Drug delivery system for poorly water-soluble compounds using lipocalin-type prostaglandin D synthase

作者：Fukuhara Ayano; Nakajima Hidemitsu; Miyamoto Yuya; Inoue Katsuaki; Kume Satoshi; Lee Young Ho; Noda Masanori; Uchiyama Susumu; Shimamoto Shigeru; Nishimura Shigenori; Ohkubo Tadayasu; Goto Yuji; Takeuchi Tadayoshi; Inui Takashi^*

来源：Journal of Controlled Release, 2012, 159(1): 143-150.

DOI：10.1016/j.jconrel.2011.12.020

• L-PGDS
• Lipid-transporter protein
• Delivery vehicle
• Protein drug interaction
• Hydrophobic drug

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 a-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 500 mu M 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.

• 出版日期2012-4-10