Reactive oxygen species-activated nanoprodrug of Ibuprofen for targeting traumatic brain injury in mice.

Morgan A Clond,Takayuki Amano,Babak Kateb,Bong-Seop Lee,John S Yu,Jeffrey J Yu,Alexander W Lamb,Matthew B Singer,Eric J Ley,Doniel Drazin,Cesar V Borlongan

doi:10.1371/journal.pone.0061819

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.

Highlights

In industrialized countries, traumatic brain injury (TBI) is the leading cause of death in those under the age of 45 [1,2,3] and traumatic injuries account for a greater number of potential years of life lost than all other causes of death [4]
Fluorescence was not detected in uninjured sham animals receiving the nanoprodrug, nor was it detected in TBI animals treated with phosphate buffered saline (PBS)
The nanoprodrug targets the injury with high specificity, which may potentially reduce off target effects on other organs

Summary

Introduction

Traumatic brain injury (TBI) is the leading cause of death in those under the age of 45 [1,2,3] and traumatic injuries account for a greater number of potential years of life lost than all other causes of death [4]. According to most recent CDC estimates (2004–2006), there are 1.7 million new cases of TBI annually, with 52,000 deaths, 275,000 hospitalizations, and 1.4 million people treated in emergency departments each year [5]. For both patients and society at large, traumatic brain injury carries a large cost burden estimated for the United States to be $60–100 billion per year due to resulting healthcare costs and lost productivity [6,7]. No interventions have been successful enough in practice to be implemented as standard of care [19,20,21]

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Discussion

Conclusion