title: Angiopep-2 modified PE-PEG based polymeric micelles for amphotericin B delivery targeted to the brain.
abstract: Amphotericin B (AmB) is a poorly water soluble antibiotic and is used to treat fungal infections of the central nervous system (CNS). However, AmB shows poor penetration into the CNS. Angiopep-2, the ligand of low-density lipoprotein receptor-related protein (LRP) present on the BBB, exhibits higher transcytosis capacity and parenchymal accumulation, which allowed us to consider the selectivity of it for receptor-mediated drug targeting to the brain. With this in mind, we prepared angiopep-2 modified PE-PEG based micellar drug delivery system loaded with the antifungal drug AmB to evaluate the efficiency of AmB accumulating into the brain. PE-PEG based micelles as nano-scaled drug carriers were investigated by incorporating AmB with high drug entrapping efficiency, improving solubilization of AmB and reducing its toxicity to mammalian cells. The AmB-incorporated angiopep-2 modified micelles showed highest efficiency in penetrating across the blood-brain barrier (BBB) than unmodified micelles and Fungizone (deoxycholate amphotericin B) in vitro and in vivo. Meanwhile, contrary to the free Rho 123, the enhancement of Rho 123-incorporated angiopep-2 modified micelles across the BBB can be explained by angiopep-2 modified polymeric micelles that have a potential to overcome the activity of efflux proteins expressed on the BBB such as P-glycoprotein. In conclusion, angiopep-2 modified polymeric micelles could be developed as a novel drug delivery system for brain targeting.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China.
authors.forename: Kun
authors.initials: K
authors.lastname: Shao
authors.forename: Rongqin
authors.initials: R
authors.lastname: Huang
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.forename: Liya
authors.initials: L
authors.lastname: Ye
authors.forename: Jinning
authors.initials: J
authors.lastname: Lou
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D002196:Capillaries / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008823:Micelles; D018625:Microscopy, Atomic Force; D010316:Particle Size; D010455:Peptides / Q000737:chemistry*; D010714:Phosphatidylethanolamines / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012756:Sheep; D014018:Tissue Distribution
chemical_list: C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); C531860:Angiopep-2; D004337:Drug Carriers; D008823:Micelles; D010455:Peptides; D010714:Phosphatidylethanolamines; D011092:Polyethylene Glycols; D000666:Amphotericin B