title":"Oncotarget"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"21810","DOI":"10.1039\/C9RA02381J","article-title":"Imaging modification of colon carcinoma cells exposed to lipid based nanovectors for drug delivery: A scanning electron microscopy investigation","volume":"9","author":"Depalo","year":"2019","journal-title":"RSC Adv."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nprot.2007.30","article-title":"In a vitro scratch assay: A convenient and inexpensive method for analysis of cell migration in vitro","volume":"2","author":"Liang","year":"2007","journal-title":"Nature Protocols."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Tutino, V., Gigante, I., Scavo, M.P., Refolo, M.G., De Nunzio, V., Milella, R.A., Caruso, M.G., and Notarnicola, M. (2020). Stearoyl-CoA Desaturase-1 Enzyme inhibition by grape skin extracts affects membrane fluidity in human colon cancer cell lines. Nutrients, 12.","DOI":"10.3390\/nu12030693"},{"key":"ref_27","first-page":"1085","article-title":"The optimal schedule for 5-fluorouracil radiosensitization in colon cancer cell lines","volume":"16","author":"Ojima","year":"2006","journal-title":"Oncolo. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4559","DOI":"10.1021\/ja01573a087","article-title":"The synthesis of 5-fluoropyrimidines","volume":"79","author":"Dushinsky","year":"1957","journal-title":"J. Am. Chem. Soc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1080\/009841000156709","article-title":"Reduced antioxidant defense capacity in myocardial tissue from guinea pigs treated with 5-fluorouracil","volume":"59","author":"Durak","year":"2000","journal-title":"J. Toxicol. Environ. Health."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1191\/0960327106ht628oa","article-title":"Cardiac lesions induced by 5-fluorouracil in the rabbit","volume":"25","author":"Tsibiribi","year":"2006","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1093\/jnci\/djt161","article-title":"Cardiotoxicity debated for anthracyclines and trastuzumab in breast cancer","volume":"105","author":"Brower","year":"2013","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5465","DOI":"10.1016\/j.ijcard.2013.07.246","article-title":"Left and right ventricular effects of anthracycline and trastuzumab chemotherapy: A prospective study using novel cardiac imaging and biochemical markers","volume":"168","author":"Grover","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1053\/j.seminoncol.2013.01.008","article-title":"Strategies to prevent and treat cardiovascular risk in cancer patients","volume":"40","author":"Cardinale","year":"2013","journal-title":"Semin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Lee, S.H., Bajracharya, R., Min, J.Y., Han, J.W., Park, B.J., and Han, H.K. (2020). Strategic approaches for colon targeted drug delivery: An overview of recent advancements. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12010068"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1007\/s13346-019-00680-9","article-title":"Basics to Advances in Nanotherapy of colorectal cancer","volume":"10","author":"Tiwari","year":"2020","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Le, V.M., Nho, T.D.T., Ly, H.T., Vo, T.S., Nguyen, H.D., Phung, T.T.H., Zou, A., and Liu, J. (2017). Enhanced anticancer efficacy and tumor targeting through folate-PEG modified nanoliposome loaded with 5-fluorouracil. Adv. Nat. Sci. Nanosci. Nanotechnol., 8.","DOI":"10.1088\/2043-6254\/aa5982"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1158\/1078-0432.CCR-14-1194","article-title":"Integrin\u03b26-targeted immunoliposomes mediate tumor-specific drug delivery and enhance therapeutic efficacy in colon carcinoma","volume":"21","author":"Liang","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_38","first-page":"245","article-title":"Cytotoxicity of 5-fluorouracil-loaded pH-sensitive liposomal nanoparticles in colorectal cancer cell lines","volume":"2","author":"Udofot","year":"2015","journal-title":"Integr. Cancer Sci. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Lopalco, A., Cutrignelli, A., Denora, N., Lopedota, A., Franco, M., and Laquintana, V. (2018). Transferrin functionalized liposomes loading dopamine HCl: Development and permeability studies across an in vitro model of human blood-brain barrier. Nanomaterials, 8.","DOI":"10.3390\/nano8030178"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.addr.2010.09.003","article-title":"Intracellular targeting delivery of liposomal drugs to solid tumors based on EPR effects","volume":"63","author":"Maruyama","year":"2011","journal-title":"Adv. Drug Delivery Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1080\/02841860500247552","article-title":"In vitro radiosensitization by oxaliplatin and 5-fluorouracil in a human colon cancer cell line","volume":"44","author":"Johnsson","year":"2005","journal-title":"Acta Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1097\/FTD.0b013e3181b9b8c0","article-title":"Multicenter evaluation of a novel nanoparticle immunoassay for 5-fluorouracil on the olympus au400 analyzer","volume":"31","author":"Beumer","year":"2009","journal-title":"Ther. Drug Monit."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1200\/JCO.2007.13.3934","article-title":"Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: Results of a multicenter randomized trial of patients with metastatic colorectal cancer","volume":"26","author":"Gamelin","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13045-017-0418-y","article-title":"Paxillin: A crossroad in pathological cell migration","volume":"10","year":"2017","journal-title":"J. Hematol. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Danielsson, F., Peterson, M.K., Ara\u00fajo, H.C., Lautenschl\u00e4ger, F., and Gad, A.K.B. (2018). Vimentin diversity in health and disease. Cells, 7.","DOI":"10.3390\/cells7100147"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1038\/cdd.2014.170","article-title":"Bcl-2 stabilization by paxillin confers 5-fluorouracil resistance in colorectal cancer","volume":"22","author":"Wu","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1111\/jcmm.12850","article-title":"Vimentin, colon cancer progression and resistance to butyrate and other HDACis","volume":"20","author":"Lazarova","year":"2016","journal-title":"J. Cell. Mol. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8698","DOI":"10.18632\/oncotarget.3537","article-title":"Paxillin promotes colorectal tumor invasion and poor patient outcomes via ERK-mediated stabilization of Bcl-2 protein by phosphorylation at Serine 87","volume":"6","author":"Huang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.12659\/MSM.893832","article-title":"Expression of paxillin is correlated with clinical prognosis in colorectal cancer patients","volume":"21","author":"Zhao","year":"2015","journal-title":"Med. Sci. Monit."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1039\/C8MD00515J","article-title":"Diversity of PEGylation methods of liposomes and their influence on RNA delivery","volume":"10","author":"Nosova","year":"2019","journal-title":"MedChemComm"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.jconrel.2010.11.018","article-title":"Development of a liposomal nanoparticle formulation of 5-fluorouracil for parenteral administration: Formulation design, pharmacokinetics and efficacy","volume":"150","author":"Thomas","year":"2011","journal-title":"J. Control. Release."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1007\/s00018-011-0735-1","article-title":"Vimentin in cancer and its potential as a molecular target for cancer therapy","volume":"68","author":"Satelli","year":"2011","journal-title":"Cell Mol. Life Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"15966","DOI":"10.18632\/oncotarget.3862","article-title":"Vimentin contributes to epithelial-mesenchymal transition cancer cell mechanics by mediating cytoskeletal organization and focal adhesion maturation","volume":"6","author":"Liu","year":"2015","journal-title":"Oncotarget"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1007\/s00018-008-8038-x","article-title":"Pressure activates colon cancer cell adhesion via paxillin phosphorylation, Crk, Cas, and Rac1","volume":"65","author":"Downey","year":"2008","journal-title":"Cell Mol. Life Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.nut.2012.05.002","article-title":"Lipid effects of a dietary supplement softgel capsule containing plant sterols\/stanols in primary hypercholesterolemia","volume":"29","author":"Maki","year":"2013","journal-title":"Nutrition"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/7\/650\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:49:39Z","timestamp":1760176179000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/7\/650"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,10]]},"references-count":55,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["pharmaceutics12070650"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics12070650","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,10]]}}}