Strategy | Example | Chemical Structure | Action |
---|---|---|---|
Lipidization | Heroin (Fernandez et al., 2003) | Acetylation of the hydroxyl group changes the physicochemical properties of heroin to favor brain uptake. | |
Chemical delivery system | Estradiol-CDS (Estredox) (Mullersman et al., 1988) | After oxidation and hydrolysis, the concentration of estradiol CDS in rat brain was elevated four to five times longer than after estradiol treatment. | |
Carrier-drug conjugates | LAT1 (Gomes and Soares-da-Silva, 1999) | The conversion of dopamine into its α-amino acid, l-dopa, enables the brain to uptake dopamine via LAT1. | |
GLUT1 (Fernandez et al., 2003) | Dopamine linked to the C6 position of glucose had the best affinity for GLUT1. | ||
SVCT2 (Manfredini et al., 2002) | When nipecotic, kynurenic, and diclophenamic acids were conjugated to ascorbic acid, interaction with SVCT2 transporters improved. | ||
Ligand-drug conjugates | Insulin/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 conjugates | N,N-dimethyl amino (Li et al., 2014) | Conjugation 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) | Chlorambucil-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.