Spinal cord injury is characterized by profound respiratory compromise secondary to the level of loss of motor, sensory and autonomic control associated with the injury. Respiratory complications remain the most common cause of mortality following spinal cord injury. Patients are most vulnerable to respiratory illness in the first year after injury but continue to suffer from respiratory complications throughout life. The injury causes reduced vital capacity, ineffective cough, compromised chest and lung wall compliance, respiratory muscles impairment, and increased oxygen cost of breathing stemming from respiratory system distortion. Severe cervical spinal cord injury interferes with the respiratory pathways from the respiratory neurons in the brain to the respiratory motoneurons in the spinal cord leading to respiratory muscles paralysis. Existing interventions include mechanical ventilation associated with infection and medications with severe side effects and low therapeutic ratios.
Previous studies have reported continuous respiratory recovery in animal models (rats) that underwent C2 spinal cord hemisection after repeated administration of caffeine-like xanthines. This suggests that prolonged drug administration could induce functional plasticity in the respiratory circuitry leading to permanent recovery, an ultimate dream of patients suffering chronic spinal cord injury and their caretakers. Although the studies reported that this intervention could be extended to humans, most spinal cord injury patients couldn’t withstand theophylline when the drug was administered systematically, owing to its severe side effects. Therefore, the main limiting factor and the unsolved problem in spinal cord injury potential therapeutics isn’t the drug but how it’s delivered.
Targeted nanotherapeutics have the potential to overcome the long-standing challenges of central nervous system disorders treatment, which include blood-spinal cord barrier and blood-brain barrier against potential drugs. In light of this, a research team led by Professor Guangzhao Mao from The University of New South Wales in Australia in collaboration with her American colleagues developed a targeted nanoformulation that could bypass the blood-brain barrier and the blood-spinal cord barrier. The research team designed the nanoconjugate preparation where they combined the peculiar characteristics of xanthine drugs and proteins found in plants, wheat germ agglutinin horseradish peroxidase (WGA-HRP), by linking them through gold nanoparticles for transporting and delivering drugs by WGA-HRP’s movement along specific respiratory neural pathways. For better clinical translation, the researchers also conducted studies to specify the purity and quality of nanoconjugate, stability, and in vitro drug-release characteristics of the protein-coupled nanoconjugates. They also aimed to specify the optimal drug storage conditions. Their research work is published in the journal ACS Chemical Neuroscience.
The research team looked at the reproducibility of the nanoconjugate and determined the batch-to-batch particle size variation to be 9.8% through dynamic light scattering measurements. They noted that the drug dosage variation at an optimized 1,3-dipropyl-8-cyclopentyl xanthine dosage of 0.15 μg/kg was less than 10%. They also discovered that the optimum storage conditions for the nanoconjugate solution were between 2-8 ℃ away from direct sunlight for up to four months without noticeable precipitation. The authors determined that the novel nanoconjugate solution could sustain drug release for several days at the physiologic pH, a much-needed prerequisite for long-distance drug delivery from the diaphragm muscle to the brainstem. Through biological transmission electron microscopy, the authors didn’t notice any gold nanoparticle agglomeration at the diaphragmatic injection site. They then modeled the drug-release profiles fitted by the first-order hydrolysis reaction, which resulted from the low ester bond hydrolysis and the drug’s poor water solubility. This The University of New South Wales study results open new research avenues for neural tracing protein-coupled nanotherapeutics for intervening in respiratory problems that come with spinal cord injury.
In a statement to Medicine Innovates, Prof Guangzhao Mao said “Many targeted drug delivery approaches have a clearly defined target but fail to deliver because of lack of considerations for problems and barriers during transport of the drug from the injection site to the target site. We therefore choose to focus on the drug transport problem by learning how certain plant proteins travel along specific neural connections when used as anatomic tract tracers”.
Md. Musfizur Hassan, Malsha Hettiarachchi, Mohamed Kilani, Xiaohua Gao, Abdulghani Sankari, Cyrille Boyer, and Guangzhao Mao. Sustained A1 Adenosine Receptor Antagonist Drug Release from Nanoparticles Functionalized by a Neural Tracing Protein. ACS Chem. Neuroscience. 2021, 12, 4438−4448.