Intrathecal delivery of Macromolecules: Clinical status and emerging technologies
Rana Ajeeb, John R. Clegg
Abstract
The proximity and association of cerebrospinal fluid (CSF) and the intrathecal (IT) space with deep targets in the central nervous system (CNS) parenchyma makes IT injection an attractive route of administration for brain drug delivery. However, the extent to which intrathecally administered macromolecules are effective in treating neurological diseases is a question of both clinical debate and technological interest. We present the biological, chemical, and physical properties of the intrathecal space that are relevant to drug absorption, distribution, metabolism, and elimination from CSF. We then analyze the evolution of IT drug delivery in clinical trials over the last 20 years. Our analysis revealed that the percentage of clinical trials assessing IT delivery for the delivery of biologics (i.e., macromolecules, cells) for treatment of chronic conditions (e.g., neurodegeneration, cancer, and metabolic diseases) has steadily increased. Clinical trials exploring cell or macromolecular delivery within the IT space have not evaluated engineering technologies, such as depots, particles, or other delivery systems. Recent pre-clinical studies have evaluated IT macromolecule delivery in small animals, postulating that delivery efficacy can be assisted by external medical devices, micro- or nanoparticles, bulk biomaterials, and viral vectors. Further studies are necessary to evaluate the extent to which engineering technologies and IT administration improve CNS targeting and therapeutic outcome.