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Brain drug delivery may be restricted by the blood-brain barrier (BBB), and enhancement by liposome-based drug delivery strategies has been investigated. As access to the human brain is limited, many studies have been performed in experimental animals. Whereas providing interesting data, such studies have room for improvement to provide mechanistic insight into the rate and extent of specifically BBB transport and intrabrain distribution processes that all together govern CNS target delivery of the free drug. This review shortly summarizes BBB transport and current liposome-based strategies to overcome BBB transport restrictions, with the emphasis on how to determine the individual mechanisms that all together determine the time course of  free  drug brain concentrations, following their administration as such, and in liposomes. Animal studies using microdialysis providing time course information on unbound drug in plasma and brain are highlighted, as these provide the mechanistic information needed to understand BBB drug transport of the drug, and the impact of a liposomal formulations of that drug on BBB transport. Overall, these studies show that brain distribution of a drug administered as liposomal formulation depends on both drug properties and liposomal formulation characteristics. In general, evidence suggests that active transporters at the BBB, either being influx or efflux transporters, are circumvented by liposomes. It is concluded that liposomal formulations may provide interesting changes in BBB transport. More mechanistic studies are needed to understand relevant mechanisms in liposomal drug delivery to the brain, providing an improved basis for its prediction in human using animal data.

Understanding Drug Delivery to the Brain Using Liposome-Based Strategies: Studies that Provide Mechanistic Insights Are Essential