Induction of Mitochondrial Cell Death and Reversal of Anticancer Drug Resistance via Nanocarriers Composed of a Triphenylphosphonium Derivative of Tocopheryl Polyethylene Glycol Succinate

Mol Pharm. 2019 Sep 3;16(9):3744-3759. doi: 10.1021/acs.molpharmaceut.9b00177. Epub 2019 Aug 23.


We have devised a nanocarrier using "tocopheryl polyethylene glycol succinate (TPGS) conjugated to triphenylphosphonium cation" (TPP-TPGS) for improving the efficacy of doxorubicin hydrochloride (DOX). Triphenylphosphonium cation (TPP) has affinity for an elevated transmembrane potential gradient (mitochondrial), which is usually high in cancer cells. Consequently, when tested in molecular docking and cytotoxicity assays, TPP-TPGS, owing to its structural similarity to mitochondrially directed anticancer compounds of the "tocopheryl succinate" family, interferes specifically in mitochondrial CII enzyme activity, increases intracellular oxidative stress, and induces apoptosis in breast cancer cells. DOX loaded nanocarrier (DTPP-TPGS) constructed using TPP-TPGS was positively charged, spherical in shape, sized below 100 nm, and had its drug content distributed evenly. DTPP-TPGS offers greater intracellular drug delivery due to its rapid endocytosis and subsequent endosomal escape. DTPP-TPGS also efficiently inhibits efflux transporter P glycoprotein (PgP), which, along with greater cell uptake and inherent cytotoxic activity of the construction material (TPP-TPGS), cumulatively results in 3-fold increment in anticancer activity of DOX in resistant breast cancer cells as well as greater induction of necroapoptosis and arrest in all phases of the cell cycle. DTPP-TPGS after intravenous administration in Balb/C mice with breast cancer accumulates preferentially in tumor tissue, which produces significantly greater antitumor activity when compared to DOX solution. Toxicity evaluation was also performed to confirm the safety of this formulation. Overall TPP-TPGS is a promising candidate for delivery of DOX.

Keywords: TPGS; doxorubicin hydrochloride; drug resistance; mitocans; molecular modeling; nanotechnology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / chemistry
  • Antibiotics, Antineoplastic / pharmacokinetics
  • Antibiotics, Antineoplastic / therapeutic use*
  • Apoptosis / drug effects*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Disease Models, Animal
  • Doxorubicin / chemistry
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / therapeutic use*
  • Drug Carriers / chemistry*
  • Drug Carriers / pharmacokinetics
  • Drug Delivery Systems / methods*
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Humans
  • MCF-7 Cells
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Mitochondria / metabolism*
  • Molecular Docking Simulation
  • Reactive Oxygen Species / metabolism
  • Tissue Distribution
  • Vitamin E / chemistry*
  • Vitamin E / pharmacokinetics


  • Antibiotics, Antineoplastic
  • Drug Carriers
  • Reactive Oxygen Species
  • Vitamin E
  • Doxorubicin
  • tocophersolan