Development of Novel Zn2+ Loaded Nanoparticles Designed for Cell-Type Targeted Drug Release in CNS Neurons: In Vitro Evidences

Intact synaptic function and plasticity are fundamental prerequisites to a healthy brain. Therefore, synaptic proteins are one of the major targets for drugs used as neuro-chemical therapeutics. Unfortunately, the majority of drugs is not able to cross the blood–brain barrier (BBB) and is therefore distributed within the CNS parenchyma. Here, we report the development of novel biodegradable Nanoparticles (NPs), made of poly-lactide-co-glycolide (PLGA) conjugated with glycopeptides that are able to cross the BBB and deliver for example Zn2+ ions. We also provide a thorough characterization of loaded and unloaded NPs for their stability, cellular uptake, release properties, toxicity, and impact on cell trafficking. Our data reveal that these NPs are biocompatible, and can be used to elevate intracellular levels of Zn2+. Importantly, by engineering the surface of NPs with antibodies against NCAM1 and CD44, we were able to selectively target neurons or glial cells, respectively. Our results indicate that these biodegradable NPs provide a potential new venue for the delivery Zn2+ to the CNS and thus a means to explore the influence of altered zinc levels linked to neuropsychological disorders such as depression.

[1]  Maria Speranza Desole,et al.  Hormones Are Key Actors in Gene X Environment Interactions Programming the Vulnerability to Parkinson's Disease: Glia as a Common Final Pathway , 2005, Annals of the New York Academy of Sciences.

[2]  C. Garner,et al.  Functional regions of the presynaptic cytomatrix protein bassoon: significance for synaptic targeting and cytomatrix anchoring , 2003, Molecular and Cellular Neuroscience.

[3]  Michael R Kreutz,et al.  Concerted action of zinc and ProSAP/Shank in synaptogenesis and synapse maturation , 2011, The EMBO journal.

[4]  D. Choi,et al.  Brief exposure to zinc is toxic to cortical neurons , 1986, Neuroscience Letters.

[5]  Bin Liu,et al.  A strategy for precision engineering of nanoparticles of biodegradable copolymers for quantitative control of targeted drug delivery. , 2010, Biomaterials.

[6]  G. Frank.  C″ and Depression , 1993, Psychological reports.

[7]  C. Garner,et al.  Caldendrin, a Novel Neuronal Calcium-binding Protein Confined to the Somato-dendritic Compartment* , 1998, The Journal of Biological Chemistry.

[8]  C. Levenson,et al.  Role of zinc in the development and treatment of mood disorders , 2010, Current opinion in clinical nutrition and metabolic care.

[9]  G. Lubec,et al.  Zinc deficiency induces enhanced depression-like behaviour and altered limbic activation reversed by antidepressant treatment in mice , 2008, Amino Acids.

[10]  M. D. de Broe,et al.  Hypozincemia in depression. , 1994, Journal of affective disorders.

[11]  C. Ferrari,et al.  Microglial activation with atypical proinflammatory cytokine expression in a rat model of Parkinson's disease , 2003, The European journal of neuroscience.

[12]  K. Yokoi,et al.  Effect of zinc supplementation on mood states in young women: a pilot study , 2010, European Journal of Clinical Nutrition.

[13]  S. Ferroni,et al.  Role of Microglia and Astrocytesin Alzheimer’s Disease , 2004 .

[14]  G. Nowak,et al.  Interaction of zinc with antidepressants in the forced swimming test in mice. , 2002, Polish journal of pharmacology.

[15]  W. Pardridge,et al.  Noninvasive gene targeting to the brain. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[16]  C. Levenson.  Zinc: the new antidepressant? , 2006, Nutrition reviews.

[17]  B. Lom,et al.  Brain-Derived Neurotrophic Factor Differentially Regulates Retinal Ganglion Cell Dendritic and Axonal Arborization In Vivo , 1999, The Journal of Neuroscience.

[18]  M A Vandelli,et al.  Sialic acid and glycopeptides conjugated PLGA nanoparticles for central nervous system targeting: In vivo pharmacological evidence and biodistribution. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[19]  Eckart D Gundelfinger,et al.  An Architectural Framework That May Lie at the Core of the Postsynaptic Density , 2006, Science.

[20]  J. Kreuter.  Nanoparticles--a historical perspective. , 2007, International journal of pharmaceutics.

[21]  W. Pardridge.  Blood-brain barrier drug targeting: the future of brain drug development. , 2003, Molecular interventions.

[22]  J. Bowie,et al.  A role for zinc in postsynaptic density asSAMbly and plasticity? , 2006, TIBS -Trends in Biochemical Sciences. Regular ed.

[23]  G. Tosi,et al.  Nanoparticles as drug delivery agents specific for CNS: in vivo biodistribution. , 2009, Nanomedicine : nanotechnology, biology, and medicine.

[24]  Manser Ww,et al.  Trace element studies on Karachi population. Part IV: Blood copper, zinc, magnesium and lead levels in psychiatric patients with depression, mental retardation and seizure disorders. , 1989 .

[25]  María J. Alonso,et al.  Development and characterization of protein-loaded poly(lactide-co-glycolide) nanospheres , 1997 .

[26]  A. Rodrigues,et al.  Involvement of NMDA receptors and l-arginine-nitric oxide pathway in the antidepressant-like effects of zinc in mice , 2003, Behavioural Brain Research.

[27]  G. Tosi,et al.  Peptide-derivatized biodegradable nanoparticles able to cross the blood-brain barrier. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[28]  G. Nowak,et al.  Mechanisms contributing to antidepressant zinc actions. , 2002, Polish journal of pharmacology.

[29]  A. Rodrigues,et al.  Interaction of zinc with antidepressants in the tail suspension test , 2008, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[30]  L. Niels-Christiansen,et al.  Endocytic trafficking from the small intestinal brush border probed with FM dye. , 2009, American journal of physiology. Gastrointestinal and liver physiology.

[31]  G. Nowak,et al.  Zinc exhibits an antidepressant-like effect in the forced swimming test in mice. , 2000, Polish journal of pharmacology.

[32]  Barbara Ruozi,et al.  Investigation on mechanisms of glycopeptide nanoparticles for drug delivery across the blood-brain barrier. , 2011, Nanomedicine.

[33]  Rikki S. Corniola,et al.  Zinc deficiency induces depression-like symptoms in adult rats , 2008, Physiology & Behavior.

[34]  P. Couvreur,et al.  Colloidal carriers and blood-brain barrier (BBB) translocation: a way to deliver drugs to the brain? , 2005, International journal of pharmaceutics.

[35]  G. Nowak,et al.  Antidepressant-like properties of zinc in rodent forced swim test , 2001, Brain Research Bulletin.

[36]  E. Florek,et al.  Antepartum/postpartum depressive symptoms and serum zinc and magnesium levels. , 2006, Pharmacological reports : PR.

[37]  W. Huttner,et al.  Exocytotic and endocytotic membrane traffic in neurons , 1991, Current Opinion in Neurobiology.

[38]  R. Amani,et al.  Correlation Between Dietary Zinc Intakes and Its Serum Levels with Depression Scales in Young Female Students , 2010, Biological Trace Element Research.

[39]  Mark P Mattson,et al.  Neuronal and glial calcium signaling in Alzheimer's disease. , 2003, Cell calcium.

[40]  J. Bowie,et al.  The Many Faces of SAM , 2005, Science's STKE.

[41]  I. McLoughlin,et al.  Zinc in depressive disorder , 1990, Acta psychiatrica Scandinavica.

[42]  D. Choi,et al.  Measurement of Intracellular Free Zinc Concentrations Accompanying Zinc-Induced Neuronal Death , 1999, The Journal of Neuroscience.

[43]  G. Nowak,et al.  Zinc and depression. An update. , 2005, Pharmacological reports : PR.

[44]  Michael Aschner,et al.  The Role of Glia in Neurotoxicity , 1996 .

[45]  G. Nowak,et al.  Antidepressant-like effects of acute and chronic treatment with zinc in forced swim test and olfactory bulbectomy model in rats , 2003, Brain Research Bulletin.

[46]  M A Vandelli,et al.  Targeting the central nervous system: in vivo experiments with peptide-derivatized nanoparticles loaded with Loperamide and Rhodamine-123. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[47]  D. Choi,et al.  AMPA receptor activation potentiates zinc neurotoxicity , 1993, Neuron.

[48]  Barbara Ruozi,et al.  Polymeric nanoparticles for the drug delivery to the central nervous system , 2008, Expert opinion on drug delivery.