Multiple Sclerosis: LIFNano-CD4 for Trojan Horse Delivery of the Neuro-Protective Biologic “LIF” Into the Brain: Preclinical Proof of Concept

Flor, Raúl de la; Robertson, Janette; Shevchenko, Rostislav V.; Alavijeh, Mohammad S.; Bickerton, Sean; Fahmy, Tarek M.; Metcalfe, Su

doi:10.3389/fmedt.2021.640569

Cited by 7 publications

(3 citation statements)

References 17 publications

(25 reference statements)

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“…For example, in rodent models of MS, suppression of disease progression and severity has been achieved after i.v. delivery of nanoparticle formulations of PEGylated bilirubin (23), leukemia inhibitory factor (24), cerium oxide (25), and multiple antigens or regulatory molecules (26)(27)(28)(29). In a rabbit model of pediatric TBI, generation-4 polyamidoamine (PA-MAM) dendrimers conjugated to sinomenine, an anti-inflammatory agent, localized in microglia and macrophages in the brain and attenuated early and acute inflammation following i.v.…”

Section: Systemic Administrationmentioning

confidence: 99%

Nanotherapeutics and the Brain

Joseph

Nance

2022

Annu. Rev. Chem. Biomol. Eng.

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Brain disease remains a significant health, social, and economic burden with a high failure rate of translation of therapeutics to the clinic. Nanotherapeutics have represented a promising area of technology investment to improve drug bioavailability and delivery to the brain, with several successes for nanotherapeutic use for central nervous system disease that are currently in the clinic. However, renewed and continued research on the treatment of neurological disorders is critically needed. We explore the challenges of drug delivery to the brain and the ways in which nanotherapeutics can overcome these challenges. We provide a summary and overview of general design principles that can be applied to nanotherapeutics for uptake and penetration in the brain. We next highlight remaining questions that limit the translational potential of nanotherapeutics for application in the clinic. Lastly, we provide recommendations for ongoing preclinical research to improve the overall success of nanotherapeutics against neurological disease. Expected final online publication date for the Annual Review of Chemical and Biomolecular Engineering, Volume 13 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Section: Systemic Administrationmentioning

confidence: 99%

Nanotherapeutics and the Brain

Joseph

Nance

2022

Annu. Rev. Chem. Biomol. Eng.

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“…These NPs blocked the ability of IL-6 to induce CD4+ cells to become pro-inflammatory IL-17-producing cells. NPs encapsulated with LIF have used as neuroprotective in multiple sclerosis to repair myelin in vivo (85,86). This work was followed up in 2015 by loading CD4-targeted PLGA NPs with IL-2 and TGF-b, the cytokines that induce Foxp3 Tregs.…”

Section: Nanoparticles That Function As Tolerogenic Artificial Antigen-presenting Cells (Aapcs) That Provide Activating Costimulatory Andmentioning

confidence: 99%

Strategies to Use Nanoparticles to Generate CD4 and CD8 Regulatory T Cells for the Treatment of SLE and Other Autoimmune Diseases

2021

Self Cite

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Autoimmune diseases are disorders of immune regulation where the mechanisms responsible for self-tolerance break down and pathologic T cells overcome the protective effects of T regulatory cells (Tregs) that normally control them. The result can be the initiation of chronic inflammatory diseases. Systemic lupus erythematosus (SLE) and other autoimmune diseases are generally treated with pharmacologic or biological agents that have broad suppressive effects. These agents can halt disease progression, yet rarely cure while carrying serious adverse side effects. Recently, nanoparticles have been engineered to correct homeostatic regulatory defects and regenerate therapeutic antigen-specific Tregs. Some approaches have used nanoparticles targeted to antigen presenting cells to switch their support from pathogenic T cells to protective Tregs. Others have used nanoparticles targeted directly to T cells for the induction and expansion of CD4+ and CD8+ Tregs. Some of these T cell targeted nanoparticles have been formulated to act as tolerogenic artificial antigen presenting cells. This article discusses the properties of these various nanoparticle formulations and the strategies to use them in the treatment of autoimmune diseases. The restoration and maintenance of Treg predominance over effector cells should promote long-term autoimmune disease remission and ultimately prevent them in susceptible individuals.

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“…Silk fibroin (SF) is a prominent biomaterial that can be used for pharmacological administration because of two specific properties: poor immunogenicity and high stability with in vivo resistance to degradation even under inflammatory conditions . In the context of the CNS, the limited but theoretically controllable degradability of SF can be exploited where either short or extended drug delivery times are required. Previous studies illustrate a wide range of possibilities of using SF in formats such as nanoparticles, films, fibers, microspheres, and hydrogels to gradually deliver small and large molecules in various tissues.…”

Section: Introductionmentioning

confidence: 99%

Permselectivity of Silk Fibroin Hydrogels for Advanced Drug Delivery Neurotherapies

Fernández-Serra,

Lekouaghet,

Peracho

et al. 2024

Biomacromolecules

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A promising trend in tissue engineering is using biomaterials to improve the control of drug concentration in targeted tissue. These vehicular systems are of specific interest when the required treatment time window is higher than the stability of therapeutic molecules in the body. Herein, the capacity of silk fibroin hydrogels to release different molecules and drugs in a sustained manner was evaluated. We found that a biomaterial format, obtained by an entirely aqueous-based process, could release molecules of variable molecular weight and charge with a preferential delivery of negatively charged molecules. Although the theoretical modeling suggested that drug delivery was more likely to be driven by Fickian diffusion, the external media had a considerable influence on the release, with lipophilic organic solvents such as acetonitrile−methanol (ACN−MeOH) intensifying the release of hydrophobic molecules. Second, we found that silk fibroin could be used as a vehicular system to treat a variety of brain disorders as this biomaterial sustained the release of different factors with neurotrophic (brain-derived neurotrophic factor) (BDNF), chemoattractant (C-X-C motif chemokine 12) (CXCL12), anti-inflammatory (TGF-β-1), and angiogenic (VEGF) capacities. Finally, we demonstrated that this biomaterial hydrogel could release cholesteronitrone ISQ201, a nitrone with antioxidant capacity, showing neuroprotective activity in an in vitro model of ischemia-reoxygenation. Given the slow degradation rate shown by silk fibroin in many biological tissues, including the nervous system, our study expands the restricted list of drug delivery-based biomaterial systems with therapeutic capacity for both short-and especially long-term treatment windows and has merit for use with brain pathologies.

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Multiple Sclerosis: LIFNano-CD4 for Trojan Horse Delivery of the Neuro-Protective Biologic “LIF” Into the Brain: Preclinical Proof of Concept

Cited by 7 publications

References 17 publications

Nanotherapeutics and the Brain

Nanotherapeutics and the Brain

Strategies to Use Nanoparticles to Generate CD4 and CD8 Regulatory T Cells for the Treatment of SLE and Other Autoimmune Diseases

Permselectivity of Silk Fibroin Hydrogels for Advanced Drug Delivery Neurotherapies

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