(498b) Biodistribution and Drug Release Kinetics of Gold Nanoconjugates for Respiratory Recovery after Spinal Cord Injury

Authors: 
Liu, F., Wayne State University
Buttry, J., Wayne State University
Minic, Z., Wayne State University
Goshgarian, H. G., Wayne State University
Mao, G., Wayne State University
This collaborative research developed a patented nanodevice for targeted drug delivery to induce respiratory recovery after spinal cord injury. The nanodevice consists of a gold nanoparticle drug carrier chemically conjugated to methylxanthine drugs, such as theophylline and 1, 3-dipropyl-8-clyclopentyl xanthine, and a transporter protein (wheat germ agglutinin coupled to horseradish peroxidase or WGA-HRP). When theophylline was tested at the clinical level, most spinal cord injured patients could not tolerate it side effects when it was delivered systemically at standard therapeutic dose levels. We have demonstrated a strategy of selectively targeting the lower motor (phrenic) and pre-motor rostral ventral respiratory group (rVRG) neurons responsible for diaphragmatic function in rats by showing persistent respiratory recovery 48 hours after a single diaphragmatic injection of the nanodevice at 0.1% free drug dosage. In order to translate this technology for clinical use, we carried out pharmacokinetic and tissue distribution studies (e.g., gold accumulation) in an animal model. The amount of gold was determined by inductively coupled plasma mass spectrometry in the blood, RES organs, and targeted tissues after injecting the nanoconjugate into the left hemidiaphragm of adult female and male Sprague Dawley rats. Our data show that the 4 nm gold conjugated to the drug and protein 1 week post injection accumulates at a significantly higher dosage in targeted tissues including the spinal cord and medulla in the brain than unconjugated gold. We also carried out drug release studies from the nanodevice in buffers and artificial cerebrospinal fluid (CSF) for time periods ranging from 1 hour to 4 weeks by LC-MS/MS. The data show that the drug is slowly released from the gold nanoparticle carrier with less than 10% released after two weeks. These data may explain the long term recovery in the in vivo animals up to 4 weeks after the injection of the nanoconjugate. The translational significance of the work is the recovery of the diaphragm in spinal cord injured rats induced by the nanodevice at a fraction of the systemic drug dosage with the promise to mitigate drug side effects.