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This study compares two Ti(IV) compounds with contrasting properties: titanocene\u2010dichloride (TDC), which rapidly hydrolyzes at physiological pH, and the more stable chelated complex [Ti(deferasirox)\n                    <jats:sub>2<\/jats:sub>\n                    ] (Ti(Def)\n                    <jats:sub>2<\/jats:sub>\n                    ), which has limited cellular uptake. To overcome these limitations, passive and active cell targeting drug delivery systems were explored. TDC was intercalated into layered zirconium phosphate nanoparticles (TDC@ZrP), passive carriers enabling acid\u2010triggered release under lysosomal environments. Bovine serum albumin (BSA) binding and conjugation to receptor\u2010targeted deferasirox\u2013peptide ligands were used as active carriers. TDC@ZrP increased intracellular Ti(IV) uptake by\u2009\u223c\u200926\u2010fold relative to free TDC, yet without an increase in antiproliferative activity. Similarly, stabilization with BSA enhanced solution stability but not cytotoxicity. In contrast, Ti(Def)\n                    <jats:sub>2<\/jats:sub>\n                    showed transporter\u2010dependent activity. While albumin binding reduced its efficacy, conjugation to a transferrin receptor\u20101 targeting peptide significantly enhanced titanium uptake and cytotoxicity. Targeting the neurokinin\u20101 receptor had minimal effect, consistent with low receptor expression. Overall, these findings demonstrate that ligand identity is critical, as deferasirox not only controls Ti(IV) release but also contributes to cytotoxicity, highlighting the importance of metal\u2013ligand design in improving anticancer performance.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70284","type":"journal-article","created":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T06:55:32Z","timestamp":1777186532000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evaluation of Active and Passive Targeting Drug Delivery Systems as a Mechanism to Improve the Anticancer Potential of Titanium(IV)"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5332-9411","authenticated-orcid":false,"given":"Oscar","family":"Claudio\u2010Ares","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Puerto Rico, R\u00edo Piedras Campus  R\u00edo Piedras Puerto Rico USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mallesh","family":"Pandrala","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Puerto Rico, R\u00edo Piedras Campus  R\u00edo Piedras Puerto Rico USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Fern\u00e1ndez\u2010Vega","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Puerto Rico, R\u00edo Piedras Campus  R\u00edo Piedras Puerto Rico USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Casa\u00f1as\u2010Montes","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Puerto Rico, R\u00edo Piedras Campus  R\u00edo Piedras Puerto Rico USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josu\u00e9","family":"Benjam\u00edn\u2010Rivera","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Puerto Rico, R\u00edo Piedras Campus  R\u00edo Piedras Puerto Rico USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louis R.","family":"Parham","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Puerto Rico, R\u00edo Piedras Campus  R\u00edo Piedras Puerto Rico USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo Marra","family":"Nazario","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Puerto Rico, R\u00edo Piedras Campus  R\u00edo Piedras Puerto Rico USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 F. 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