Drug Delivery to the Central Nervous Syatem

Intrathecal drug (IT) delivery can efficiently target regions in the central nervous system without hindering the blood-brain barrier. This delivery mode is especially promising for novel therapeutics such as enzyme replacement, gene, or antisense oligonucleotide (ASO) therapies for treating neurodegenerative diseases, including Alzheimer’s, Huntington’s disease, and stroke. Due to the high risk to patients and technical limitations of acquiring high-speed cerebrospinal fluid (CSF) flow and bio-distribution data with existing imaging modalities (e.g., MRI, PET) in humans in vivo, the study cannot be performed. A novel, fast, relatively economical, and subject-specific in-vitro method to study the drug bio-dispersion mechanism and optimize IT drug therapies for individual patients is in great need. This method of drug delivery has been studied using experiments, with the use of a manufactured in vitro model of the human spine, which is subjected to the effect of pulsation as experienced in the actual human spine, and computational approaches. Model design and additive manufacturing process for producing a subject-specific spine that replicates the interaction of the human spine with the CSF has been presented. A numerical solution was developed to solve the 1D diffusion problem to generate and compare the concentration profile with those obtained experimentally. Also, to understand how drug can be targeted in the central nervous system (CNS), magnetophoresis – movement of paramagnetic nanoparticles in the presence of external magnetic field, was also studied. Analytical solutions to the magnetic field-driven transport of particles in 1-D and 3D were developed with application to drug delivery through cerebrospinal fluid. This solution gives rise to concentration profiles of the paramagnetic nanoparticle. The results obtained from our models and experiment show that the manufactured spine is functional and can be utilized for optimizing drug dosing guidelines for IT administration before human trials and as a complement or substitute for animal trials. The computational results also provide confidence in the in-vitro experiments as the results are comparable. The developed magnetophoresis model and experiment show that paramagnetic nanoparticle can be confined in a particular domain of the central nervous system (CNS) which will aid the delivery and targeting of drug to the domain.