New technologies for drug delivery across the blood brain barrier

Abstract

The blood-brain barrier (BBB) efficiently restricts penetration of therapeutic agents to the brain from the periphery. Therefore, discovery of new modalities allowing for effective delivery of drugs and biomacromolecules to the central nervous system (CNS) is of great need and importance for treatment of neurodegenerative disorders. This manuscript focuses on three relatively new strategies. The first strategy involves inhibition of the drug efflux transporters expressed in BBB by Pluronic block copolymers, which allows for the increased transport of the substrates of these transporters to the brain. The second strategy involves the design of nanoparticles conjugated with specific ligands that can target receptors in the brain microvasculature and carry the drugs to the brain through the receptor mediated transcytosis. The third strategy involves artificial hydrophobization of peptides and proteins that facilitates the delivery of these peptides and proteins across BBB. This review discusses the current state, advantages and limitations of each of the three technologies and outlines their future prospects.

Fig. 1

Schematic illustrating two-fold effects of Pluronic® block copolymers with intermediate lipophilicity on Pgp and MRPs drug efflux system. These effects include (a) decrease in membrane viscosity (“fluidization”) resulting in inhibition of Pgp and MRPs ATPase activity, and (b) ATP depletion in BMVEC. Extremely lipophilic or hydrophilic Pluronic^® block copolymers do not cross the cellular membranes and do not cause energy depletion in the cells.

Fig. 2

Schematic illustration of Nanogel^™ principle using a model: (a) swollen Nanogel^™ has large pores, through which the drug (“ball”) can enter; (b) binding of a drug to results in Nanogel^™ collapse. (c) Transmission electron microphotograph of PEG-cl-PEI Nanogel^™ loaded with ODN. Bar = 50 nm. PEG-cl-PEI networks were synthesized by cross-linking of PEI (M≈25000) with double end N,N′-carbonyldiimidazole-activated PEG (M_n≈8000) using the emulsification-solvent evaporation technique (64). Following the synthesis the Nanogel^™ particles were fractionated by gel-permeation chromatography and a fraction with an average particle diameter of ca. 250 nm was used for complex formation with phosphorothioate ODN.

Fig. 3

Chemical modification of the protein with a water-insoluble reagent in the reverse micelles of Aerosol OT in octane (77). The protein molecule is entrapped in the reverse micelle is surrounded by a cover of hydrated surfactant molecules. The water-insoluble reagent is located in the bulk organic phase and can be incorporated into the micelle surface layer coming in contact with the reactive group in the protein. After completion of the reaction the reverse micelle system is disintegrated and the protein is precipitated by cold acetone.

Fig. 4

Schematic representation of major mechanisms of interaction of fatty acylated proteins with cell membranes: (a) attachment to the lipid membrane by the fatty acid anchor group; (b) binding with fatty acid receptor; (c) two-point attachment via the the fatty acid anchor and specific binding with the protein receptor.