Prodrug strategies for the transport of drugs into the CNS

StrategyExampleChemical StructureAction
LipidizationHeroin (Fernandez et al., 2003)Embedded ImageAcetylation of the hydroxyl group changes the physicochemical properties of heroin to favor brain uptake.
Chemical delivery systemEstradiol-CDS (Estredox) (Mullersman et al., 1988)Embedded ImageAfter oxidation and hydrolysis, the concentration of estradiol CDS in rat brain was elevated four to five times longer than after estradiol treatment.
Carrier-drug conjugatesLAT1 (Gomes and Soares-da-Silva, 1999)Embedded ImageThe conversion of dopamine into its α-amino acid, l-dopa, enables the brain to uptake dopamine via LAT1.
GLUT1 (Fernandez et al., 2003)Embedded ImageDopamine linked to the C6 position of glucose had the best affinity for GLUT1.
SVCT2 (Manfredini et al., 2002)Embedded ImageWhen nipecotic, kynurenic, and diclophenamic acids were conjugated to ascorbic acid, interaction with SVCT2 transporters improved.
Ligand-drug conjugatesInsulin/transferrin (Friden et al., 1991; Fukuta et al., 1994; Wang et al., 2014)CNS accumulation of methotrexate is improved by conjugating it to an antibody (OX-26), which is recognized by the transferrin receptor.
Targeting moiety-drug conjugatesN,N-dimethyl amino (Li et al., 2014)Embedded ImageConjugation with N,N-dimethyl amino significantly enhanced the brain-uptake efficiency of dexibuprofen, naproxen, 5-fluorouracil, and dopamine.
Scopine, cyclic tertiary amine (Wang et al., 2014)Embedded ImageChlorambucil-scopine prodrug significantly improved the cellular uptake both in vitro and in vivo.
  • GLUT1, glucose transporter; LAT, large neutral amino acid transporter; SVCT2, sodium-dependent vitamin C transporter 2.