This presentation describes a targeted nanomedicine approach for drug delivery to the spinal cord and the brain of the central nervous system (CNS). We synthesize hybrid nanoparticles consisting of a targeting neural tracing protein, wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP), chemically linked to a gold nanoparticle, which in turn is chemically conjugated to a pro-drug, pro-theophylline or pro-1,3-dipropyl-8-cyclopentylxanthine (pro-DPCPX). WGA-HRP is a widely used neural tracer to visualize neuronal connectivity and axonal transport and for the understanding of neural plasticity in the CNS. WGA binds to <i>N</i>-acetylglucosamine and <i>N</i>-acetylneuraminic acid (sialic acid) residues, abundant at the neuronal cell membrane. By functionalizing drug-carrying nanoparticles with neural tracers such as WGA-HRP, we aim to simultaneously address multiple unsolved problems plaguing neurotherapeutics including low drug solubility, low biological stability, low delivery efficiency, off-target effects, and inability to penetrate the biological barriers. Our synthesized nanoparticles are characterized by transmission electron microscopy, dynamic light scattering, HPLC, and thermogravimetric analysis. We present in vitro results demonstrating active axonal transport of the hybrid nanoparticles in microfluidic culture plates containing microchannels separating the cell body from the axon terminals of the neuronal cells. Real-time axonal transport movements of gold nanoparticles with and without the bound protein are captured by two-photon fluorescence microscopy at the single entity level. While both types of nanoparticles move in a “stop and go” fashion, the protein-bound gold nanoparticle moves at a higher average speed by persistent engagement with the dynein motor machinery. In our in vivo studies, the targeted nanomedicine induces diaphragmatic recovery in rats with spinal cord injury at a fraction of the systemic dose. For comparison, the systemic dose of theophylline in rats is 15 mg/kg, while the theophylline content in the nanoconjugate is only 0.12 mg/kg. The systemic dose of DPCPX in rats is 0.1 mg/kg, while the DPCPX content in the nanoconjugate is 0.15 µg/kg, ~0.1% of the systemic dose. The success of making safe nanoparticles with significantly reduced drug dosage will move the technology rapidly towards regulatory approval for human use.

Active neuronal transport of drug-carrying gold nanoparticles by neural tracing proteins

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ACS Fall 2022

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