Sustained A1 Adenosine Receptor Antagonist Drug Release from Nanoparticles Functionalized by a Neural Tracing Protein
- 21 October 2021
- journal article
- research article
- Published by American Chemical Society (ACS) in ACS Chemical Neuroscience
- Vol. 12 (23), 4438-4448
- https://doi.org/10.1021/acschemneuro.1c00538
Abstract
Respiratory dysfunction is a major cause of death in people with spinal cord injury (SCI). A remaining unsolved problem in treating SCI is the intolerable side effects of the drugs to patients. In a significant departure from conventional targeted nanotherapeutics to overcome the blood–brain barrier (BBB), this work pursues a drug-delivery approach that uses neural tracing retrograde transport proteins to bypass the BBB and deliver an adenosine A1 receptor antagonist drug, 1,3-dipropyl-8-cyclopentyl xanthine, exclusively to the respiratory motoneurons in the spinal cord and the brainstem. A single intradiaphragmatic injection at one thousandth of the native drug dosage induces prolonged respiratory recovery in a hemisection animal model. To translate the discovery into new treatments for respiratory dysfunction, we carry out this study to characterize the purity and quality of synthesis, stability, and drug-release properties of the neural tracing protein (wheat germ agglutinin chemically conjugated to horseradish peroxidase)-coupled nanoconjugate. We show that the batch-to-batch particle size and drug dosage variations are less than 10%. We evaluate the nanoconjugate size against the spatial constraints imposed by transsynaptic transport from pre to postsynaptic neurons. We determine that the nanoconjugate formulation is capable of sustained drug release lasting for days at physiologic pH, a prerequisite for long-distance transport of the drug from the diaphragm muscle to the brainstem. We model the drug-release profiles using a first-order reaction model and the Noyes–Whitney diffusion model. We confirm via biological electron microscopy that the nanoconjugate particles do not accumulate in the tissues at the injection site. We define the nanoconjugate storage conditions after monitoring the solution dispersion stability under various conditions for 4 months. This study supports further development of neural tracing protein-enabled nanotherapeutics for treating respiratory problems associated with SCI.Keywords
Funding Information
- National Institute of Neurological Disorders and Stroke (R61NS112443)
This publication has 50 references indexed in Scilit:
- Effect of gold nanoparticle morphology on adsorbed protein structure and functionBiomaterials, 2011
- Polylactide‐cyclosporin A nanoparticles for targeted immunosuppressionThe FASEB Journal, 2010
- Gold nanoparticles: Optical properties and implementations in cancer diagnosis and photothermal therapyJournal of Advanced Research, 2010
- Drug-Eluting Stent for Delivery of Signal Pathway-Specific 1,3-Dipropyl-8-cyclopentyl XanthineMolecular Pharmaceutics, 2009
- Administration of phosphodiesterase inhibitors and an adenosine A1 receptor antagonist induces phrenic nerve recovery in high cervical spinal cord injured ratsExperimental Neurology, 2008
- The optimal height of the synaptic cleftProceedings of the National Academy of Sciences of the United States of America, 2007
- The most infectious prion protein particlesNature, 2005
- Structural comparison of the two distinct sugar binding sites in wheat germ agglutinin isolectin IIJournal of Molecular Biology, 1984
- Simple Method for the Esterification of Carboxylic AcidsAngewandte Chemie, 1978
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976