Targeting the Choroid Plexuses for Protein Drug Delivery

Abstract

Delivery of therapeutic agents to the central nervous system is challenged by the barriers in place to regulate brain homeostasis. This is especially true for protein therapeutics. Targeting the barrier formed by the choroid plexuses at the interfaces of the systemic circulation and ventricular system may be a surrogate brain delivery strategy to circumvent the blood-brain barrier. Heterogenous cell populations located at the choroid plexuses provide diverse functions in regulating the exchange of material within the ventricular space. Receptor-mediated transcytosis may be a promising mechanism to deliver protein therapeutics across the tight junctions formed by choroid plexus epithelial cells. However, cerebrospinal fluid flow and other barriers formed by ependymal cells and perivascular spaces should also be considered for evaluation of protein therapeutic disposition. Various preclinical methods have been applied to delineate protein transport across the choroid plexuses, including imaging strategies, ventriculocisternal perfusions, and primary choroid plexus epithelial cell models. When used in combination with simultaneous measures of cerebrospinal fluid dynamics, they can yield important insight into pharmacokinetic properties within the brain. This review aims to provide an overview of the choroid plexuses and ventricular system to address their function as a barrier to pharmaceutical interventions and relevance for central nervous system drug delivery of protein therapeutics. Protein therapeutics targeting the ventricular system may provide new approaches in treating central nervous system diseases.

Immunohistochemical expression of osteopontin and collagens in choroid plexus of human brains

“…Evidence that the choroid plexus plays a central role not only in regulation of the microenvironment of the central nervous system by secreting most of the cerebrospinal fluid (CSF) 1,2 but also in adjustment of the circadian rhythm 3 is accumulating. Accordingly, it is reasonable to consider that damage to the choroid plexus induces brain dysfunction.…”

Experimental approaches for manipulating choroid plexus epithelial cells

“…Recent advances that are beyond the scope of this review and were not covered include peptide- and ligand-mediated targeting of the ChP [ 150 , 151 ]. Recombinant proenzymes and antibodies can be delivered by I.C.V.…”

Special delEVery: Extracellular Vesicles as Promising Delivery Platform to the Brain

“…Next to targeting the mostly studied BBB, it was recently suggested that targeting other brain barriers such as the blood–CSF barrier might have added value in CNS drug delivery [ 25 , 26 ]. The blood–CSF barrier is located at the choroid plexus (CP) tissue, a cauliflower-like structure projecting into the four brain ventricles.…”

“…Overall, detailed studies are needed to characterize the transport mechanisms at the blood–CSF barrier. Furthermore, the influence of factors such as CSF clearance flow rate and other cell layers to overcome (e.g., the ependymal cell layer lining the brain ventricles, the pia mater and glia limitans layers at the brain surface and the perivascular spaces) need to be further investigated [ 25 , 26 ]. It was for example reported that the pial membrane does not seem to impede molecule entry from CSF to the brain, while the dense network of glial cells in the glia limitans may slow down diffusion or be a site of accumulation [ 34 ].…”