Traumatic brain injury opens blood–brain barrier to stealth liposomes via an enhanced permeability and retention (EPR)-like effect

Abstract

The opening of the tight junctions in the blood–brain barrier (BBB) following traumatic brain injury (TBI) is hypothesized to be sufficient to enable accumulation of large drug carriers, such as stealth liposomes, in a similar manner to the extravasation seen in tumor tissue via the enhanced permeability and retention (EPR) effect. The controlled cortical impact model of TBI was used to evaluate liposome accumulation in mice. Dual-radiolabeled PEGylated liposomes were administered either immediately after induction of TBI or at increasing times post-TBI to mimic the likely clinical scenario. The accumulation of radiolabel in the brain tissue ipsilateral and contralateral to the site of trauma, as well as in other organs, was evaluated. Selective influx of liposomes occurred at 0–8 h after injury, while the barrier closed between 8 and 24 hr after injury, consistent with reports on albumin infiltration. Significantly enhanced accumulation of liposomes occurred in mice subjected to TBI compared to anaesthetized controls, and accumulation was greater in the injured versus the contralateral side of the brain. Thus, stealth liposomes show potential to enhance drug delivery to the site of brain injury with a wide range of encapsulated therapeutic candidates.

• Albumin
• blood–brain barrier
• extravasation
• stealth liposomes
• traumatic brain injury

Acknowledgements

The authors thank Joseph Nicolazzo for useful discussions.

Declaration of interest

The authors report no declarations of interest. The authors acknowledge the Faculty of Medicine, Nursing and Health Sciences, Monash University for funding Strategic Grant (SPG-L 016) and the John and Joan Power Charitable Trust awarded to JVR. B.J.B. acknowledges the Australian Research Council for a Future Fellowship.

Supplementary material available online

Supplementary Figure S1-S4