Nanoscale effects in dendrimer-mediated targeting of neuroinflammation.
Neuroinflammation, mediated by activated microglia and astrocytes, plays a key role in the pathogenesis of many neurological disorders. Systemically-administered dendrimers target neuroinflammation and deliver drugs with significant efficacy, without the need for ligands. Elucidating the nanoscale aspects of targeting neuroinflammation will enable superior nanodevices for eventual translation. Using a rabbit model of cerebral palsy, we studied the in vivo contributions of dendrimer physicochemical properties and disease pathophysiology on dendrimer brain uptake, diffusion, and cell specific localization. Neutral dendrimers move efficiently within the brain parenchyma and rapidly localize in glial cells in regions of injury. Dendrimer uptake is also dependent on the extent of blood-brain-barrier breakdown, glial activation, and disease severity (mild, moderate, or severe), which can lend the dendrimer to be used as an imaging biomarker for disease phenotype. This new understanding of the in vivo mechanism of dendrimer-mediated delivery in a clinically-relevant rabbit model provides greater opportunity for clinical translation of targeted brain injury therapies.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Elizabeth
E
Nance
Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Fan
F
Zhang
Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Manoj K
MK
Mishra
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Zhi
Z
Zhang
Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Siva P
SP
Kambhampati
Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Hugo Moser Research Institute, Kennedy-Krieger Institute, Baltimore, MD 21205, USA; Kennedy Krieger Institute - Johns Hopkins University for Cerebral Palsy Research Excellence, Baltimore, MD 21287, USA. Electronic address: krangar1@jhmi.edu.
Rangaramanujam M
RM
Kannan
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Hugo Moser Research Institute, Kennedy-Krieger Institute, Baltimore, MD 21205, USA; Kennedy Krieger Institute - Johns Hopkins University for Cerebral Palsy Research Excellence, Baltimore, MD 21287, USA. Electronic address: skannan3@jhmi.edu.
Sujatha
S
Kannan
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002547:Cerebral Palsy / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D050091:Dendrimers / Q000378:metabolism / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000378:metabolism / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053758:Nanoparticles / Q000378:metabolism; D011817:Rabbits
D050091:Dendrimers; D004337:Drug Carriers
Brain injury; Dendrimer; Glia; Nanoparticle; Neuroinflammation