The development of Alzheimer's disease (AD) is the collective consequence of the toxicities induced by β-amyloid (Aβ) plaques, tau protein-formed neurofibrillary tangles, and malfunction of microglia due to inflammation and oxidative damage. Most AD therapeutics only target one of these key factors; the failed clinical trials proved the insufficiency of these individual approaches. In addition, although many inhibitors of key molecular targets in AD either exist or could be easily designed, 98% of small molecules and almost all macromolecules cannot effectively pass through the blood-brain barrier (BBB). Thus, drugs capable of curing orstably alleviating the symptoms of AD are still not available. Cerium oxide nanoparticles (CeNPs) act as a metalcatalyst, exhibiting both superoxide dismutase (SOD) and catalase (CAT) mimicking activities, which scavengesnoxious intracellular reactive oxygen species (ROS). Our preliminary study revealed that CeNPs show outstanding antioxidant and anti-inflammatory effects. However, the clinical application of CeNPs is hindered byits poor solubility and inability to cross the BBB. During neuroinflammation, the receptor for advanced glycationend products (RAGE) is over expressed on the BBB. Thus, the objective of this study is to develop an AD braintargeted CeNP by utilizing the RAGE overexpression on the BBB and the bioactivities of CeNP. We developed a CeNP-embedded Poly(lactide-co-glycolide) (PLGA) nanoparticle to overcome the pharmacokinetic limitation of free CeNP and equipped it with a targeting ligand for the RAGE receptor to facilitate BBB penetration. Our preliminary data demonstrates that this AD brain targeted-CeNP (T-CeNP) can effectively cross the BBB, quench the elevated ROS, attenuate the activation of microglia, and reduce Aβ burden in the brain in an AD mouse model. In this STTR Phase I proof-of-concept study, we will validate our hypothesis that our proprietary T-CeNPcan be developed as a novel therapy for AD through two specific aims. SA1: Evaluate the toxicity and pharmacokinetic properties of T-CeNP in mice. The maximum tolerated dose (MTD) of T-CeNP will be first determined in C57BL/6J mice; and then the pharmacokinetic properties of T-CeNP will be examined in the mice.SA2: Test the therapeutic efficiency of the T-CeNP and evaluate its systemic toxicity in AD mouse models. Our preliminary study showed efficacy of T-CeNP in a 5xFAD AD mouse model. To further validate if T-CeNP could be used for AD treatment, we will evaluate the anti-inflammatory effects of the T-CeNP in a 3xTg-AD mouse model, which displays all three pathological hallmarks of AD, assess the effect of T-CeNP in protecting learning and memory of the mice using Morris water maze test and nest construction assay, and measure the systemictoxicity. Upon completion of this Phase I project, we will start an IND-enabling STTR Phase II project to complete more advanced toxicology and efficacy studies using large animal models of AD in a GLP setting and carry out cGMP manufacturing of T-CeNP for human use. Our proprietary AD brain-targeted delivery technology can also be used for the delivery of other agents that do not cross BBB but may be otherwise effective for AD treatment.
Public Health Relevance Statement: Narrative. Alzheimer's disease is the sixth-leading cause of death in the United States and costs about $305 billion in 2020. This research will develop an AD brain targeted delivery system that can carry a multifunctional cerium oxide nanoparticle into the brain to stop the progression of Alzheimer's disease. The success of validating this concept will open a new era for treating Alzheimer's disease, which is consistent with the mission of the NIH.
Project Terms: Alzheimer's Disease, AD dementia, Alzheimer, Alzheimer Type Dementia, Alzheimer disease, Alzheimer sclerosis, Alzheimer syndrome, Alzheimer's, Alzheimer's disease dementia, Alzheimers Dementia, Alzheimers disease, Primary Senile Degenerative Dementia, dementia of the Alzheimer type, primary degenerative dementia, senile dementia of the Alzheimer type, inhibitor, Antioxidants, anti-oxidant, Biological Assay, Assay, Bioassay, Biologic Assays, Blood - brain barrier anatomy, Blood-Brain Barrier, Hemato-Encephalic Barrier, bloodbrain barrier, Brain, Brain Nervous System, Encephalon, catalase, Cause of Death, Clinical Trials, Disease, Disorder, Pharmaceutical Preparations, Drugs, Medication, Pharmaceutic Preparations, drug/agent, Investigational Drugs, Investigational New Drugs, Engineering, Exhibits, Cyclic GMP, Guanosine Cyclic Monophosphate, cGMP, Half-Life, Human, Modern Man, In Vitro, Inflammation, Learning, Ligands, macrophage, MÏ, Maintenance, Memory, Metals, Mission, Mus, Mice, Mice Mammals, Murine, Mutation, Genetic Alteration, Genetic Change, Genetic defect, genome mutation, Names, NIH, National Institutes of Health, United States National Institutes of Health, Pharmacokinetics, Drug Kinetics, pilot study, Pilot Projects, Play, Dioxanedione Polymer with Dimethyldioxanedione Polymer, Poly(Lactide-Co-Glycolide), Polyglactin, Glycolic-Lactic Acid Polyester, Research, social role, Role, Safety, Solubility, Erythrocuprein, Hemocuprein, cytocuprein, Superoxide Dismutase, Survey Instrument, Surveys, Technology, Testing, Toxicology, United States, Amyloid beta-Protein, Alzheimer beta-Protein, Alzheimer's Amyloid beta-Protein, Alzheimer's amyloid, Amyloid Alzheimer's Dementia Amyloid Protein, Amyloid Beta-Peptide, Amyloid Protein A4, Amyloid β, Amyloid β-Peptide, Amyloid β-Protein, Aβ, a beta peptide, abeta, amyloid beta, amyloid-b protein, beta amyloid fibril, soluble amyloid precursor protein, Measures, Neurofibrillary Tangles, neurofibrillary degeneration, neurofibrillary lesion, neurofibrillary pathology, tangle, tau Proteins, MT-bound tau, microtubule bound tau, microtubule-bound tau, tau, tau factor, Ï Proteins, Healthcare, health care, receptor for advanced glycation endproducts, AGE receptor, RAGE receptor, advanced glycosylation end product receptor, amphoterin receptor, receptor for AGE, receptor for advanced glycation end product, receptor of AGE, Reactive Oxygen Species, Active Oxygen, Oxygen Radicals, Pro-Oxidants, Investigational New Drug Application, catalyst, macromolecule, improved, Phase, Microglia, Hortega cell, gitter cell, mesoglia, microglial cell, microgliocyte, perivascular glial cell, Link, Individual, Transgenes, PSEN1, S182 protein, presenilin 1 protein, presenilin-1, Therapeutic, Attenuated, Amyloid Plaques, Neuritic Plaques, amyloid beta plaque, amyloid-b plaque, aβ plaques, cored plaque, diffuse plaque, Senile Plaques, Deposit, Deposition, tool, Area Under Curve, System, success, Animal Models and Related Studies, model of animal, model organism, Animal Model, Toxicities, Toxic effect, Maximal Tolerated Dose, Maximally Tolerated Dose, Maximum Tolerated Dose, Property, Inflammatory Response, preventing, prevent, therapeutic testing, therapeutic evaluation, small molecule, Dose, Data, Molecular Target, Antiinflammatory Effect, anti-inflammatory effect, Small Business Technology Transfer Research, STTR, Pathologic, Process, Development, developmental, cost, neuroinflammation, neuroinflammatory, design, designing, cerium oxide nanoparticle, cerium oxide nano particle, morris water maze, morris watermaze, nanoparticle, nano particle, nano-sized particle, nanosized particle, targeted delivery, site targeted delivery, clinical application, clinical applicability, novel therapeutics, new drug treatments, new drugs, new therapeutics, new therapy, next generation therapeutics, novel drug treatments, novel drugs, novel therapy, mouse model, murine model, Alzheimer's disease model, AD model, alzheimer model, 3xTg-AD mouse, 3xTg, 3xTg-AD mice, therapy development, develop therapy, intervention development, treatment development, overexpression, overexpress, oxidative damage, oxidative injury, safety testing, drug candidate, Inductively Coupled Plasma Mass Spectrometry, ICP-MS, systemic toxicity, reduce symptoms, alleviate symptom, ameliorating symptom, decrease symptom, fewer symptoms, relieves symptoms, symptom alleviation, symptom reduction, symptom relief, efficacy study, Injections, nanoparticle delivery, nano particle delivery, nanoparticle delivered, blood-brain barrier penetration, BBB penetration, bloodbrain barrier penetration, Alzheimer's disease therapeutic, Alzheimer's therapeutic, Alzheimer's disease therapy, Alzheimer's therapy, Alzheimer's disease brain, Alzheimer's brain, β-amyloid burden, Aβ burden, a-beta burden, abeta burden, amyloid burden, beta amyloid burden, βamyloid burden
