{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T08:10:11Z","timestamp":1778659811128,"version":"3.51.4"},"reference-count":29,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T00:00:00Z","timestamp":1700870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Charles H. Kimberly Professorship"},{"name":"The WhiteOak Group, Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Bortezomib (BTZ), a boronic acid-derived proteasome inhibitor, is commonly employed in treating multiple myeloma (MM). However, the applications of BTZ are limited due to its poor stability and low bioavailability. Herein, we develop an optimized liposomal formulation of BTZ (L-BTZ) by employing a remote-loading strategy. This formulation uses Tiron, a divalent anionic catechol derivative, as the internal complexing agent. Compared to earlier BTZ-related formulations, this alternative formulation showed significantly greater stability due to the Tiron\u2013BTZ complex\u2019s higher pH stability and negative charges, compared to the meglumine\u2013BTZ complex. Significantly, the plasma AUC of L-BTZ was found to be 30 times greater than that of free BTZ, suggesting an extended blood circulation duration. In subsequent therapeutic evaluations using two murine xenograft tumor models of MM, the NCI-H929 and OPM2 models showed tumor growth inhibition (TGI) values of 37% and 57%, respectively. In contrast, free BTZ demonstrated TGI values of 17% and 11% in these models. Further, L-BTZ presented enhanced antitumor efficacy in the Hepa1-6 HCC syngeneic model, indicating its potential broader applicability as an antineoplastic agent. These findings suggest that the optimized L-BTZ formulation offers a significant advancement in BTZ delivery, holding substantial promise for clinical investigation in not merely MM, but other cancer types.<\/jats:p>","DOI":"10.3390\/pharmaceutics15122674","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T03:33:56Z","timestamp":1701056036000},"page":"2674","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Optimized Liposomal Delivery of Bortezomib for Advancing Treatment of Multiple Myeloma"],"prefix":"10.3390","volume":"15","author":[{"given":"Chi","family":"Zhang","sequence":"first","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jimmy Chun-Tien","family":"Kuo","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yirui","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingwen","family":"Hu","sequence":"additional","affiliation":[{"name":"The Whiteoak Group, Inc., Rockville, MD 20855, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lan","family":"Deng","sequence":"additional","affiliation":[{"name":"The Whiteoak Group, Inc., Rockville, MD 20855, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bryant C.","family":"Yung","sequence":"additional","affiliation":[{"name":"The Whiteoak Group, Inc., Rockville, MD 20855, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaobin","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Whiteoak Group, Inc., Rockville, MD 20855, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2829-2387","authenticated-orcid":false,"given":"Zhongkun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junjie","family":"Pan","sequence":"additional","affiliation":[{"name":"William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9371-4365","authenticated-orcid":false,"given":"Yifan","family":"Ma","sequence":"additional","affiliation":[{"name":"William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5981-5867","authenticated-orcid":false,"given":"Robert J.","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3960\/jslrt.18014","article-title":"The histopathology of myeloma in the bone marrow","volume":"58","author":"Fujino","year":"2018","journal-title":"J. Clin. Exp. Hematop."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/nrd1159","article-title":"Bortezomib","volume":"2","author":"Paramore","year":"2003","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/sj.leu.2404528","article-title":"Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma","volume":"21","author":"Bonvini","year":"2007","journal-title":"Leukemia"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"859","DOI":"10.2165\/00003495-200969070-00006","article-title":"Bortezomib: A review of its use in patients with multiple myeloma","volume":"69","author":"Curran","year":"2009","journal-title":"Drugs"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.expneurol.2006.11.010","article-title":"Bortezomib-induced peripheral neurotoxicity: A neurophysiological and pathological study in the rat","volume":"204","author":"Cavaletti","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1080\/14740338.2018.1513487","article-title":"The safety of bortezomib for the treatment of multiple myeloma","volume":"17","author":"Beksac","year":"2018","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"51","DOI":"10.2147\/CMAR.S105163","article-title":"Update on the optimal use of bortezomib in the treatment of multiple myeloma","volume":"9","author":"Mohan","year":"2017","journal-title":"Cancer Manag. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1097\/CAD.0000000000000036","article-title":"Thermally targeted p21 peptide enhances bortezomib cytotoxicity in androgen-independent prostate cancer cell lines","volume":"25","author":"Mikecin","year":"2014","journal-title":"Anti-Cancer Drugs"},{"key":"ref_9","first-page":"100011","article-title":"Development and characterization of liposomal formulation of bortezomib","volume":"1","author":"Deshantri","year":"2019","journal-title":"Int. J. Pharm. X"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5282","DOI":"10.1021\/jm500352v","article-title":"Liposomal Bortezomib Nanoparticles via Boronic Ester Prodrug Formulation for Improved Therapeutic Efficacy in Vivo","volume":"57","author":"Ashley","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_11","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_12","doi-asserted-by":"crossref","first-page":"20210217","DOI":"10.1002\/EXP.20210217","article-title":"mRNA nanomedicine: Design and recent applications","volume":"2","author":"Kubiatowicz","year":"2022","journal-title":"Exploration"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.ijpharm.2011.01.056","article-title":"Improving solubility and chemical stability of natural compounds for medicinal use by incorporation into liposomes","volume":"416","author":"Coimbra","year":"2011","journal-title":"Int. J. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.jsps.2015.02.014","article-title":"Remote loading of doxorubicin into liposomes by transmembrane pH gradient to reduce toxicity toward H9c2 cells","volume":"24","author":"Alyane","year":"2016","journal-title":"Saudi Pharm. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3778","DOI":"10.1182\/blood-2013-06-507426","article-title":"Eradicating acute myeloid leukemia in a MllPTD\/wt:Flt3ITD\/wt murine model: A path to novel therapeutic approaches for human disease","volume":"122","author":"Bernot","year":"2013","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"36382","DOI":"10.18632\/oncotarget.8871","article-title":"Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR\/ABL axis","volume":"7","author":"Yang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e463","DOI":"10.1097\/HS9.0000000000000463","article-title":"Complete Tumor Regression by Liposomal Bortezomib in a Humanized Mouse Model of Multiple Myeloma","volume":"4","author":"Deshantri","year":"2020","journal-title":"HemaSphere"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.electacta.2009.09.031","article-title":"A study of tiron in aqueous solutions for redox flow battery application","volume":"55","author":"Xu","year":"2010","journal-title":"Electrochim. Acta"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"128541","DOI":"10.1016\/j.cej.2021.128541","article-title":"Direct three-dimensional printing of a highly customized freestanding hyperelastic bioscaffold for complex craniomaxillofacial reconstruction","volume":"411","author":"Ma","year":"2021","journal-title":"Chem. Eng. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.actbio.2016.08.023","article-title":"PEGylated poly(glycerol sebacate)-modified calcium phosphate scaffolds with desirable mechanical behavior and enhanced osteogenic capacity","volume":"44","author":"Ma","year":"2016","journal-title":"Acta Biomater."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2302622","DOI":"10.1002\/advs.202302622","article-title":"Exosomal mRNAs for Angiogenic-Osteogenic Coupled Bone Repair","volume":"10","author":"Ma","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6692","DOI":"10.1038\/s41467-023-42402-3","article-title":"Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer","volume":"14","author":"Chiang","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"239","DOI":"10.2174\/156800911794519752","article-title":"Bortezomib as the First Proteasome Inhibitor Anticancer Drug: Current Status and Future Perspectives","volume":"11","author":"Chen","year":"2011","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5569","DOI":"10.1038\/s41598-020-62501-1","article-title":"Optimization of Docetaxel Loading Conditions in Liposomes: Proposing potential products for metastatic breast carcinoma chemotherapy","volume":"10","author":"Rezayat","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.1016\/j.clnu.2020.09.009","article-title":"The efficacy of bortezomib in human multiple myeloma cells is enhanced by combination with omega-3 fatty acids DHA and EPA: Timing is essential","volume":"40","author":"Chen","year":"2021","journal-title":"Clin. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Korani, M., Ghaffari, S., Attar, H., Mashreghi, M., and Jaafari, M.R. (2019). Preparation and characterization of nanoliposomal bortezomib formulations and evaluation of their anti-cancer efficacy in mice bearing C26 colon carcinoma and B16F0 melanoma. Nanomed. Nanotechnol. Biol. Med., 20.","DOI":"10.1016\/j.nano.2019.04.016"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.jconrel.2015.05.286","article-title":"Tumor vascular targeted liposomal-bortezomib minimizes side effects and increases therapeutic activity in human neuroblastoma","volume":"211","author":"Zuccari","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1097\/CAD.0b013e3282f24031","article-title":"Antioxidants block proteasome inhibitor function in endometrial carcinoma cells","volume":"19","author":"Llobet","year":"2008","journal-title":"Anti-Cancer Drugs"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4850","DOI":"10.1182\/blood.V110.11.4850.4850","article-title":"The Korean Multiple Myeloma Working Party (KMMWP) (-)-Epigallocatechin-3-Gallate (EGCG), Green Tea Component, Antagonize the Anti-Myeloma Activity of Proteasome Inhibitor PS-341 by Direct Chemical Interaction","volume":"110","author":"Kim","year":"2007","journal-title":"Blood"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/12\/2674\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:30:20Z","timestamp":1760131820000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/12\/2674"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,25]]},"references-count":29,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["pharmaceutics15122674"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15122674","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,25]]}}}