Evaluating differential nanoparticle accumulation and retention kinetics in a mouse model of traumatic brain injury via Ktrans mapping with MRI

Abstract

Traumatic brain injury (TBI) is a leading cause of injury-related death worldwide, yet there are no approved neuroprotective therapies that improve neurological outcome post-injury. Transient opening of the blood-brain barrier following injury provides an opportunity for passive accumulation of intravenously administered nanoparticles through an enhanced permeation and retention-like effect. However, a thorough understanding of physicochemical properties that promote optimal uptake and retention kinetics in TBI is still needed. In this study, we present a robust method for magnetic resonance imaging of nanoparticle uptake and retention kinetics following intravenous injection in a controlled cortical impact mouse model of TBI. Three contrast-enhancing nanoparticles with different hydrodynamic sizes and relaxivity properties were compared. Accumulation and retention were monitored by modelling the permeability coefficient, Ktrans, for each nanoparticle within the reproducible mouse model. Quantification of Ktrans for different nanoparticles allowed for non-invasive, multi-time point assessment of both accumulation and retention kinetics in the injured tissue. Using this method, we found that 80 nm poly(lactic-co-glycolic acid) nanoparticles had maximal Ktrans in a TBI when injected 3 hours post-injury, showing significantly higher accumulation kinetics than the small molecule, Gd-DTPA. This robust method will enable optimization of administration time and nanoparticle physicochemical properties to achieve maximum delivery.

Pharmacokinetic Analysis of Peptide-Modified Nanoparticles with Engineered Physicochemical Properties in a Mouse Model of Traumatic Brain Injury

“…This effect may be due to the reduced accumulation of neutral, negative, and zwitterionic peptide-modified nanoparticles in off-target organs (Figure 5a ) and improved blood retention when compared to R9- and K9-modified nanoparticles (Figure 4b ). Previous research supports increased nanomaterial blood half-life with increased passive injury accumulation in TBI models due to the EPR-like effect in the injured tissue ( 11 , 26 , 75 ). Nanomaterials engineered to have long blood half-lives, such as PEG-modified materials, are also well-established nanomedicine platforms in cancer research due to their greater passive accumulation in solid tumors ( 65 , 66 ).…”

Evolution of blood–brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies

“…On blast-induced TBI mouse model, BBB opening in the acute period was ∼70 kDa (hydrodynamic diameters ∼10 nm), followed by recovery of BBB integrity by 1 day post-injury 138 . On controlled cortical impact model, selective influx of 82 nm PEG-liposomes was found at 0–8 h after injury 128 , and both 20 and 40 nm PEGylated polystyrene NPs accumulated significantly in the injury penumbra up to 13 h after injury 75 , 139 . On diffuse TBI model, PEGylated polystyrene NPs failed to accumulate in the brain tissue after mild closed-head injury 140 .…”

“…The release of intracellular contents from disrupted neurons and the influx of blood components cause secondary injury including ionic imbalance, cytotoxicity, free radical production, oxidative stress, inflammation and further BBB breakdown. These responses lead to vasogenic/osmotic edema for hours and days, resulting in lifelong physical, cognitive and psychosocial impairments 74 , 75 . The primary injury appears to be irreversible, making the focus of therapeutic strategies on neuroprotective approaches that suppress progressive cell death and tissue damages during the secondary injury 74 .…”

Sensitive detection of extremely small iron oxide nanoparticles in living mice using MP2RAGE with advanced image co-registration

“…This would limit the quantitative reliability of T1 weighted imaging for IONPs in vivo. Considering the potential benefits of longitudinal studies, there have been efforts to utilize quantitative T1 mapping of the effects of IONPs in rodent studies 41 , 42 . The T1 (or R1) mapping provided objective quantification of IONPs induced R1 (= 1/T1) enhancement.…”