Drug Delivery to the Brain by Liposomes : Understanding Factors Governing Delivery Outcomes In Vivo

Abstract: The blood-brain barrier (BBB) is the primary obstacle for efficient drug delivery to the central nervous system (CNS). One promising strategy to enhance brain delivery is to utilize nanocarriers (NC), e.g., liposomes, encapsulating CNS drugs. However, there is still a lack of understanding of how carrier- and payload-associated factors with liposomal brain delivery may influence brain drug uptake and ultimately therapeutic performance. In this thesis, the impact of factors including the liposomal formulation, the addition of a BBB-targeting ligand and the BBB transport properties of the payload itself on brain drug delivery were quantitatively investigated in vivo with microdialysis. Furthermore, by using a model-based approach, the benefits of NCs with different properties to increase the therapeutic index of CNS drugs were studied and key parameters influencing the therapeutic performance were identified.The formulation of PEGylated (PEG) liposomes could significantly influence brain delivery of methotrexate (MTX). Compared to free MTX, PEG liposomes based on egg-yolk phosphatidylcholine (EYPC) increased brain uptake of MTX by 3-fold, while the formulation based on hydrogenated soy phosphatidylcholine (HSPC) did not affect the uptake at all. Also, PEG liposomes could influence the BBB transport of payloads differently, depending on if the payload itself show active uptake or efflux at the BBB. For diphenhydramine (DPH), a drug with active uptake at the BBB, PEG-EYPC liposomes significantly reduced its uptake into the brain. Moreover, the brain-targeting effect of glutathione (GSH)-tagged PEG liposomal MTX was highly dependent on the liposomal formulation that is combined with GSH. Compared to the PEG control formulations, GSH-PEG-HSPC liposomes increased brain delivery of MTX 4-fold, while GSH-coating on PEG-EYPC liposomes did not further enhance the uptake. In the last simulation study, two independent processes of nanodelivery to the brain were identified. A NC only prolonging circulation time increases the therapeutic index by reducing peripheral toxicity, while a NC with increased circulation time and brain uptake improves the therapeutic index due to both elevated central effect and decreased peripheral toxicity. Faster in vivo drug release and faster systemic elimination of the intact NC reduce the therapeutic performance. A drug with shorter half-life will obtain more therapeutic benefit from NC-encapsulation.In summary, this thesis work contributes to a better understanding of factors governing the success of liposomal brain delivery and gives important insights on what needs to be considered and how to optimize the properties of a NC when developing NC-based strategies for treating CNS diseases.