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.

Mitochondrial uncoupling prodrug improves tissue sparing, cognitive outcome, and mitochondrial bioenergetics after traumatic brain injury in male mice

“…Since mitochondria are evolutionarily conserved and the mitochondrial uncoupling mechanism of action is initially nongenomic based upon biophysics rather than a protein pathway, which are not always well conserved from rodents to humans, translation is predicted to be excellent (Geisler, ; Miwa & Brand, ). Prodrugs are typically used for drugs with poor absorption or poor transport across the blood‐brain barrier (Clond et al, ; Feng et al, ), however in the case of DNP, it is employed to slow elimination thereby providing a “trickle‐like” effect of providing DNP's bioavailability. This longer residence time can provide sustained neuroprotection with lowering ROS, mitigating on‐going apoptosis and potentially raising BDNF, which could restore some neural connections as a growth factor (da Costa, Martinez, & Ferreira, ; De Felice & Ferreira, ; Korde, Pettigrew, Craddock, & Maragos, ).…”

Sex-dependent macromolecule and nanoparticle delivery in experimental brain injury

“…The secondary injury develops over hours and days following a TBI allowing a time window for intervention. Most consequences of BBB disruption after brain injury are known to be detrimental, yet the disruption may also provide a transient window for delivery of therapeutics that normally would not cross this barrier from the systemic circulation [8][9][10][11] . Macromolecules such as specific antibodies and proteins have been identified as promising therapeutic agents for the treatment of various brain pathologies 1,12 .…”

“…Previously, we and others have established in both focal and diffuse injury models of TBI that macromolecular weight tracer (~40 kDa) 19,[24][25][26] and NPs 10,19,[26][27][28] robustly accumulate within injured brain tissue in the first 4h following TBI. Moreover, seminal TBI studies in male rodents suggest a biphasic BBB opening to macromolecular weight tracers with the first peak at acute (~3-6h) time points followed by a delayed opening (~3 d) after TBI 25,29 .…”

Fishing for fire: strategies for biological targeting and criteria for material design in anti‐inflammatory therapies

“…in multiple sclerosis, cerebral malaria, and autoimmune encephalomyelitis . In other studies, lipid micelles and liposomes have shown accumulation in myocardial and cerebral infarction (stroke), cross‐linked micelles in RA, (PEGylated) PLGA nanoparticles in IBDs and RA, poly(butyl cyanoacrylate) nanoparticles or ibuprofen/tocopherol nanoparticles in traumatic brain injuries, and perfluorocarbon emulsions in cancer‐associated inflammation …”