Targeted Drug Delivery to the Central Nervous System Using Extracellular Vesicles

Abstract

The blood brain barrier (BBB) maintains the homeostasis of the central nervous system (CNS) and protects the brain from toxic substances present in the circulating blood. However, the impermeability of the BBB to drugs is a hurdle for CNS drug development, which hinders the distribution of the most therapeutic molecules into the brain. Therefore, scientists have been striving to develop safe and effective technologies to advance drug penetration into the CNS with higher targeting properties and lower off-targeting side effects. This review will discuss the limitation of artificial nanomedicine in CNS drug delivery and the use of natural extracellular vesicles (EVs), as therapeutic vehicles to achieve targeted delivery to the CNS. Information on clinical trials regarding CNS targeted drug delivery using EVs is very limited. Thus, this review will also briefly highlight the recent clinical studies on targeted drug delivery in the peripheral nervous system to shed light on potential strategies for CNS drug delivery. Different technologies engaged in pre- and post-isolation have been implemented to further utilize and optimize the natural property of EVs. EVs from various sources have also been applied in the engineering of EVs for CNS targeted drug delivery in vitro and in vivo. Here, the future feasibility of those studies in clinic will be discussed.

Keywords: BBB; CNS; brain; drug-loading; extracellular vesicles; nanoparticles; target drug delivery.

Figure 1

A schematic coverage of this review. We first discuss a brief explanation of the structure of the blood brain barrier (BBB) and its effect on drug permeability followed by the limitations of the current nanoformulation in drug delivery. Afterwards, we introduce EVs for targeted drug delivery, in which we list several clinical studies on targeted delivery in the peripheral system. Furthermore, we focus on engineering extracellular vesicles (EVs) for targeted delivery in the central nervous system (CNS) with four examples that are discussed in detail. Finally, we provide some limitations regarding an EV-based drug delivery system (DDS) during manufacturing.

Figure 2

Schematic representation of the engineering of EVs for CNS targeting before isolation. Two studies, as shown in Figure 2, used two different engineering methods before isolation of the EVs from the cell media to deliver therapeutic molecules to the target site in the brain. Dendritic cells were transfected with the targeted gene and fused with RVG peptides to endow the CNS target delivery of EVs, and the therapeutical siRNA was loaded by electroporation before EV isolation. As shown on the right side of the figure, the microglia were infected by a pseudotype virus to overexpress Mfg-e8, and transfected with plasmid coded with IL-4, which has a therapeutical effect on experimental autoimmune encephalomyelitis (EAE) mice. Then, the EVs were produced with a targeting property towards phagocytes in the CNS to treat EAE mice.

Figure 3

Schematic diagram of engineering of EVs during post isolation to endow EVs with a CNS targeting property. Ye et al. treated parent cells with the drug, Methotrexate (MTX), and fused a peptide onto EVs after isolation. Compared to free drugs, MTX primed EVs delivered more of the active drug across the BBB and reached the glioma site in the mice glioblastoma model. To grant EVs specific targeting capability in the ischemic site in the brain, Tian et al. modified the surface of EVs by click chemistry and loaded EVs with curcumin to treat ischemia, which demonstrated a better safety and efficacy than the control group.

Figure 4

A conceptual process flow chart describing the unit operations for EV drug products. This flow chart summarizes the key steps to maintain the consistency of safety, efficacy, and quality in EV drug products based on the regulatory requirements of the FDA and the feasibility in manufacture process.