Unique features of brain metastases-targeted AGuIX nanoparticles vs their constituents: A focus on glutamate-/GABA-ergic neurotransmission in cortex nerve terminals

Food Chem Toxicol. 2021 Mar;149:112004. doi: 10.1016/j.fct.2021.112004. Epub 2021 Jan 20.

Abstract

Gadolinium-based radiosensitizing AGuIX nanoparticles (AGuIX) currently tested two phase 2 clinical trials in association with radiotherapy for the treatment of brain metastases. Here, excitatory/inhibitory neurotransmission was assessed in rat cortex nerve terminals in the presence of AGuIX and their constituents (DOTAGA and DOTAGA/Gd3+) at concentrations used for medical treatment, and those 5-24 times higher. The ambient level, transporter-mediated, tonic and exocytotic release of L-[14C]glutamate and [3H]GABA, the membrane potential of nerve terminals were not changed in the presence of AGuIX at concentrations used for medical treatment ([Gd3+] = 0.25 mM, corresponding to 0.25 g.L-1), and DOTAGA (0.25 mM) and DOTAGA/Gd3+ (0.25 mM/0.01 mM). Difference between AGuIX and the precursors was uncovered, when their concentrations were increased. AGuIX (1.25-6 mM) did not change any transport characteristics of L-[14C]glutamate and [3H]GABA, whereas, DOTAGA (1.25-6 mM) affected the membrane potential, ambient level, and exocytotic release of L-[14C]glutamate and [3H]GABA. Gd3+ did not mask, but even enhanced above effects of DOTAGA. Therefore, AGuIX did not influence glutamate- and GABA-ergic neurotransmission at the presynaptic site. In contrast, DOTAGA and mixture DOTAGA/Gd3+ significantly affected synaptic neurotransmission at high concentrations. AGuIX own structure that overcomes neurotoxic features of their constituents.

Keywords: AGuIX nanoparticles; DOTAGA; Exocytosis; GABA; Gd(3+); Glutamate; Neurotoxicity risk assessment; Neurotransmitter release; Presynaptic nerve terminals; Transporters.

MeSH terms

  • Animals
  • Brain Neoplasms / secondary*
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology
  • Dose-Response Relationship, Drug
  • Exocytosis
  • Gadolinium / administration & dosage
  • Gadolinium / pharmacology*
  • Glutamic Acid / metabolism*
  • Male
  • Nanoparticles / administration & dosage
  • Radiation-Sensitizing Agents
  • Rats
  • Rats, Wistar
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • AGuIX
  • Radiation-Sensitizing Agents
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Gadolinium