PEGylated γ-tocotrienol isomer of vitamin E: Synthesis, characterization, in vitro cytotoxicity, and oral bioavailability

Eur J Pharm Biopharm. 2015 Oct;96:185-95. doi: 10.1016/j.ejpb.2015.07.022. Epub 2015 Jul 30.

Abstract

Vitamin E refers to a family of eight isomers divided into two subgroups, tocopherols and the therapeutically active tocotrienols (T3). The PEGylated α-tocopherol isomer of vitamin E (vitamin E TPGS) has been extensively investigated for its solubilizing capacity as a nonionic surfactant in various drug delivery systems. Limited information, however, is available about the PEG conjugates of the tocotrienol isomers of vitamin E. In this study two PEGylated γ-T3 variants with mPEG molecular weights of 350 (γ-T3PGS 350) and 1000 (γ-T3PGS 1000) were synthesized by a two-step reaction procedure and characterized by (1)H NMR, HPLC, and mass spectroscopy. The physical properties of their self-assemblies in water were characterized by zeta, CMC, and size analysis. Similar physical properties were found between the PEGylated T3 and vitamin E TPGS. PEGylated T3 were also found to retain the in vitro cytotoxic activity of the free T3 against the MCF-7 and the triple-negative MDA-MB-231 breast cancer cells. PEGylated γ-T3 also increased the oral bioavailability of γ-T3 by threefolds when compared to the bioavailability of γ-T3 formulated into a self-emulsified drug delivery system. No significant differences in biological activity were found between the PEG 350 and 100 conjugates. Results from this study suggest that PEGylation of γ-T3 represents a viable platform for the oral and parenteral delivery of γ-T3 for potential use in the prevention of breast cancer.

Keywords: Bioavailability; Cytotoxicity; PEGylation; TPGS; Tocotrienol; Vitamin E.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / pharmacokinetics
  • Antineoplastic Agents* / pharmacology
  • Biological Availability
  • Cell Survival / drug effects
  • Chromatography, High Pressure Liquid
  • Cryoelectron Microscopy
  • Humans
  • MCF-7 Cells
  • Magnetic Resonance Spectroscopy
  • Male
  • Molecular Structure
  • Molecular Weight
  • Particle Size
  • Polyethylene Glycols / chemical synthesis
  • Polyethylene Glycols / pharmacokinetics
  • Polyethylene Glycols / pharmacology
  • Rats, Sprague-Dawley
  • Spectrometry, Mass, Electrospray Ionization
  • Surface Properties
  • Vitamin E / analogs & derivatives*
  • Vitamin E / chemical synthesis
  • Vitamin E / pharmacokinetics
  • Vitamin E / pharmacology

Substances

  • Antineoplastic Agents
  • Vitamin E
  • Polyethylene Glycols
  • tocophersolan