{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T22:55:04Z","timestamp":1787871304517,"version":"build-2784847793"},"reference-count":127,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2019,9,13]],"date-time":"2019-09-13T00:00:00Z","timestamp":1568332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P20GM103480"],"award-info":[{"award-number":["P20GM103480"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS109488"],"award-info":[{"award-number":["R01NS109488"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Nebraska Settlement Biomedical Research Development Funds","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Traumatic brain injury (TBI) is one of the main causes of disability in children and young adults, as well as a significant concern for elderly individuals. Depending on the severity, TBI can have a long-term impact on the quality of life for survivors of all ages. The primary brain injury can result in severe disability or fatality, and secondary brain damage can increase the complexities in cellular, inflammatory, neurochemical, and metabolic changes in the brain, which can last decades post-injury. Thus, survival from a TBI is often accompanied by lifelong disabilities. Despite the significant morbidity, mortality, and economic loss, there are still no effective treatment options demonstrating an improved outcome in a large multi-center Phase III trial, which can be partially attributed to poor target engagement of delivered therapeutics. Thus, there is a significant unmet need to develop more effective delivery strategies to overcome the biological barriers that would otherwise inhibit transport of materials into the brain to prevent the secondary long-term damage associated with TBI. The complex pathology of TBI involving the blood-brain barrier (BBB) has limited the development of effective therapeutics and diagnostics. Therefore, it is of great importance to develop novel strategies to target the BBB. The leaky BBB caused by a TBI may provide opportunities for therapeutic delivery via nanoparticles (NP). The focus of this review is to provide a survey of NP-based strategies employed in preclinical models of TBI and to provide insights for improved NP based diagnostic or treatment approaches. Both passive and active delivery of various NPs for TBI are discussed. Finally, potential therapeutic targets where improved NP-mediated delivery could increase target engagement are identified with the overall goal of providing insight into open opportunities for NP researchers to begin research in TBI.<\/jats:p>","DOI":"10.3390\/pharmaceutics11090473","type":"journal-article","created":{"date-parts":[[2019,9,13]],"date-time":"2019-09-13T10:32:41Z","timestamp":1568370761000},"page":"473","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["A Role for Nanoparticles in Treating Traumatic Brain Injury"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5139-6541","authenticated-orcid":false,"given":"Badrul Alam","family":"Bony","sequence":"first","affiliation":[{"name":"Department of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, NE 68583-0726, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Forrest","family":"Kievit","sequence":"additional","affiliation":[{"name":"Department of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, NE 68583-0726, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,13]]},"reference":[{"key":"ref_1","unstructured":"Prevention, C.F.D.C.A. (2019). Surveillance Report of Traumatic Brain Injury-related Emergency Department Visits, Hospitalizations, and Deaths\u2014United States, 2014, Centers for Disease Control and Prevention."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1700668","DOI":"10.1002\/adhm.201700668","article-title":"Nanoparticle-Based Therapeutics for Brain Injury","volume":"7","author":"Bharadwaj","year":"2018","journal-title":"Adv. Healthc. Mater."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.bpa.2010.10.006","article-title":"Epidemiology of ischaemic stroke and traumatic brain injury","volume":"24","author":"Feigin","year":"2010","journal-title":"Best Pract. Res. Clin. Anaesthesiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1097\/00001199-200609000-00001","article-title":"The epidemiology and impact of traumatic brain injury: A brief overview","volume":"21","author":"Langlois","year":"2006","journal-title":"J. Head Trauma Rehabil."},{"key":"ref_5","first-page":"51","article-title":"Antioxidant therapies for traumatic brain injury","volume":"7","author":"Hall","year":"2010","journal-title":"Neurother. J. Am. Soc. Exp. Neurother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"404","DOI":"10.2174\/092986708783497337","article-title":"Antioxidants and Free Radical Scavengers for the Treatment of Stroke, Traumatic Brain Injury and Aging","volume":"15","author":"Slemmer","year":"2008","journal-title":"Curr. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1089\/ars.2010.3576","article-title":"Oxidative Stress in Ischemic Brain Damage: Mechanisms of Cell Death and Potential Molecular Targets for Neuroprotection","volume":"14","author":"Chen","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3530","DOI":"10.1002\/jnr.22510","article-title":"Increase in blood\u2013brain barrier permeability, oxidative stress, and activated microglia in a rat model of blast-induced traumatic brain injury","volume":"88","author":"Readnower","year":"2010","journal-title":"J. Neurosci. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1089\/ars.2012.4981","article-title":"Traumatic Brain Injury: Oxidative Stress and Neuroprotection","volume":"19","author":"Cornelius","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_10","unstructured":"Heidenrreich, K.A. (2017). Carbonyl Scavenging as an Antioxidant Neuroprotective Strategy for Acute Traumatic Brain Injury. N. Ther. Trauma. Brain Inj. Prev. Second. Brain Damage Enhanc. Repair Regen, Elsevier."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/nrneurol.2017.13","article-title":"The far-reaching scope of neuroinflammation after traumatic brain injury","volume":"13","author":"Simon","year":"2017","journal-title":"Nat. Rev. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1093\/brain\/aws322","article-title":"Inflammation and white matter degeneration persist for years after a single traumatic brain injury","volume":"136","author":"Johnson","year":"2013","journal-title":"Brain"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","article-title":"Neuroinflammation in Alzheimer\u2019s disease","volume":"14","author":"Heneka","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1093\/brain\/aws307","article-title":"The spectrum of disease in chronic traumatic encephalopathy","volume":"136","author":"McKee","year":"2013","journal-title":"Brain"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1001\/jamaneurol.2014.2668","article-title":"Dementia risk after traumatic brain injury vs nonbrain trauma: The role of age and severity","volume":"71","author":"Gardner","year":"2014","journal-title":"JAMA Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1002\/ana.24101","article-title":"Traumatic brain injury and young onset dementia: A nationwide cohort study","volume":"75","author":"Gustafson","year":"2014","journal-title":"Ann. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1001\/archneurol.2011.3747","article-title":"Dementia resulting from traumatic brain injury: What is the pathology?","volume":"69","author":"Shively","year":"2012","journal-title":"Arch. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"613","DOI":"10.2165\/11634020-000000000-00000","article-title":"A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury","volume":"26","author":"McConeghy","year":"2012","journal-title":"CNS Drugs"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.annemergmed.2006.07.932","article-title":"ProTECT: A randomized clinical trial of progesterone for acute traumatic brain injury","volume":"49","author":"Wright","year":"2007","journal-title":"Ann. Emerg. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF02815156","article-title":"Progesterone protects against lipid peroxidation following traumatic brain injury in rats","volume":"31","author":"Roof","year":"1997","journal-title":"Mol. Chem. Neuropathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1038\/aps.2013.160","article-title":"The neuroprotective effects of progesterone on traumatic brain injury: Current status and future prospects","volume":"34","author":"Wei","year":"2013","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1006\/exnr.1999.7338","article-title":"Cyclosporin ameliorates traumatic brain-injury-induced alterations of hippocampal synaptic plasticity","volume":"162","author":"Albensi","year":"2000","journal-title":"Exp. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1093\/milmed\/usx184","article-title":"Operation Brain Trauma Therapy: 2016 Update","volume":"183","author":"Kochanek","year":"2018","journal-title":"Mil. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1021\/acsnano.6b06040","article-title":"Diverse Applications of Nanomedicine","volume":"11","author":"Pelaz","year":"2017","journal-title":"ACS Nano"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/nnano.2010.58","article-title":"Tuning payload delivery in tumour cylindroids using gold nanoparticles","volume":"5","author":"Kim","year":"2010","journal-title":"Nat. Nanotechnol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1021\/bc700464m","article-title":"Enhanced intracellular delivery of quantum dot and adenovirus nanoparticles triggered by acidic pH via surface charge reversal","volume":"19","author":"Mok","year":"2008","journal-title":"Bioconjugate Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4999","DOI":"10.1002\/anie.200605254","article-title":"Targeted charge-reversal nanoparticles for nuclear drug delivery","volume":"46","author":"Xu","year":"2007","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3580","DOI":"10.1002\/adfm.200900825","article-title":"Charge-Reversal Drug Conjugate for Targeted Cancer Cell Nuclear Drug Delivery","volume":"19","author":"Zhou","year":"2009","journal-title":"Adv. Funct. Mater."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4587","DOI":"10.1021\/nn1008512","article-title":"Chlorotoxin labeled magnetic nanovectors for targeted gene delivery to glioma","volume":"4","author":"Kievit","year":"2010","journal-title":"ACS Nano"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1073\/pnas.0914140107","article-title":"Mechanism of active targeting in solid tumors with transferrin-containing gold nanoparticles","volume":"107","author":"Choi","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6732","DOI":"10.1158\/0008-5472.CAN-05-4199","article-title":"Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models","volume":"66","author":"Kirpotin","year":"2006","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1021\/nn205070h","article-title":"Targeting of primary breast cancers and metastases in a transgenic mouse model using rationally designed multifunctional SPIONs","volume":"6","author":"Kievit","year":"2012","journal-title":"ACS Nano"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7926","DOI":"10.1021\/acsnano.6b03858","article-title":"Neuron-Targeted Nanoparticle for siRNA Delivery to Traumatic Brain Injuries","volume":"10","author":"Kwon","year":"2016","journal-title":"ACS Nano"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"476","DOI":"10.3171\/jns.1996.85.3.0476","article-title":"Blood-brain barrier breach following cortical contusion in the rat","volume":"85","author":"Baldwin","year":"1996","journal-title":"J. Neurosurg."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1161\/CIRCRESAHA.116.306534","article-title":"Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability","volume":"120","author":"Komarova","year":"2017","journal-title":"Circ. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"E524","DOI":"10.1073\/pnas.1614336114","article-title":"Dual role of ALCAM in neuroinflammation and blood-brain barrier homeostasis","volume":"114","author":"Lecuyer","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12987-017-0067-0","article-title":"Blood-brain barrier and foetal-onset hydrocephalus, with a view on potential novel treatments beyond managing CSF flow","volume":"14","author":"Guerra","year":"2017","journal-title":"Fluids Barriers CNS"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"CNC45","DOI":"10.2217\/cnc-2017-0013","article-title":"Neurometabolic indicators of mitochondrial dysfunction in repetitive mild traumatic brain injury","volume":"2","author":"Kim","year":"2017","journal-title":"Concussion"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s13024-018-0249-5","article-title":"Apolipoprotein E4 impairs spontaneous blood brain barrier repair following traumatic brain injury","volume":"13","author":"Main","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/S1474-4422(07)70326-5","article-title":"Strategies to advance translational research into brain barriers","volume":"7","author":"Neuwelt","year":"2008","journal-title":"Lancet Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3520","DOI":"10.1080\/10717544.2016.1199609","article-title":"Brain-derived neurotrophic factor delivered to the brain using poly (lactide-co-glycolide) nanoparticles improves neurological and cognitive outcome in mice with traumatic brain injury","volume":"23","author":"Khalin","year":"2016","journal-title":"Drug Deliv."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1007\/s12035-015-9235-x","article-title":"PLGA Nanoparticles Loaded Cerebrolysin: Studies on Their Preparation and Investigation of the Effect of Storage and Serum Stability with Reference to Traumatic Brain Injury","volume":"52","author":"Ruozi","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1038\/nnano.2014.274","article-title":"Squalenoyl adenosine nanoparticles provide neuroprotection after stroke and spinal cord injury","volume":"9","author":"Gaudin","year":"2014","journal-title":"Nat. Nanotechnol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/j.1525-1594.2008.00700.x","article-title":"Liposome-encapsulated hemoglobin alleviates brain edema after permanent occlusion of the middle cerebral artery in rats","volume":"33","author":"Kawaguchi","year":"2009","journal-title":"Artif. Organs"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.jneuroim.2009.05.019","article-title":"Pegylated nanoliposomes remote-loaded with the antioxidant tempamine ameliorate experimental autoimmune encephalomyelitis","volume":"213","author":"Kizelsztein","year":"2009","journal-title":"J. Neuroimmunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"10582","DOI":"10.1021\/nn403743b","article-title":"Custom cerium oxide nanoparticles protect against a free radical mediated autoimmune degenerative disease in the brain","volume":"7","author":"Heckman","year":"2013","journal-title":"ACS Nano"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11039","DOI":"10.1002\/anie.201203780","article-title":"Ceria Nanoparticles that can Protect against Ischemic Stroke","volume":"51","author":"Kim","year":"2012","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.jconrel.2016.05.044","article-title":"Nanoparticle-mediated brain drug delivery: Overcoming blood-brain barrier to treat neurodegenerative diseases","volume":"235","author":"Saraiva","year":"2016","journal-title":"J. Control. Release"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/1743-8977-7-3","article-title":"Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: Perspectives on tracking and neuroimaging","volume":"7","author":"Bhaskar","year":"2010","journal-title":"Part. Fibre Toxicol."},{"key":"ref_50","first-page":"11","article-title":"Pathways for small molecule delivery to the central nervous system across the blood-brain barrier","volume":"6","author":"Mikitsh","year":"2014","journal-title":"Perspect. Med. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S0168-3659(99)00248-5","article-title":"Tumor vascular permeability and the EPR effect in macromolecular therapeutics: A review","volume":"65","author":"Maeda","year":"2000","journal-title":"J. Control. Release"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/nrneurol.2010.74","article-title":"Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury","volume":"6","author":"Shlosberg","year":"2010","journal-title":"Nat. Rev. Neurol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1155\/2013\/238428","article-title":"Nanoparticles for Brain Drug Delivery","volume":"2013","author":"Masserini","year":"2013","journal-title":"ISRN Biochem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"847","DOI":"10.3109\/1061186X.2015.1034280","article-title":"Traumatic brain injury opens blood-brain barrier to stealth liposomes via an enhanced permeability and retention (EPR)-like effect","volume":"23","author":"Boyd","year":"2015","journal-title":"J. Drug. Target."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Clond, M.A., Lee, B.S., Yu, J.J., Singer, M.B., Amano, T., Lamb, A.W., Drazin, D., Kateb, B., Ley, E.J., and Yu, J.S. (2013). Reactive oxygen species-activated nanoprodrug of Ibuprofen for targeting traumatic brain injury in mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061819"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4124","DOI":"10.1002\/adfm.201504416","article-title":"Theranostic Oxygen Reactive Polymers for Treatment of Traumatic Brain Injury","volume":"26","author":"Xu","year":"2016","journal-title":"Adv. Funct. Mater."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"29988","DOI":"10.1038\/srep29988","article-title":"Temporal assessment of nanoparticle accumulation after experimental brain injury: Effect of particle size","volume":"6","author":"Bharadwaj","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.jconrel.2015.12.029","article-title":"Effect of PLGA NP size on efficiency to target traumatic brain injury","volume":"223","author":"Cruz","year":"2016","journal-title":"J. Control. Release"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.jconrel.2017.01.032","article-title":"Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model","volume":"249","author":"Zhang","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"8600","DOI":"10.1021\/acsnano.7b03426","article-title":"Core-Cross-Linked Nanoparticles Reduce Neuroinflammation and Improve Outcome in a Mouse Model of Traumatic Brain Injury","volume":"11","author":"Yoo","year":"2017","journal-title":"ACS Nano"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1016\/j.nano.2018.06.004","article-title":"Blood-brainbarrier disruption dictates nanoparticle accumulation following experimental brain injury","volume":"14","author":"Bharadwaj","year":"2018","journal-title":"Nanomedicine"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.biomaterials.2016.05.044","article-title":"Nanoscale effects in dendrimer-mediated targeting of neuroinflammation","volume":"101","author":"Nance","year":"2016","journal-title":"Biomaterials"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.jconrel.2015.07.009","article-title":"Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury","volume":"214","author":"Nance","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"149ra119","DOI":"10.1126\/scitranslmed.3003594","article-title":"A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue","volume":"4","author":"Nance","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.1021\/nn404872e","article-title":"Dendrimer brain uptake and targeted therapy for brain injury in a large animal model of hypothermic circulatory arrest","volume":"8","author":"Mishra","year":"2014","journal-title":"ACS Nano"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Alnasser, Y., Kambhampati, S.P., Nance, E., Rajbhandari, L., Shrestha, S., Venkatesan, A., Kannan, R.M., and Kannan, S. (2018). Preferential and Increased Uptake of Hydroxyl-Terminated PAMAM Dendrimers by Activated Microglia in Rabbit Brain Mixed Glial Culture. Molecules, 23.","DOI":"10.3390\/molecules23051025"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.colsurfb.2018.06.050","article-title":"Colloidal stability as a determinant of nanoparticle behavior in the brain","volume":"170","author":"Curtis","year":"2018","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.jconrel.2017.07.028","article-title":"Strategies to enhance the distribution of nanotherapeutics in the brain","volume":"267","author":"Zhang","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1002\/smll.201502554","article-title":"Biodegradable DNA Nanoparticles that Provide Widespread Gene Delivery in the Brain","volume":"12","author":"Mastorakos","year":"2016","journal-title":"Small"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"13761","DOI":"10.1523\/JNEUROSCI.4246-09.2009","article-title":"A Nanomedicine Transports a Peptide Caspase-3 Inhibitor across the Blood-Brain Barrier and Provides Neuroprotection","volume":"29","author":"Karatas","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1089\/hum.2010.111","article-title":"Postacute ischemia vascular endothelial growth factor transfer by transferrin-targeted liposomes attenuates ischemic brain injury after experimental stroke in rats","volume":"22","author":"Zhao","year":"2011","journal-title":"Hum. Gene Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1007\/s12274-016-1023-z","article-title":"Targeted nanoparticles for the non-invasive detection of traumatic brain injury by optical imaging and fluorine magnetic resonance imaging","volume":"9","author":"Cruz","year":"2016","journal-title":"Nano Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1159\/000330855","article-title":"Efficacy of CG(3)R(6)TAT nanoparticles self-assembled from a novel antimicrobial peptide for the treatment of Candida albicans meningitis in rabbits","volume":"57","author":"Xu","year":"2011","journal-title":"Chemotherapy"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"6227","DOI":"10.2147\/IJN.S84656","article-title":"Anti-transferrin receptor-modified amphotericin B-loaded PLA-PEG nanoparticles cure Candidal meningitis and reduce drug toxicity","volume":"10","author":"Tang","year":"2015","journal-title":"Int. J. Nanomed."},{"key":"ref_75","first-page":"603","article-title":"Electroresponsive Nanoparticles Improve Antiseizure Effect of Phenytoin in Generalized Tonic-Clonic Seizures","volume":"13","author":"Wang","year":"2016","journal-title":"Neurother. J. Am. Soc. Exp. Neurother."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.ijpharm.2011.05.062","article-title":"Lactoferrin conjugated PEG-PLGA nanoparticles for brain delivery: Preparation, characterization and efficacy in Parkinson\u2019s disease","volume":"415","author":"Hu","year":"2011","journal-title":"Int. J. Pharm."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2860","DOI":"10.1021\/acsnano.5b08045","article-title":"Mitochondria-Targeting Ceria Nanoparticles as Antioxidants for Alzheimer\u2019s Disease","volume":"10","author":"Kwon","year":"2016","journal-title":"ACS Nano"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1038\/nnano.2012.207","article-title":"Biomolecular coronas provide the biological identity of nanosized materials","volume":"7","author":"Monopoli","year":"2012","journal-title":"Nat. Nanotechnol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"8007","DOI":"10.1021\/nn302615f","article-title":"Antioxidant carbon particles improve cerebrovascular dysfunction following traumatic brain injury","volume":"6","author":"Bitner","year":"2012","journal-title":"ACS Nano"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1007\/s12010-008-8232-1","article-title":"Superoxide dismutase-loaded PLGA nanoparticles protect cultured human neurons under oxidative stress","volume":"151","author":"Reddy","year":"2008","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e903","DOI":"10.1038\/cddis.2013.362","article-title":"Nanoparticle-mediated catalase delivery protects human neurons from oxidative stress","volume":"4","author":"Singhal","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1096\/fj.08-116947","article-title":"Nanoparticle-mediated delivery of superoxide dismutase to the brain: An effective strategy to reduce ischemia-reperfusion injury","volume":"23","author":"Reddy","year":"2009","journal-title":"FASEB J."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.jconrel.2015.06.021","article-title":"SOD1 nanozyme salvages ischemic brain by locally protecting cerebral vasculature","volume":"213","author":"Jiang","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"165101","DOI":"10.1088\/0957-4484\/23\/16\/165101","article-title":"Delivery of large molecules via poly(butyl cyanoacrylate) nanoparticles into the injured rat brain","volume":"23","author":"Lin","year":"2012","journal-title":"Nanotechnology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"11980","DOI":"10.1038\/ncomms11980","article-title":"A peptide for targeted, systemic delivery of imaging and therapeutic compounds into acute brain injuries","volume":"7","author":"Mann","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1039\/C6NH00082G","article-title":"Porous silicon\u2013graphene oxide core\u2013shell nanoparticles for targeted delivery of siRNA to the injured brain","volume":"1","author":"Joo","year":"2016","journal-title":"Nanoscale Horiz."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1517\/17425247.2013.766714","article-title":"Liposomes for brain delivery","volume":"10","author":"Lai","year":"2013","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1096\/fj.12-221325","article-title":"Treatment of cerebral ischemia-reperfusion injury with PEGylated liposomes encapsulating FK506","volume":"27","author":"Ishii","year":"2012","journal-title":"FASEB J."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1007\/s11095-012-0723-7","article-title":"Treatment of Experimental Brain Metastasis with MTO-Liposomes: Impact of Fluidity and LRP-Targeting on the Therapeutic Result","volume":"29","author":"Orthmann","year":"2012","journal-title":"Pharm. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"433","DOI":"10.2478\/v10007-012-0040-z","article-title":"Solid lipid based nanocarriers: An overview","volume":"62","author":"Pardeshi","year":"2012","journal-title":"Acta Pharm."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.addr.2007.04.011","article-title":"Solid lipid nanoparticles for targeted brain drug delivery","volume":"59","author":"Blasi","year":"2007","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/0169-409X(95)00024-2","article-title":"Mechanisms regulating body distribution of nanospheres conditioned with pluronic and tetronic block co-polymers","volume":"16","author":"Moghimi","year":"1995","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_93","first-page":"38","article-title":"Nanocapsules with a reduced liver uptake: Targeting of phthalocyanines to EMT-6 mouse mammary tumour in vivo","volume":"41","author":"Lenaerts","year":"1995","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/S0939-6411(02)00083-8","article-title":"Enhanced brain targeting by synthesis of 3\u2019, 5\u2019-dioctanoyl-5-fluoro-2\u2019-deoxyuridine and incorporation into solid lipid nanoparticles","volume":"54","author":"Wang","year":"2002","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.ijpharm.2012.09.054","article-title":"Brain delivery of camptothecin by means of solid lipid nanoparticles: Formulation design, in vitro and in vivo studies","volume":"439","author":"Martins","year":"2012","journal-title":"Int. J. Pharm."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/0006-8993(95)00023-J","article-title":"Passage of peptides through the blood-brain barrier with colloidal polymer particles (nanoparticles)","volume":"674","author":"Kreuter","year":"1995","journal-title":"Brain Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1046\/j.1460-9568.2000.00078.x","article-title":"Polysorbate-80 coating enhances uptake of polybutylcyanoacrylate (PBCA)-nanoparticles by human and bovine primary brain capillary endothelial cells","volume":"12","author":"Ramge","year":"2000","journal-title":"Eur. J. Neurosci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/wnan.59","article-title":"Quinoline-n-butylcyanoacrylate-based nanoparticles for brain targeting for the diagnosis of Alzheimer\u2019s disease","volume":"2","author":"Kulkarni","year":"2010","journal-title":"Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"18837","DOI":"10.1073\/pnas.1111405108","article-title":"Nanoparticles enhance brain delivery of blood\u2013brain barrier-impermeable probes for in vivo optical and magnetic resonance imaging","volume":"108","author":"Koffie","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.colsurfb.2011.11.007","article-title":"Transcytosis of CRM197-grafted polybutylcyanoacrylate nanoparticles for delivering zidovudine across human brain-microvascular endothelial cells","volume":"91","author":"Kuo","year":"2012","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ejpb.2014.02.013","article-title":"Surfactants, not size or zeta-potential influence blood\u2013brain barrier passage of polymeric nanoparticles","volume":"87","author":"Voigt","year":"2014","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1600-0773.1992.tb00512.x","article-title":"Recent Developments in Peptide Drug Delivery to the Brain","volume":"71","author":"Pardridge","year":"1992","journal-title":"Pharmacol. Toxicol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1021\/mp300391v","article-title":"In Vivo Distribution and Toxicity of PAMAM Dendrimers in the Central Nervous System Depend on Their Surface Chemistry","volume":"10","author":"Albertazzi","year":"2013","journal-title":"Mol. Pharm."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"5137","DOI":"10.1002\/smll.201400654","article-title":"Blood-brain barrier permeable gold nanoparticles: An efficient delivery platform for enhanced malignant glioma therapy and imaging","volume":"10","author":"Cheng","year":"2014","journal-title":"Small"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s12951-015-0133-1","article-title":"Spontaneous penetration of gold nanoparticles through the blood brain barrier (BBB)","volume":"13","author":"Sela","year":"2015","journal-title":"J. Nanobiotechnol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"5020","DOI":"10.1021\/acsnano.7b01744","article-title":"Gold Nanoparticles Induced Endothelial Leakiness Depends on Particle Size and Endothelial Cell Origin","volume":"11","author":"Setyawati","year":"2017","journal-title":"ACS Nano"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/s41565-018-0356-z","article-title":"Nanoparticles promote in vivo breast cancer cell intravasation and extravasation by inducing endothelial leakiness","volume":"14","author":"Peng","year":"2019","journal-title":"Nat. Nanotechnol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1038\/ncomms2655","article-title":"Titanium dioxide nanomaterials cause endothelial cell leakiness by disrupting the homophilic interaction of VE-cadherin","volume":"4","author":"Setyawati","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"3759","DOI":"10.1021\/acs.chemmater.8b00840","article-title":"Targeting Endothelial Cell Junctions with Negatively Charged Gold Nanoparticles","volume":"30","author":"Wang","year":"2018","journal-title":"Chem. Mater."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1080\/17435390.2019.1571646","article-title":"Angiopoietin-1 accelerates restoration of endothelial cell barrier integrity from nanoparticle-induced leakiness","volume":"13","author":"Tee","year":"2019","journal-title":"Nanotoxicology"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Chen, X. (2008). Sieve Extremum Estimation. The New Palgrave Dictionary of Economics, Palgrave Macmillan UK.","DOI":"10.1057\/978-1-349-95121-5_2695-1"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1093\/toxsci\/kfq244","article-title":"Silver Nanoparticle Induced Blood-Brain Barrier Inflammation and Increased Permeability in Primary Rat Brain Microvessel Endothelial Cells","volume":"118","author":"Trickler","year":"2010","journal-title":"Toxicol. Sci."},{"key":"ref_113","first-page":"6105","article-title":"Silver nanoparticles induce tight junction disruption and astrocyte neurotoxicity in a rat blood-brain barrier primary triple coculture model","volume":"10","author":"Xu","year":"2015","journal-title":"Int. J. Nanomed."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1016\/j.stemcr.2019.05.008","article-title":"A Simplified, Fully Defined Differentiation Scheme for Producing Blood-Brain Barrier Endothelial Cells from Human iPSCs","volume":"12","author":"Neal","year":"2019","journal-title":"Stem Cell Rep."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"6811","DOI":"10.1021\/acsami.5b11730","article-title":"Tailoring Particle Size of Mesoporous Silica Nanosystem To Antagonize Glioblastoma and Overcome Blood\u2013Brain Barrier","volume":"8","author":"Mo","year":"2016","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"20410","DOI":"10.1021\/acsami.7b03504","article-title":"In Vitro Study of Receptor-Mediated Silica Nanoparticles Delivery across Blood\u2013Brain Barrier","volume":"9","author":"Song","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"16662","DOI":"10.1039\/C6NR05055G","article-title":"Transferrin conjugated nontoxic carbon dots for doxorubicin delivery to target pediatric brain tumor cells","volume":"8","author":"Li","year":"2016","journal-title":"Nanoscale"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"6325","DOI":"10.2147\/IJN.S119252","article-title":"Hydrothermal synthesis of nitrogen-doped carbon dots with real-time live-cell imaging and blood-brain barrier penetration capabilities","volume":"11","author":"Lu","year":"2016","journal-title":"Int. J. Nanomed."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"e12441","DOI":"10.1111\/micc.12441","article-title":"Brain oxygenation with a non-vasoactive perfluorocarbon emulsion in a rat model of traumatic brain injury","volume":"25","author":"Abutarboush","year":"2018","journal-title":"Microcirculation"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1227\/01.NEU.0000325493.51900.53","article-title":"Perfluorocarbon emulsions improve cognitive recovery after lateral fluid percussion brain injury in rats","volume":"63","author":"Zhou","year":"2008","journal-title":"Neurosurgery"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1227\/01.NEU.0000119238.68938.5D","article-title":"Perfluorocarbon emulsion improves cerebral oxygenation and mitochondrial function after fluid percussion brain injury in rats","volume":"54","author":"Daugherty","year":"2004","journal-title":"Neurosurgery"},{"key":"ref_122","unstructured":"Graham, K., Moon-Massat, P.F., and Unger, E.C. (2017). 2017 Military Supplement: Dodecafluoropentane Emulsion (Ddfpe) as a Resuscitation Fluid for Treatment of Hemorrhagic Shock and Traumatic Brain Injury: A Review. Shock."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.brainres.2016.01.012","article-title":"Perfluorocarbon NVX-108 increased cerebral oxygen tension after traumatic brain injury in rats","volume":"1634","author":"Mullah","year":"2016","journal-title":"Brain Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"220","DOI":"10.2174\/1570163811666140709110301","article-title":"Effects of perfluorocarbon dodecafluoropentane (NVX-108) on cerebral microvasculature in the healthy rat","volume":"11","author":"Abutarboush","year":"2014","journal-title":"Curr. Drug Discov. Technol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"5529","DOI":"10.7150\/thno.29039","article-title":"Targeting Mitochondrial Dysfunction and Oxidative Stress in Activated Microglia using Dendrimer-Based Therapeutics","volume":"8","author":"Sharma","year":"2018","journal-title":"Theranostics"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1089\/neu.2013.3147","article-title":"PEG-PDLLA micelle treatment improves axonal function of the corpus callosum following traumatic brain injury","volume":"31","author":"Ping","year":"2014","journal-title":"J. Neurotrauma."},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Jiang, Y., Fay, J.M., Poon, C.D., Vinod, N., Zhao, Y., Bullock, K., Qin, S., Manickam, D.S., Yi, X., and Banks, W.A. (2018). Nanoformulation of Brain-Derived Neurotrophic Factor with Target Receptor-Triggered-Release in the Central Nervous System. Adv. Funct. Mater., 28.","DOI":"10.1002\/adfm.201703982"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/11\/9\/473\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:19:49Z","timestamp":1760188789000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/11\/9\/473"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,13]]},"references-count":127,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2019,9]]}},"alternative-id":["pharmaceutics11090473"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics11090473","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,13]]}}}