Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain.

In this study, exosomes used to encapsulate curcumin (Exo-cur) or a signal transducer and activator of transcription 3 (Stat3) inhibitor, i.e., JSI124 (Exo-JSI124) were delivered noninvasively to microglia cells via an intranasal route. The results generated from three inflammation-mediated disease models, i.e., a lipopolysaccharide (LPS)-induced brain inflammation model, experimental autoimmune encephalitis and a GL26 brain tumor model, showed that mice treated intranasally with Exo-cur or Exo-JSI124 are protected from LPS-induced brain inflammation, the progression of myelin oligodendrocyte glycoprotein (MOG) peptide induced experimental autoimmune encephalomyelitis (EAE), and had significantly delayed brain tumor growth in the GL26 tumor model. Intranasal administration of Exo-cur or Exo-JSI124 led to rapid delivery of exosome encapsulated drug to the brain that was selectively taken up by microglial cells, and subsequently induced apoptosis of microglial cells. Our results demonstrate that this strategy may provide a noninvasive and novel therapeutic approach for treating brain inflammatory-related diseases.

[1]  W. Frey,et al.  Trigeminal pathways deliver a low molecular weight drug from the nose to the brain and orofacial structures. , 2010, Molecular pharmaceutics.

[2]  J. García-Rodríguez,et al.  The Nasal Route as a Potential Pathway for Delivery of Erythropoietin in the Treatment of Acute Ischemic Stroke in Humans , 2009, TheScientificWorldJournal.

[3]  W. Grizzle,et al.  Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. , 2010, The American journal of pathology.

[4]  I. Berquin,et al.  Multi-targeted therapy of cancer by omega-3 fatty acids. , 2008, Cancer letters.

[5]  W. Grizzle,et al.  Thymus Exosomes-Like Particles Induce Regulatory T Cells1 , 2008, The Journal of Immunology.

[6]  J. Kappes,et al.  Expansion of spleen myeloid suppressor cells represses NK cell cytotoxicity in tumor-bearing host. , 2007, Blood.

[7]  C. Théry,et al.  Membrane vesicles as conveyors of immune responses , 2009, Nature Reviews Immunology.

[8]  M. Vogelbaum,et al.  Novel drug delivery strategies in neuro-oncology , 2009, Neurotherapeutics.

[9]  Dongmei Sun,et al.  A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[10]  A. Murakami,et al.  Targeting NOX, INOS and COX‐2 in inflammatory cells: Chemoprevention using food phytochemicals , 2007, International journal of cancer.

[11]  Sheng Zhao,et al.  Comprehensive Algorithm for Quantitative Real-Time Polymerase Chain Reaction , 2005, J. Comput. Biol..

[12]  R. G. Thorne,et al.  Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration , 2004, Neuroscience.

[13]  F. Flowers,et al.  Chemoprevention of nonmelanoma skin cancer. , 2006, Journal of the American Academy of Dermatology.

[14]  N. Mori,et al.  THIS ARTICLE HAS BEEN RETRACTED Curcumin targets Akt cell survival signaling pathway in HTLV‐I‐infected T‐cell lines , 2006, Cancer science.

[15]  B. Badie,et al.  Induction of Anti-Glioma Natural Killer Cell Response following Multiple Low-Dose Intracerebral CpG Therapy , 2010, Clinical Cancer Research.

[16]  B. Patil,et al.  Bioactive compounds: historical perspectives, opportunities, and challenges. , 2009, Journal of Agricultural and Food Chemistry.

[17]  H. Potschka.  Targeting the brain--surmounting or bypassing the blood-brain barrier. , 2010, Handbook of experimental pharmacology.

[18]  Lawrence Steinman,et al.  T helper type 1 and 17 cells determine efficacy of interferon-β in multiple sclerosis and experimental encephalomyelitis , 2010, Nature Medicine.

[19]  R. Collman,et al.  CNS Inflammation and Macrophage/Microglial Biology Associated with HIV-1 Infection , 2009, Journal of Neuroimmune Pharmacology.

[20]  P. Peterson,et al.  Microglia as a Pharmacological Target in Infectious and Inflammatory Diseases of the Brain , 2006, Journal of Neuroimmune Pharmacology.

[21]  M. Gräler.  Targeting Sphingosine 1-phosphate (S1P) Levels and S1P Receptor Functions for Therapeutic Immune Interventions , 2010, Cellular Physiology and Biochemistry.

[22]  R. Shelton,et al.  Eating ourselves to death (and despair): The contribution of adiposity and inflammation to depression , 2010, Progress in Neurobiology.

[23]  P. Carvey,et al.  The blood–brain barrier in neurodegenerative disease: a rhetorical perspective , 2009, Journal of neurochemistry.

[24]  A. Frey.  Myeloid suppressor cells regulate the adaptive immune response to cancer. , 2006, The Journal of clinical investigation.

[25]  D. Curiel,et al.  Gene therapy that inhibits nuclear translocation of nuclear factor κB results in tumor necrosis factor α–induced apoptosis of human synovial fibroblasts , 2000 .

[26]  G. Graham,et al.  Emerging roles for phospholipase A2 enzymes in cancer. , 2010, Biochimie.

[27]  B. Aggarwal,et al.  Curcumin and Cancer Cells: How Many Ways Can Curry Kill Tumor Cells Selectively? , 2009, The AAPS Journal.

[28]  Lisbeth Illum,et al.  Nanoparticles for direct nose-to-brain delivery of drugs. , 2009, International journal of pharmaceutics.

[29]  A. Poliakov,et al.  Adipose Tissue Exosome-Like Vesicles Mediate Activation of Macrophage-Induced Insulin Resistance , 2009, Diabetes.

[30]  Xiao‐Kang Li,et al.  Amelioration of experimental autoimmune encephalomyelitis by curcumin treatment through inhibition of IL-17 production. , 2009, International immunopharmacology.

[31]  H. Harizi,et al.  Pivotal role of PGE2 and IL-10 in the cross-regulation of dendritic cell-derived inflammatory mediators. , 2006, Cellular & molecular immunology.

[32]  David B. Allison,et al.  Novel tumor necrosis factor α-regulated genes in rheumatoid arthritis , 2004 .

[33]  D. Gabrilovich,et al.  Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species , 2003, Journal of leukocyte biology.

[34]  A. Gescher,et al.  Dietary polyphenolic phytochemicals—promising cancer chemopreventive agents in humans? A review of their clinical properties , 2007, International journal of cancer.

[35]  M. Salcman,et al.  Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey , 1986, The Journal of comparative neurology.

[36]  C. Divino,et al.  Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. , 2006, Cancer research.

[37]  Xin-guo Jiang,et al.  From nose to brain: understanding transport capacity and transport rate of drugs , 2008, Expert opinion on drug delivery.

[38]  F. Campbell,et al.  Chemopreventive properties of curcumin. , 2005, Future oncology.

[39]  W. Pan,et al.  Intranasal leptin: blood-brain barrier bypass (BBBB) for obesity? , 2006, Endocrinology.

[40]  Kyoko Noguchi,et al.  LPA receptors: subtypes and biological actions. , 2010, Annual review of pharmacology and toxicology.

[41]  D. Gabrilovich,et al.  Immature myeloid cells and cancer-associated immune suppression , 2002, Cancer Immunology, Immunotherapy.

[42]  S. Koh,et al.  Role of Brain Inflammation in Epileptogenesis , 2008, Yonsei medical journal.

[43]  G. Krishnamoorthy,et al.  Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis , 2011, Journal of Cell Science.

[44]  R. Gabathuler.  Blood-brain barrier transport of drugs for the treatment of brain diseases. , 2009, CNS & neurological disorders drug targets.

[45]  Isaac Yang,et al.  The role of microglia in central nervous system immunity and glioma immunology , 2010, Journal of Clinical Neuroscience.

[46]  R. Thorne,et al.  Quantitative analysis of the olfactory pathway for drug delivery to the brain , 1995, Brain Research.

[47]  W. Grizzle,et al.  JAB1 determines the response of rheumatoid arthritis synovial fibroblasts to tumor necrosis factor-alpha. , 2006, The American journal of pathology.

[48]  Zhongyu Liu,et al.  CII-DC-AdTRAIL cell gene therapy inhibits infiltration of CII-reactive T cells and CII-induced arthritis. , 2003, The Journal of clinical investigation.

[49]  V. O’Donnell,et al.  Inflammation and immune regulation by 12/15-lipoxygenases. , 2006, Progress in lipid research.

[50]  B. Aggarwal,et al.  Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. , 2008, Biochemical pharmacology.