Localization of Multi-Lamellar Vesicle Nanoparticles to Injured Brain Tissue in a Controlled Cortical Impact Injury Model of Traumatic Brain Injury in Rodents

Abstract

Severe traumatic brain injury (TBI), such as that suffered by patients with cerebral contusion, is a major cause of death and disability in young persons. Effective therapeutics to treat or mitigate the effects of severe TBI are lacking, in part because drug delivery to the injured brain remains a challenge. Promising therapeutics targeting secondary injury mechanisms may have poor pharmacokinetics/pharmacodynamics, unwanted side effects, or high hydrophobicity. To address these challenges, we have developed a multi-lamellar vesicle nanoparticle (MLV-NP) formulation with a narrow size distribution (243?nm in diameter, 0.09 polydispersity index) and the capability of encapsulating hydrophobic small molecule drugs for delivery to the injured brain. To demonstrate the utility of these particles, we produced dual-fluorescent labeled nanoparticles containing the organic dyes, coumarin 153 and rhodamine B, that were delivered intravenously to Sprague-Dawley rats and C57Bl6/J mice at 1, 1 and 4, 24, or 48?h after controlled cortical impact injury. Distribution of particles was measured at 5, 25, 48, or 49?h post-injury by fluorescence microscopy of coronal brain sections. In all cases of MLV administration, a 1.2- to 1.9-fold enhancement of ipsilateral fluorescence signal was observed compared to the contralateral cortex. Enhanced fluorescence was also observed in the injured hippocampal tissue in these animals. MLV-NPs administered at 1?h were observed intracellularly in the injured hemisphere at 48?h, suggesting the possibility of concentrated drug delivery to injured cells. These results suggest that MLV-NP delivery of therapeutic agents may be a viable strategy for treating cerebral contusion TBI.

Keywords

• blood?brain barrier
• controlled cortical impact
• in vivo studies
• traumatic brain injury