Drug delivery system for poorly water-soluble compounds using lipocalin-type prostaglandin D synthase.
Lipocalin-type prostaglandin D synthase (L-PGDS) is a member of the lipocalin superfamily and a secretory lipid-transporter protein, which binds a wide variety of hydrophobic small molecules. Here we show the feasibility of a novel drug delivery system (DDS), utilizing L-PGDS, for poorly water-soluble compounds such as diazepam (DZP), a major benzodiazepine anxiolytic drug, and 6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-dione (NBQX), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist and anticonvulsant. Calorimetric experiments revealed for both compounds that each L-PGDS held three molecules with high binding affinities. By mass spectrometry, the 1:3 complex of L-PGDS and NBQX was observed. L-PGDS of 500μM increased the solubility of DZP and NBQX 7- and 2-fold, respectively, compared to PBS alone. To validate the potential of L-PGDS as a drug delivery vehicle in vivo, we have proved the prospective effects of these compounds via two separate delivery strategies. First, the oral administration of a DZP/L-PGDS complex in mice revealed an increased duration of pentobarbital-induced loss of righting reflex. Second, the intravenous treatment of ischemic gerbils with NBQX/L-PGDS complex showed a protective effect on delayed neuronal cell death at the hippocampal CA1 region. We propose that our novel DDS could facilitate pharmaceutical development and clinical usage of various water-insoluble compounds.
Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka, Japan.
Ayano
A
Fukuhara
Hidemitsu
H
Nakajima
Yuya
Y
Miyamoto
Katsuaki
K
Inoue
Satoshi
S
Kume
Young-Ho
YH
Lee
Masanori
M
Noda
Susumu
S
Uchiyama
Shigeru
S
Shimamoto
Shigenori
S
Nishimura
Tadayasu
T
Ohkubo
Yuji
Y
Goto
Tadayoshi
T
Takeuchi
Takashi
T
Inui
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000737:chemistry*; D000927:Anticonvulsants / Q000008:administration & dosage / Q000737:chemistry*; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology; D056547:CA1 Region, Hippocampal; D003975:Diazepam / Q000008:administration & dosage / Q000737:chemistry*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005849:Gerbillinae; D005982:Glutathione Transferase / Q000008:administration & dosage / Q000737:chemistry; D019746:Intramolecular Oxidoreductases / Q000008:administration & dosage / Q000737:chemistry*; D054834:Lipocalins / Q000008:administration & dosage / Q000737:chemistry*; D008297:Male; D051379:Mice; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology; D011810:Quinoxalines / Q000008:administration & dosage / Q000737:chemistry*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000737:chemistry; D012995:Solubility; D014867:Water / Q000737:chemistry
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D054834:Lipocalins; D011810:Quinoxalines; D011993:Recombinant Fusion Proteins; D014867:Water; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D005982:Glutathione Transferase; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D003975:Diazepam