Getting into the brain: liposome-based strategies for effective drug delivery across the blood-brain barrier

Abstract

This review summarizes articles that have been reported in literature on liposome-based strategies for effective drug delivery across the blood-brain barrier. Due to their unique physicochemical characteristics, liposomes have been widely investigated for their application in drug delivery and in vivo bioimaging for the treatment and/or diagnosis of neurological diseases, such as Alzheimer's, Parkinson's, stroke, and glioma. Several strategies have been used to deliver drug and/or imaging agents to the brain. Covalent ligation of such macromolecules as peptides, antibodies, and RNA aptamers is an effective method for receptor-targeting liposomes, which allows their blood-brain barrier penetration and/or the delivery of their therapeutic molecule specifically to the disease site. Additionally, methods have been employed for the development of liposomes that can respond to external stimuli. It can be concluded that the development of liposomes for brain delivery is still in its infancy, although these systems have the potential to revolutionize the ways in which medicine is administered.

Keywords: Alzheimer; Parkinson; blood–brain barrier; cerebral ischemia; glioma; liposomes; stroke.

Figure 1

Pathways for crossing the blood–brain barrier (BBB). Notes: The BBB is located at the walls of the blood vessels that supply the central nervous system, including the brain. (A) Cross-section of a cerebral capillary, showing the structure of the BBB. The barrier is composed of a network of astrocytes, pericytes, neurons, and endothelial cells that form the tight junctions. (B) Different mechanisms for drug delivery across the BBB: water-soluble molecules penetrate the BBB through the tight junctions (I); lipid-soluble molecules are able to diffuse across the endothelial cells passively (II); carrier-mediated transport machineries are responsible for transporting peptides and small molecules (III); cationic drug increases its uptake by adsorptive-mediated transcytosis or endocytosis (IV); larger molecules are transported through receptor-mediated transcytosis (V).

Figure 2

Schematic representation of the main liposomal drugs and targeting agents that improve liposome affinity and selectivity for brain delivery. Abbreviation: PEG, polyethylene glycol.

Figure 3

Flow diagram of studies that were identified based on the search terms described in the body of this article. Abbreviation: ref, reference.

Figure 4

Delivery of therapeutic molecules or imaging agents to the brain by liposomes (m) is highly challenging. Notes: Liposomes can be administered to the central nervous system via systemic delivery (a), intracarotid (b), intracranial (c), intranasal (e), and intraperitoneal (f) injections, or via convection-enhanced delivery (d/n). Liposome-based strategies consist in encapsulating the molecules of interest in liposomes (V). The ability to increase their blood-circulation time is created with the ligation of polyethylene glycol on the liposome surface (III). Liposomes can also be targeted to cross the blood–brain barrier (I), target the site of disease (IX), or both (II). Surface modification of liposomes can be achieved by covalent ligation of antibodies (IX), RNA aptamers (VI), or peptides (XII). Cationic lipids can be incorporated into the bilayer, facilitating their association with nucleic acids for gene therapy (VIII and XI). This figure also summarizes therapeutic mechanisms, such as hyperthermia (IV), temperature increase (VII), and ultrasound (X).