Tumor regression after systemic administration of tocotrienol entrapped in tumor-targeted vesicles.
The therapeutic potential of tocotrienol, an extract of vitamin E with anti-cancer properties, is hampered by its failure to specifically reach tumors after intravenous administration, without secondary effects on normal tissues. We hypothesize that the encapsulation of tocotrienol-rich fraction (TRF) within vesicles bearing transferrin, whose receptors are overexpressed on many cancer cells, could result in a selective delivery to tumors after intravenous administration. The objectives of this study are therefore to prepare and characterize transferrin-targeted vesicles encapsulating TRF, and to evaluate their therapeutic efficacy in vitro and in vivo. The entrapment of TRF in transferrin-bearing vesicles led to a 3-fold higher TRF uptake and more than 100-fold improved cytotoxicity in A431 (epidermoid carcinoma), T98G (glioblastoma) and A2780 (ovarian carcinoma) cell lines compared to TRF solution. The intravenous administration of TRF encapsulated in transferrin-bearing vesicles led to tumor regression and improvement of animal survival in a murine xenograft model, contrary to that observed with controls. The treatment was well tolerated by the animals. This work corresponds to the first preparation of a tumor-targeted delivery system able to encapsulate tocotrienol. Our findings show that TRF encapsulated in transferrin-bearing vesicles is a highly promising therapeutic system, leading to tumor regression after intravenous administration without visible toxicity.
Fu
Ju Yen
JY
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G40NR, United Kingdom.
Blatchford
David R
DR
Tetley
Laurence
L
Dufès
Christine
C
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D001692:Biological Transport; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004339:Drug Compounding; D005260:Female; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010316:Particle Size; D011990:Receptors, Transferrin / Q000378:metabolism; D012997:Solvents / Q000737:chemistry; D013997:Time Factors; D024508:Tocotrienols / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D014168:Transferrin / Q000737:chemistry / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004337:Drug Carriers; D011990:Receptors, Transferrin; D012997:Solvents; D024508:Tocotrienols; D014168:Transferrin