Saponins modulate the intracellular trafficking of protein toxins

J Control Release. 2012 Nov 28;164(1):74-86. doi: 10.1016/j.jconrel.2012.10.002. Epub 2012 Oct 10.

Abstract

Type I ribosome inactivating proteins such as saporin from the plant Saponaria officinalis L. are widely used as toxin moieties of targeted anti-tumor toxins. For exerting cytotoxicity the toxin moieties have to be released into the cytosol of tumor cells. However the cytosolic transfer of toxin molecules into the cytosol is mostly an inefficient process. In this report we demonstrate that certain saponins, which are also biosynthesized by Saponaria officinalis L., specifically mediate the release of saporin out of the intracellular compartments into the cytosol without affecting the integrity of the plasma membrane. The relevant cellular compartments were identified as late endosomes and lysosomes. Further studies revealed that endosomal acidification is a prerequisite for the saponin-mediated release of saporin. Binding analysis demonstrated an association of the saponins with saporin in a pH-dependent manner. The applicability of the saponin-mediated effect was demonstrated in vivo in a syngeneic tumor model using a saporin-based targeted anti-tumor toxin in combination with characterized saponins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage*
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Antineoplastic Agents, Phytogenic / toxicity
  • Cell Line
  • Cell Survival / drug effects
  • Cell Tracking
  • Cytosol / metabolism*
  • Drug Carriers / chemistry*
  • Drug Carriers / pharmacokinetics
  • Drug Carriers / toxicity
  • Endocytosis
  • Epidermal Growth Factor / metabolism
  • Humans
  • Hydrogen-Ion Concentration
  • Mice
  • Mice, Inbred BALB C
  • Molecular Structure
  • Protein Binding
  • Protein Transport
  • Ribosome Inactivating Proteins, Type 1 / administration & dosage*
  • Ribosome Inactivating Proteins, Type 1 / pharmacokinetics
  • Ribosome Inactivating Proteins, Type 1 / therapeutic use
  • Ribosome Inactivating Proteins, Type 1 / toxicity
  • Saponins / chemistry*
  • Saponins / pharmacokinetics
  • Saponins / toxicity
  • Saporins
  • Single-Cell Analysis
  • Surface Plasmon Resonance
  • Tissue Distribution
  • Toxicity Tests, Acute
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Phytogenic
  • Drug Carriers
  • Ribosome Inactivating Proteins, Type 1
  • Saponins
  • Epidermal Growth Factor
  • Saporins