Novel tocotrienol-entrapping vesicles can eradicate solid tumors after intravenous administration

• Published in: Journal of controlled release 2011-08, Vol.154 (1), p.20-26
• Main Authors: Fu, Ju Yen, Zhang, Wei, Blatchford, David R., Tetley, Laurence, McConnell, Gail, Dufès, Christine
• Format: Article
• Language: English
• Subjects: Animals; anticarcinogenic activity; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biological Transport; Cancer therapy; carcinoma; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Delivery system; Drug Compounding; Drug Delivery Systems - methods; drugs; Female; General pharmacology; Humans; Injections, Intravenous; intravenous injection; Medical sciences; melanoma; Melanoma, Experimental - drug therapy; Melanoma, Experimental - metabolism; Mice; Mice, Inbred BALB C; Microscopy, Electron, Transmission; neoplasm cells; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; receptors; Receptors, Transferrin - biosynthesis; Receptors, Transferrin - metabolism; Surface Properties; Survival Analysis; therapeutics; Tocotrienol; Tocotrienols - administration & dosage; Tocotrienols - chemistry; Tocotrienols - therapeutic use; toxicity; Transferrin; Transferrin - chemistry; Tumor targeting; vitamin E; Xenograft Model Antitumor Assays
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2011.04.015

The therapeutic potential of tocotrienol, a vitamin E extract with anti-cancer properties, is hampered by its failure to specifically reach tumors after intravenous administration. In this work, we demonstrated that novel transferrin-bearing, tocopheryl-based multilamellar vesicles entrapping tocotrienol significantly improved tocotrienol uptake by cancer cells overexpressing transferrin receptors. This led to a dramatically improved therapeutic efficacy in vitro, ranging from 17-fold to 72-fold improvement depending on the cell lines, compared to the free drug. In vivo, the intravenous administration of this novel tocotrienol formulation led to complete tumor eradication for 40% of B16-F10 murine melanoma tumors and 20% of A431 human epidermoid carcinoma tumors. Animal survival was improved by more than 20 days compared to controls, for the two tumor models tested. These therapeutic effects, together with the lack of toxicity, potentially make transferrin-bearing vesicles entrapping tocotrienol a highly promising therapeutic system as part as an anti-cancer therapeutic strategy. Bioluminescence imaging of the tumoricidal activity of tocotrienol entrapped in transferrin-bearing vesicles in a mouse B16-F10-luc tumor model. [Display omitted]