Lipopolysaccharide Modified Liposomes for Amyotropic Lateral Sclerosis Therapy: Efficacy in SOD1 Mouse Model

Abstract

Activation of microglia is a histological feature observed in neurodegenerative diseases like ALS. The oral administration of minocycline has been demonstrated to have minimal neuroprotection ability in the animal models and is also associated with inadvertent toxicity due to non-specific oral absorption of the drug. Nonetheless, the drug itself shows promise in a number of disease models suggesting it could be effective if delivered optimally. Thus, we utilized LPS modified liposomes to target TLR4 receptor on the microglia in SOD1 G93A mice and compared its efficacy with nontargeted nanoliposomes. The in vitro results indicate that targeting the TLR4 receptor on microglia significantly increases (p < 0.01) the uptake of drug by 29% compared to non-targeted liposomes. In the SOD1 G93A mouse model of ALS, targeted and non-targeted minocycline treatment significantly increased (p < 0.05) latency to endpoint stages compared to control mice. Targeting liposomes to microglia significantly delayed disease progression. Both targeted and non-targeted liposomes administration in SOD1 mice resulted in decreased TNF-α secretion in activated BV-2 microglial cells as compared to activated cells receiving no treatment. The non-targeted liposomes had a greater effect than the targeted liposomes in reducing the levels of TNF-α released by the BV-2 cells. In SOD1 G93A mice, the nontargeted nanovesicles significantly increased the latency to rotarod failure and both targeted and non-targeted nanovesicles significantly delayed disease endpoints.

Antioxidants and Nanotechnology: Promises and Limits of Potentially Disruptive Approaches in the Treatment of Central Nervous System Diseases

“…Wiley et al designed lipopolysaccharide (LPS)‐modified liposomes targeting TLR4 receptor on the microglia in SOD‐1 mutant mice and loaded them with minocycline demonstrating preferential targeting of microglia cells and a delay in disease progression . Interestingly, the administration of Cu, Zn SOD liposomes favored the delivery of the antioxidant enzyme to the brain, enhancing its protective activity in ischemia/reperfusion injury …”

The Prospect of Nanoparticle Systems for Modulating Immune Cell Polarization During Central Nervous System Infection

“…For microglial specificity, nanoparticles can leverage receptor-targeting ligands and the inherent phagocytic properties of microglia, while maintaining biocompatibility ( 140 ). An early study of microglial targeting used liposomal nanoparticles modified with the TLR4 ligand lipopolysaccharide (LPS), which significantly increased uptake of the encapsulated drug compared to non-targeted liposomes ( 141 ). In a later study, ceria-zirconia nanoparticles decorated with CD11b antibody showed preferential uptake by microglia compared to other cell types in the brain and higher internalization compared to nanoparticles conjugated to an isotype-matched control antibody ( 142 ).…”

Pharmacological Tools to Activate Microglia and their Possible use to Study Neural Network Patho-physiology

“…In addition to the use of liposomes as PS carriers, this preparation can be used to deliver a variety of agents including LPS [ 299 ], minocycline [ 299 ], antiinflammatory drugs [ 290 , 300 - 303 ], RGD [ 301 ], enzymes [ 304 - 306 ], fluorescent dyes [ 290 , 291 ], hormones [ 307 , 308 ], antivirals [ 309 ], protease inhibitors [ 310 ], ion-channel modulators [ 311 ], antibiotics [ 312 , 313 ], antioxidants [ 293 , 306 , 314 ], plasmids [ 315 ], signaling-pathway modulators [ 296 ] and toxic compounds [ 292 , 295 , 296 ]. Just to give an example of their use, liposomes containing superoxide dismutase can be incorporated into microglia, which increases their reductive power and favors retinal activity [ 306 ].…”