title: Reactive oxygen species-activated nanoprodrug of Ibuprofen for targeting traumatic brain injury in mice.
abstract: Traumatic brain injury (TBI) is an enormous public health problem, with 1.7 million new cases of TBI recorded annually by the Centers for Disease Control. However, TBI has proven to be an extremely challenging condition to treat. Here, we apply a nanoprodrug strategy in a mouse model of TBI. The novel nanoprodrug contains a derivative of the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen in an emulsion with the antioxidant α-tocopherol. The ibuprofen derivative, Ibu2TEG, contains a tetra ethylene glycol (TEG) spacer consisting of biodegradable ester bonds. The biodegradable ester bonds ensure that the prodrug molecules break down hydrolytically or enzymatically. The drug is labeled with the fluorescent reporter Cy5.5 using nonbiodegradable bonds to 1-octadecanethiol, allowing us to reliably track its accumulation in the brain after TBI. We delivered a moderate injury using a highly reproducible mouse model of closed-skull controlled cortical impact to the parietal region of the cortex, followed by an injection of the nanoprodrug at a dose of 0.2 mg per mouse. The blood brain barrier is known to exhibit increased permeability at the site of injury. We tested for accumulation of the fluorescent drug particles at the site of injury using confocal and bioluminescence imaging of whole brains and brain slices 36 hours after administration. We demonstrated that the drug does accumulate preferentially in the region of injured tissue, likely due to an enhanced permeability and retention (EPR) phenomenon. The use of a nanoprodrug approach to deliver therapeutics in TBI represents a promising potential therapeutic modality.
authors: Department of Surgery, Division of Trauma and Critical Care, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors: Morgan A
authors: MA
authors: Clond
authors: Bong-Seop
authors: BS
authors: Lee
authors: Jeffrey J
authors: JJ
authors: Yu
authors: Matthew B
authors: MB
authors: Singer
authors: Takayuki
authors: T
authors: Amano
authors: Alexander W
authors: AW
authors: Lamb
authors: Doniel
authors: D
authors: Drazin
authors: Babak
authors: B
authors: Kateb
authors: Eric J
authors: EJ
authors: Ley
authors: John S
authors: JS
authors: Yu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D000975:Antioxidants / Q000737:chemistry; D001522:Behavior, Animal; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D059907:Functional Neuroimaging; D007052:Ibuprofen / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D008163:Luminescent Measurements; D008297:Male; D018782:Maze Learning; D051379:Mice; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism*; D024502:alpha-Tocopherol / Q000737:chemistry
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D011355:Prodrugs; D017382:Reactive Oxygen Species; D024502:alpha-Tocopherol; D007052:Ibuprofen
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