Tumor Regression After Systemic Administration of Tocotrienol Entrapped in Tumor-Targeted Vesicles

J Control Release. 2009 Dec 3;140(2):95-9. doi: 10.1016/j.jconrel.2009.08.017. Epub 2009 Aug 23.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / toxicity
  • Biological Transport
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chemistry, Pharmaceutical
  • Dose-Response Relationship, Drug
  • Drug Carriers*
  • Drug Compounding
  • Female
  • Inhibitory Concentration 50
  • Injections, Intravenous
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred BALB C
  • Particle Size
  • Receptors, Transferrin / metabolism
  • Solvents / chemistry
  • Time Factors
  • Tocotrienols / administration & dosage*
  • Tocotrienols / chemistry
  • Tocotrienols / metabolism
  • Tocotrienols / toxicity
  • Transferrin / chemistry
  • Transferrin / metabolism*
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Drug Carriers
  • Receptors, Transferrin
  • Solvents
  • Tocotrienols
  • Transferrin