title: Polymersomes conjugated with des-octanoyl ghrelin for the delivery of therapeutic and imaging agents into brain tissues.
abstract: The effective protection of the blood-brain barrier (BBB) from tight junctions and efflux transport systems ultimately results in the limited entry of 95% of drug/gene candidates, which are potentially beneficial for central nervous system (CNS) diseases. In order to enhance the brain-specific delivery, in this study we developed a targeting carrier system, which consists of poly(carboxyl ethylene glycol-g-glutamate)-co-poly(distearin-g-glutamate) (CPEGGM-PDSGM) polymersomes with the conjugation of des-octanoyl ghrelin. Des-octanoyl ghrelin across the BBB was reported to be unidirectional (blood-to-brain direction). However, there is no report about the conjugation of des-octanoyl ghrelin to a drug carrier system to confer the BBB targeting property through des-octanoyl ghrelin binding sites mediated endocytosis. To qualitatively and quantitatively investigate this carrier's properties, coumarin 6, Cy5.5 and met-enkephalin were individually encapsulated in these polymersomes. The experimental results showed that the cellular uptake was significantly higher for des-octanoyl ghrelin-conjugated polymersomes (GPs) than unconjugated polymersomes when co-incubated with the BBB cells. In addition, an enhanced accumulation in brain together with a reduced accumulation in liver and spleen was observed in animal study, indicating better brain selectivity for the GPs. In a hot-plate test, a significant inhibition of nociceptive response could be achieved for an intravenous injection of GPs encapsulated with met-enkephalin. The overall results demonstrated that GPs own a great potential for targeting delivery of drug across the BBB to treat CNS diseases.
authors: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan; Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsinchu, Taiwan.
authors: Yung-Chu
authors: YC
authors: Chen
authors: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan.
authors: Chi-Feng
authors: CF
authors: Chiang
authors: Divison of Neurosurgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors: Li-Fang
authors: LF
authors: Chen
authors: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan; Center for Thin Film Technologies and Applications, Ming Chi University of Technology, New Taipei City, Taiwan.
authors: Shu-Chuan
authors: SC
authors: Liao
authors: Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsinchu, Taiwan. Electronic address: hsiehw@itri.org.tw.
authors: Wen-Yuan
authors: WY
authors: Hsieh
authors: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan; Division of Medical Engineering Research, National Health Research Institutes, Miaoli, Taiwan. Electronic address: winli@ntu.edu.tw.
authors: Win-Li
authors: WL
authors: Lin
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D054439:Ghrelin / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008962:Models, Theoretical; D050997:Nanomedicine; D011108:Polymers / Q000737:chemistry*; D051381:Rats
chemical_list: D004337:Drug Carriers; D054439:Ghrelin; D011108:Polymers
keywords: Blood-brain barrier (BBB); Brain delivery; Des-octanoyl ghrelin; Nanomedicine; Polymersomes; Targeting