Dendrimer drug delivery has also shown major promise as a potential solution for many traditionally difficult drug delivery problems. In the case of drug delivery to the brain, dendrimers are able to take advantage of the EPR effect and blood-brain barrier (BBB) impairment to cross the BBB effectively in vivo. For example, hydroxyl-terminated PAMAM dendrimers possess an intrinsic targeting ability to inflamed macrophages in the brain, verified using fluorescently labeled neutral generation dendrimers in a rabbit model of cerebral palsy. This intrinsic targeting has enabled drug delivery in a variety of conditions, ranging from cerebral palsy and other neuroinflammatory disorders to traumatic brain injury and hypothermic circulatory arrest, across a variety of animal models ranging from mice and rabbits to canines. Dendrimer uptake into the brain correlates with severity of inflammation and BBB impairment and it is believed that the BBB impairment is the key driving factor allowing dendrimer penetration. Localization is heavily skewed towards activated microglia. Dendrimer-conjugated N-acetyl cysteine has shown efficacy in vivo as an anti-inflammatory at more than 1000-fold lower dose than free drug on a drug basis, reversing the phenotype of cerebral palsy, Rett syndrome, macular degeneration and other inflammatory diseases.