Application of nanomedicine for crossing the blood–brain barrier: Theranostic opportunities in multiple sclerosis

Figures & data

Figure 1. Schematic representation of the immunological and pathological events observed in MS. Oxidative stress in endothelial cells leads to damage to astrocytes, activation of macro-phages/microglial cells and apoptosis in oligodendrocytes. Oxidative stress also increases the production and function of MMPS in endothelial cells and macrophages. These sequential events enhance disruption of BBB. Destruction of the CNS parenchyma and BBB lead to generation of creates chemotactic factors for leukocytes. Therefore, these events disturb BBB integrity and attract leukocytes into the CNS. The myelin-derived antigens will be taken by APC and presented to CD4⁺ and CD8⁺ T-cells. Inflammatory mediators such as osteopontin, IL-1, IL-12, TNFα, IL-23 and other cytokines enhance the differentiation of CD4⁺ T_H cells toward T_H1 and T_H17 cells. These inflammatory leukocytes in the CNS can either directly or indirectly induce neuronal, axonal and oligodendrocyte damage. MS: multiple sclerosis, CNS: central nervous system, TGF: transforming growth factor, IL: interleukin, MQ: macrophage, IFN: interferon, H1R: histamine receptor 1, H2R: histamine receptor 2, JAM: junctional adhesion molecules, MMPs: matrix metalloproteinases, PBM: parenchymal basement membrane, ROS: reactive oxygen species, VBM: vascular basement membrane.

Figure 2. (A) The size of the nanoparticles is an important criteria in transportation of loaded drugs. (B) Poly-dispersity of particle size may create variability in the release rates. (C) Surface properties of NP can significantly affect their drug delivery into the CNS. Modification of the surface with polymers such as polyethylene glycol (PEG) can increase the circulation time of conjugated particles. Moreover, surface modification of nanoparticles can affect the interaction of these particles with immune cells.

Table 1. Studies related to the role of nanoparticles in the treatment of EAE and MS.

Nanoparticles	Drug	Main claim	References
Biotinylated albumin	–	Albumin NPs can effectively cross BBB and reach to brain in EAE rat models	(Merodio et al. 2000)
Liposome	–	Cationic (but not anionic) liposomes target acute neuroinflammatory sites in EAE rats	(Cavaletti et al. 2009)
NMDA receptor antagonist conjugated-ABS-75 compound (fullerene derivative)	–	ABS-75 compound ameliorate EAE in NOD mice in part through antioxidant and anti-excitotoxic mechanisms	(Basso et al. 2008)
PEGylated liposomes	Tempamine	Tempamine loaded PEGylated nanoliposomes can markedly inhibit EAE in mice	(Kizelsztein et al. 2009)
Magnetic NPs	–	Magnetic NPs are effective tools for gene delivery to rat oligodendrocyte precursor cells derived for transplantation therapies	(Jenkins et al. 2011)
Cerium and yttrium oxides (CeO2 and Y2O3) NPs	–	Cerium and yttrium oxides (CeO2 and Y2O3) NPs can effectively decrease the oxidative stress in hippocampal neuronal cells, rat hippocampus and EAE mice	(Heckman et al. 2013; Schubert et al. 2006; Hosseini et al. 2014)
Polyamidoamine dendrimers	–	Polyamidoamine dendrimers can localize in activated microglia and astrocytes in rabbit model of cerebral palsy	(Dai et al. 2010; Kannan et al. 2012)
Polyamidoamine dendrimers	NAC	NAC-loaded dendrimers suppress neuroinflammation and increase motor function in the cerebral palsy	(Kannan et al. 2012)
Gold NPs	MOG (35–55) peptide	Gold NPs induce tolerance in EAE mice in part through expansion of Treg cells.	(Yeste et al. 2012)
Mannosylated liposomes	MBP peptides (46–62, 124–139 and 147–160)	Administration of MBP peptides (46–62, 124–139 and 147–160) incorporated into liposomes to DA rats inhibited disease progression and decreased level of anti-MBP antibodies	(Yeste et al. 2012)
PLGA	PLP peptide (139–151)	Administration of antigen-conjugated PLGA NPs to EAE mice effectively inhibits disease induction	(Eaton et al. 2013)
PEGylated liposomes	Prednisolone	The intravenous administration of PEG-coated prednisolone liposomes into EAE rats leads to increased accumulation of prednisolone in the CNS and spinal cord of EAE animals compared to healthy control animals	(Schmidt et al. 2003)
Liposomes	Prednisolone and methylprednisolone	Methylprednisolone liposomes are better than prednisolone-containing liposomes and free methylprednisolone in EAE mitigation	(Linker et al. 2008)
PEGylated-liposomes	Minocycline	Minocycline loaded PEGylated-liposomes can attenuate CNS autoimmune disease	(Hu et al. 2009)
Tat49-57 cationic peptide conjugated to MOG33-35	Plasmid containing murine BTLA gene	Administration of DCs pulsed with Tat49-57 cationic peptide and MOG33-35, accompanied with the plasmid containing murine BTLA gene into EAE animal model can induce immune tolerance in CD4^+ T cells and inhibit disease progression	(Yuan et al. 2014)
Bifunctional peptide, SAgAs and PLGA	–	The physical characteristics of the carrier such as structure, size and solubility can modulate the immune response following treating EAE	(Sestak et al. 2014)
PLGA	PLP peptide (138–151)	PLP peptide (138–151)-loaded PLGA NPs induce antigen-specific T cell tolerance and inhibit leukocyte infiltration in CNS of relapsing-remitting EAE mice	(Hunter et al. 2014)
PLGA	MOG peptide and IL-10	PLGA-NP loaded with the MOG35–55 and recombinant IL-10 attanuates EAE.	(Cappellano et al. 2014)
NG-2-targeted PLGA	LIF	LIF-loaded NPs promote remyelination	(Rittchen et al. 2015)
PNP	–	Peptide functionalized PNPs can specifically target damaged tissue in EAE.	(Führmann et al. 2015)
Cerium oxide NPs (nanoceria)	Lenalidomide	Combination therapy with lenalidomide and nanoceria ameliorates EAE.	(Eitan et al. 2015)

NPs: nanoparticles, EAE: experimental autoimmune encephalomyelitis, NAC: N-acetyl-l-cysteine, MOG: myelin oligodendrocyte glycoprotein, PLP: proteolipid protein, MBP: myelin basic protein, Treg: regulatory T cell, PLGA: poly(lactic-co-glycolic acid), PEG: polyethylene glycol, BTLA: B and T lymphocyte attenuator, SAgAs: Soluble Antigen Arrays, CNS: central nervous system, PNP: polymeric NP.

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