Efficacy and toxicity of the DPCPX nanoconjugate drug study for the treatment of spinal cord injury in rats

J Appl Physiol (1985). 2022 Aug 1;133(2):262-272. doi: 10.1152/japplphysiol.00195.2022. Epub 2022 Jun 30.

Abstract

Effects of the Adenosine A1 blockade using 8-cyclopentyl-1,3-diprophyxanthine (DPCPX) nanoconjugate on inducing recovery of the hemidiaphragm paralyzed by hemisection have been thoroughly examined previously; however, the toxicology of DPCPX nanoconjugate remains unknown. This research study investigates the therapeutic efficacy and toxicology of the nanoconjugate DPCPX in the cervical spinal cord injury (SCI) rat model. We hypothesized that a single injection of nanoconjugate DPCPX in the paralyzed left hemidiaphragm (LDH) of hemisected rats at the 2nd cervical segment (C2Hx) would lead to the long-term recovery of LDH while showing minimal toxicity. Adult male rats underwent left C2Hx surgery and the diaphragms' baseline electromyography (EMG). Subsequently, rats were randomized into a control group and four treated subgroups. Three subgroups received a single intradiaphragmatic dose of either 0.09, 0.15, or 0.27 µg/kg, and one subgroup received 0.1 mg/kg of native DPCPX two times per day intravenously (i.v.) for 3 days (total 0.6 mg/kg). Rats were monitored for a total of 56 days. Compared with control, the treatment with nanoconjugate DPCPX at 0.09 µg/kg, 0.15 µg/kg, and 0.27 µg/kg doses elicited significant recovery of paralyzed LDH (i.e., 67% recovery at 8 wk) (P < 0.05). DPCPX nanoconjugate-treated rats had significant weight loss for first 2 wk but recovered significantly by day 56 (P < 0.05). The levels of gold in the blood and body tissues were below the recommended levels. No sign of weakness, histology of tissue damage, or organ abnormality was observed. A dose of DPCPX nanoconjugate can induce long-term diaphragm recovery after SCI without observed toxicity.NEW & NOTEWORTHY The intradiaphragmatic administration of nanoconjugate is safe and has the promise to significantly reduce the therapeutic dosage for the treatment and achieve long-term and possibly permanent recovery in respiratory muscle dysfunction after SCI. No toxicity of nanoconjugate was found in any of the experimental animals.

Keywords: gold nanoparticles; nano therapy; nanotoxicity; respiratory function recovery; spinal cord injury.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Diaphragm
  • Male
  • Nanoconjugates* / therapeutic use
  • Nanoconjugates* / toxicity
  • Rats
  • Recovery of Function
  • Spinal Cord Injuries* / drug therapy
  • Xanthines* / therapeutic use
  • Xanthines* / toxicity

Substances

  • Nanoconjugates
  • Xanthines
  • 1,3-dipropyl-8-cyclopentylxanthine