title: Pyrilamine-sensitive proton-coupled organic cation (H+/OC) antiporter for brain-specific drug delivery.
abstract: Blood-brain barrier (BBB) represents the greatest challenge that hampers therapeutic molecules entering the brain. Here, we described a novel brain-specific delivery strategy targeting to pyrilamine-sensitive H+/OC antiporter to facilitate therapeutic molecules cross the BBB and penetrate into the brain. In this study, four cyclic tertiary amines were selected as the brain-targeting moieties to modify naproxen (NP), a non-steroidal anti-inflammatory drug. The obtained NP conjugates displayed cell uptake efficiencies over 144-fold higher than that of unmodified NP in endothelial cells. The cell uptake process of the conjugates was primarily driven by pyrilamine-sensitive H+/OC antiporter in a pH-dependent, Na+-independent, and membrane potential-independent pathway, which could be further inhibited by pyrilamine, propranolol, and imipramine. Moreover, the NP conjugates showed significantly higher AUC0-tand Cmaxin the brain compared with unmodified NP, and significantly higher accumulation than NP in the in situ brain perfusion study. Also, the conjugates showed superior neuroprotective effect in vitro and in vivo. Thus, the chemical modification of therapeutics with a cyclic tertiary amine moiety represents a promising and efficient strategy for brain-specific drug delivery via pyrilamine-sensitive H+/OC antiporter.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Qi
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
authors.forename: Huifang
authors.initials: H
authors.lastname: Su
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
authors.forename: Qin
authors.initials: Q
authors.lastname: He
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China. Electronic address: yfu4@scu.edu.cn.
authors.forename: Yao
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China. Electronic address: zrzzl@vip.sina.com.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D017920:Antiporters / Q000378:metabolism*; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects*; D002460:Cell Line; D016503:Drug Delivery Systems / Q000379:methods*; D065546:Drug Liberation; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials; D051379:Mice; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D011522:Protons; D011738:Pyrilamine / Q000378:metabolism*; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D017920:Antiporters; D018696:Neuroprotective Agents; D027701:Organic Cation Transport Proteins; D011522:Protons; D012964:Sodium; D011738:Pyrilamine
keywords: Brain-targeting; Cyclic tertiary amine; Organic cation transporter; Pyrilamine