title: Highly Stable Tetra-Phenolato Titanium(IV) Agent Formulated into Nanoparticles Demonstrates Anti-Tumoral Activity and Selectivity.
abstract: Titanium(IV) complexes exhibit high potential as anti-tumor agents, particularly due to their low intrinsic toxicity and cytotoxicity toward cisplatin resistant cells. Nevertheless, Ti(IV) complexes generally undergo rapid hydrolysis that previously hampered their utilization as anticancer drugs. We recently overcame this difficulty by developing a highly stable Ti(IV) complex that is based on tetra-phenolato, hexadentate ligand, formulated into organic nanoparticles. Herein we investigated the activity of this complex in vitro and in vivo. Although inactive when tested directly due to poor solubility, when formulated, this complex displayed (a) high cytotoxicity toward cisplatin resistant human ovarian cells, A2780-cp, with resistance factor of 1.1; (b) additive behavior in combination with cisplatin toward ovarian and colon cancer cells; (c) selectivity toward cancer cells as implied by its mild activity toward non-cancerous, fibroblast lung cells, MRC-5; (d) high stability and durability as manifested by the ability to maintain cytotoxicity, even following one week of incubation in 100% aquatic medium solution; and (e) in vivo efficacy toward solid tumors of human colon cancer cells, HT-29, in nude mice without any clinical signs of toxicity. These features support the formulated phenolato Ti(IV) complex being an effective and selective anti-tumoral agent.
authors.affiliation: The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. sigi.meker@gmail.com.
authors.forename: Sigalit
authors.initials: S
authors.lastname: Meker
authors.affiliation: Department of Cell and Developmental Biology, Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. ori.braitbard@mail.huji.ac.il.
authors.forename: Ori
authors.initials: O
authors.lastname: Braitbard
authors.affiliation: The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. katymargulis@gmail.com.
authors.forename: Katrin
authors.initials: K
authors.lastname: Margulis-Goshen
authors.affiliation: The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. sigi.meker@gmail.com.
authors.forename: Shlomo
authors.initials: S
authors.lastname: Magdassi
authors.affiliation: Department of Cell and Developmental Biology, Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. hochman@mail.huji.ac.il.
authors.forename: Jacob
authors.initials: J
authors.lastname: Hochman
authors.affiliation: The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. edit.tshuva@mail.huji.ac.il.
authors.forename: Edit Y
authors.initials: EY
authors.lastname: Tshuva
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004355:Drug Stability; D004357:Drug Synergism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D053768:Metal Nanoparticles / Q000737:chemistry* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009928:Organ Specificity; D010636:Phenols / Q000737:chemistry; D014025:Titanium / Q000737:chemistry* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D010636:Phenols; D014025:Titanium; D002945:Cisplatin
keywords: anti-tumor; cisplatin; cisplatin resistant cells; cytotoxicity; phenolato ligands; titanium(IV)