title: Mesoporous silica-supported lipid bilayers (protocells) for DNA cargo delivery to the spinal cord.
abstract: Amorphous mesoporous silica nanoparticles ('protocells') that support surface lipid bilayers recently characterized in vitro as carrier constructs for small drug and DNA delivery are reported here as highly biocompatible both in vitro and in vivo, involving the brain and spinal cord following spinal delivery into the lumbosacral subarachnoid space (intrathecal; i.t.). Specifically, positively charged, 1, 2-Dioleoyl-3-Trimethylammonium-Propane (DOTAP)-cholesterol (DOTAP:Chol) liposome-formulated protocells revealed stable in vitro cargo release kinetics and cellular interleukin-10 (IL-10) transgene transfection. Recent approaches using synthetic non-viral vector platforms to deliver the pain-suppressive therapeutic transgene, IL-10, to the spinal subarachnoid space have yielded promising results in animal models of peripheral neuropathy, a condition involving aberrant neuronal communication within sensory pathways in the nervous system. Non-viral drug and gene delivery protocell platforms offer potential flexibility because cargo release-rates can be pH-dependent. We report here that i.t. delivery of protocells, with modified chemistry supporting a surface coating of DOTAP:Chol liposomes and containing the IL-10 transgene, results in functional suppression of pain-related behavior in rats for extended periods. This study is the first demonstration that protocell vectors offer amenable and enduring in vivo biological characteristics that can be applied to spinal gene delivery.
authors.affiliation: Department of Neurosciences, Health Sciences Center, University of New Mexico, Albuquerque, NM, USA. edengler@salud.unm.edu
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Dengler
authors.forename: Juewen
authors.initials: J
authors.lastname: Liu
authors.forename: Audra
authors.initials: A
authors.lastname: Kerwin
authors.forename: Sergio
authors.initials: S
authors.lastname: Torres
authors.forename: Clara M
authors.initials: CM
authors.lastname: Olcott
authors.forename: Brandi N
authors.initials: BN
authors.lastname: Bowman
authors.forename: Leisha
authors.initials: L
authors.lastname: Armijo
authors.forename: Katherine
authors.initials: K
authors.lastname: Gentry
authors.forename: Jenny
authors.initials: J
authors.lastname: Wilkerson
authors.forename: James
authors.initials: J
authors.lastname: Wallace
authors.forename: Xingmao
authors.initials: X
authors.lastname: Jiang
authors.forename: Eric C
authors.initials: EC
authors.lastname: Carnes
authors.forename: C Jeffrey
authors.initials: CJ
authors.lastname: Brinker
authors.forename: Erin D
authors.initials: ED
authors.lastname: Milligan
mesh_terms: D000818:Animals; D058045:Artificial Cells / Q000737:chemistry*; D002460:Cell Line; D002470:Cell Survival; D002784:Cholesterol / Q000737:chemistry; D004247:DNA / Q000008:administration & dosage*; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D006801:Humans; D007278:Injections, Spinal; D016753:Interleukin-10 / Q000235:genetics*; D008051:Lipid Bilayers / Q000737:chemistry; D008081:Liposomes; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D010713:Phosphatidylcholines / Q000737:chemistry; D010957:Plasmids; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000293:injuries; D012822:Silicon Dioxide / Q000737:chemistry; D013116:Spinal Cord / Q000378:metabolism*
chemical_list: D005229:Fatty Acids, Monounsaturated; D008051:Lipid Bilayers; D008081:Liposomes; D010713:Phosphatidylcholines; D000644:Quaternary Ammonium Compounds; D016753:Interleukin-10; D009569:Nitric Oxide; D012822:Silicon Dioxide; D004247:DNA; D002784:Cholesterol; C017251:1,2-oleoylphosphatidylcholine; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane