{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:30:55Z","timestamp":1785429055434,"version":"3.56.0"},"reference-count":55,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NCI R01 CA244993"],"award-info":[{"award-number":["NCI R01 CA244993"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NCI R01 CA259599"],"award-info":[{"award-number":["NCI R01 CA259599"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NCI R01 CA280194"],"award-info":[{"award-number":["NCI R01 CA280194"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH-NCI Cancer Center","award":["P30 CA016059"],"award-info":[{"award-number":["P30 CA016059"]}]},{"name":"VCU George Lavinia Blick Research Fund"},{"DOI":"10.13039\/100013759","name":"Commonwealth Health Research Board","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100013759","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/01x5qb890","id-type":"ROR","asserted-by":"publisher"}]},{"name":"VCU Institute of Molecular Medicine"},{"name":"Thelma Newmeyer Corman Endowment"},{"name":"InVaMet Therapeutics, Inc."},{"name":"VCU"},{"name":"UVA Cryo-TEM service"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The pro-metastatic gene MDA-9\/Syntenin-1 and its tandem PDZ domains (PDZ1 and PDZ2) provide established targets for intervening in tumor progression and metastasis. Recently, we generated and validated MDA-9\/Syntenin-1 antagonists targeting a single PDZ domain (PDZ1i) or both PDZ domains (IVMT-Rx-3) in carcinomas and melanoma. Data reveal that IVMT-Rx-3 possesses immunomodulatory and anti-angiogenic properties, in addition to its well-established anti-invasive capabilities. Despite its significant druggable properties, it cannot be delivered orally, limiting its clinical potential. Here, we characterized an oral microemulsion (ME) formulation of IVMT-Rx-3, IVMT-Rx-3-ME to enhance intestinal permeability, bioavailability, and therapeutic efficacy. Physicochemical analyses demonstrated that the optimized formulation produced a stable IVMT-Rx-3-ME with high drug content (&gt;90%). In vitro permeability and dissolution assays confirmed improved membrane transport and solubility compared with the free drug dispersion control. Pharmacokinetic studies in rats revealed that the ME enabled rapid absorption and sustained systemic exposure, whereas the free drug showed negligible bioavailability. In murine metastatic melanoma models, oral IVMT-Rx-3-ME suppressed tumor growth and lung metastases, and when combined with anti-PD-L1 antibody, produced synergistic antitumor effects with minimal toxicity. Collectively, these findings highlight IVMT-Rx-3-ME as a potent and viable oral metronomic chemotherapy platform for metastatic melanoma, with enhanced combinatorial translational potential with immunotherapies.<\/jats:p>","DOI":"10.3390\/cells15131178","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T08:45:20Z","timestamp":1782722720000},"page":"1178","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["IVMT-Rx-3 Microemulsion as Low-Dose Metronomic Chemotherapy for Melanoma Metastasis"],"prefix":"10.3390","volume":"15","author":[{"given":"Rudra","family":"Pangeni","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Padmanabhan","family":"Mannangatti","sequence":"additional","affiliation":[{"name":"VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Department of Cellular, Molecular and Genetic Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1903-6690","authenticated-orcid":false,"given":"Ehsan","family":"Kaffash","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9279-0896","authenticated-orcid":false,"given":"Madeline","family":"Gunawardena","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitai D.","family":"Mukhopadhyay","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark C.","family":"Mochel","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swadesh K.","family":"Das","sequence":"additional","affiliation":[{"name":"VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Department of Cellular, Molecular and Genetic Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"VCU Massey Comprehensive Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3191-0771","authenticated-orcid":false,"given":"Qingguo","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"VCU Massey Comprehensive Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Department of Ophthalmology, Biomedical Engineering, Pediatrics, Center for Pharmaceutical Engineering, and Center for Drug Discovery, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul B.","family":"Fisher","sequence":"additional","affiliation":[{"name":"VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Department of Cellular, Molecular and Genetic Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"VCU Massey Comprehensive Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1016\/j.gendis.2022.04.004","article-title":"Melanoma: Molecular genetics, metastasis, targeted therapies, immunotherapies, and therapeutic resistance","volume":"9","author":"Wagstaff","year":"2022","journal-title":"Genes Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0378-1119(97)00562-3","article-title":"Melanoma differentiation associated gene-9, mda-9, is a human gamma interferon responsive gene","volume":"207","author":"Lin","year":"1998","journal-title":"Gene"},{"key":"ref_3","first-page":"317","article-title":"Characterization of a novel melanoma 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