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Intratumoral drug administration offers a promising potential treatment alternative with localized delivery and minimal systemic toxicity. Vanadium(V) coordination complexes, incorporating Schiff base and catecholate ligands, have shown effects as antiproliferative agents with tunable efficacy and reactivity, stability, steric bulk, hydrophobicity, uptake, and toxicity optimized for the intratumoral administration vehicle. A new series of oxovanadium(V) Schiff base\u2013catecholate complexes were synthesized and characterized using nuclear magnetic resonance (NMR), UV-Vis, and infrared spectroscopy and mass spectrometry. Stability under physiological conditions was assessed via UV-Vis spectroscopy, and the antiproliferative activity was evaluated in T98G glioblastoma and SVG p12 normal glial cells using viability assays. The newly synthesized [VO(3-tBuHSHED)(TIPCAT)] complex was more stable (t1\/2 ~4.5 h) and had strong antiproliferative activity (IC50 ~1.5 \u00b5M), comparing favorably with the current lead compound, [VO(HSHED)(DTB)]. The structural modifications enhanced stability, hydrophobicity, and steric bulk through substitution with iso-propyl and tert-butyl groups. The improved properties were attributed to steric hindrance associated with the new Schiff base and catecholato ligands, as well as the formation of non-toxic byproducts upon degradation. The [VO(3-tBuHSHED)(TIPCAT)] complex emerges as a promising candidate for glioblastoma therapy by demonstrating enhanced stability and a greater selectivity, which highlights the role of strategic ligand design in developing localized therapies for the treatment of resistant cancers. In reporting the new class of compounds effective against T98G glioblastoma cells, we describe the generally desirable properties that potential drugs being developed for intratumoral administration should have.<\/jats:p>","DOI":"10.3390\/ijms26030994","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T08:48:23Z","timestamp":1737708503000},"page":"994","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Optimizing Therapeutics for Intratumoral Cancer Treatments: Antiproliferative Vanadium Complexes in Glioblastoma"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8102-8309","authenticated-orcid":false,"given":"Andrew C.","family":"Bates","sequence":"first","affiliation":[{"name":"Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kameron L.","family":"Klugh","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna O.","family":"Galaeva","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raley A.","family":"Patch","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Manganaro","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Skyler A.","family":"Markham","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Scurek","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7311-3263","authenticated-orcid":false,"given":"Aviva","family":"Levina","sequence":"additional","affiliation":[{"name":"School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3232-2720","authenticated-orcid":false,"given":"Peter A.","family":"Lay","sequence":"additional","affiliation":[{"name":"School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7792-3450","authenticated-orcid":false,"given":"Debbie C.","family":"Crans","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA"},{"name":"Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s13046-022-02349-7","article-title":"Emerging therapies for glioblastoma: Current state and future directions","volume":"41","author":"Rong","year":"2022","journal-title":"J. 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