Respiratory problems such as pneumonia, septicemia, and pulmonary emboli are the leading causes of death in spinal cord injury (SCI) patients. Persistent respiratory recovery in rats can be achieved by multiple administrations of adenosine receptor antagonists such as theophylline. This suggests that chronic drug administration induces functional plasticity in the respiratory circuitry. However, while theophylline works in humans in a similar manner as in rats, most SCI patients cannot tolerate theophylline due to its deleterious side effects. To directly address the problem of the side effects of SCI drugs, we have developed a novel approach that combines nanotechnology with proven neurobiological principles to selectively target the lower motor and premotor neurons responsible for diaphragm muscle function. Our nanotherapeutic design consists of a targeting transport 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-DPCPX. Our targeted drug administration can induce recovery of the hemidiaphragm in SCI rats by using a fraction of the systemic dose necessary to induce the same recovery. 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. In addition, the nanoconjugate is capable of inducing persistent recovery after only one injection. This talk will focus on our recent work to demonstrate quality control in the synthesis of the nanoconjugate, its storage and biological stability, sustained release of the drug in biological pH, and retrograde movements of individual particles from axon to cell body in neurons compartmentalized in microfluidic channels. We apply the microfluidic method to screen for retrograde protein-nanoconjugates capable of delivering and releasing drug cargos at precise locations in the motor neuron circuitry to reduce and possibly eliminate the drug’s side effects.

Targeted delivery of spinal cord injury nanomedicine to motor neurons using retrograde transport proteins

ACS Fall 2021

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