Leveraging the interplay of nanotechnology and neuroscience: Designing new avenues for treating central nervous system disorders

Smith, Elizabeth S.; Porterfield, Joshua E.; Kannan, Rangaramanujam M.

doi:10.1016/j.addr.2019.02.009

Cited by 33 publications

(16 citation statements)

References 236 publications

(274 reference statements)

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“…Our results indicate that microglial phagocytosis is highly dependent on nanoparticle platform, and disease‐induced changes in microglial behavior are not leveraged equally among all nanoparticle types. These platforms differ in size, rigidity, and chemical composition which can influence nanoparticle–cell interactions 67,68 suggesting that nanoparticle physicochemical parameters must be well‐tuned to achieve accumulation in target cells at sites of injury. For example, rigid lipid nanoparticles could more easily pass through cell membranes compared to less rigid nanoparticles 69 .…”

Section: Discussionmentioning

confidence: 99%

Nanoparticle‐microglial interaction in the ischemic brain is modulated by injury duration and treatment

Joseph

Liao

Zhang

et al. 2020

Bioengineering & Transla Med

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Cerebral ischemia is a major cause of death in both neonates and adults, and currently has no cure. Nanotechnology represents one promising area of therapeutic development for cerebral ischemia due to the ability of nanoparticles to overcome biological barriers in the brain. ex vivo injury models have emerged as a highthroughput alternative that can recapitulate disease processes and enable nanoscale probing of the brain microenvironment. In this study, we used oxygen-glucose deprivation (OGD) to model ischemic injury and studied nanoparticle interaction with microglia, resident immune cells in the brain that are of increasing interest for therapeutic delivery. By measuring cell death and glutathione production, we evaluated the effect of OGD exposure time and treatment with azithromycin (AZ) on slice health. We found a robust injury response with 0.5 hr of OGD exposure and effective treatment after immediate application of AZ. We observed an OGD-induced shift in microglial morphology toward increased heterogeneity and circularity, and a decrease in microglial number, which was reversed after treatment. OGD enhanced diffusion of polystyrene-poly(ethylene glycol) (PS-PEG) nanoparticles, improving transport and ability to reach target cells. While microglial uptake of dendrimers or quantum dots (QDs) was not enhanced after injury, internalization of PS-PEG was significantly increased. For PS-PEG, AZ treatment restored microglial uptake to normal control levels. Our results suggest that different nanoparticle platforms should be carefully screened before application and upon doing so; disease-mediated changes in the brain microenvironment can be leveraged by nanoscale drug delivery devices for enhanced cell interaction.

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Section: Discussionmentioning

confidence: 99%

Nanoparticle‐microglial interaction in the ischemic brain is modulated by injury duration and treatment

Joseph

Liao

Zhang

et al. 2020

Bioengineering & Transla Med

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“…In addition, dendrimers are non-toxic, non-immunogenic and cleared intact through the kidneys. We have previously demonstrated that these dendrimers selectively localize in activated microglia in the retina and the brain in small and large animal models and can deliver drugs specifically to these cells ( Arteaga Cabeza et al, 2019 ; Smith et al, 2019 ). Here we demonstrate that HI leads to overexpression of GCPII in activated microglia in the neonatal mouse brain and treatment with D-2MPPA leads to decreased brain injury.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effects of a dendrimer-based glutamate carboxypeptidase inhibitor on superoxide dismutase transgenic mice after neonatal hypoxic-ischemic brain injury

Arteaga

Zhang

Khoury

et al. 2021

Neurobiology of Disease

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The result of a deprivation of oxygen and glucose to the brain, hypoxic–ischemic encephalopathy (HIE), remains the most common cause of death and disability in human neonates globally and is mediated by glutamate toxicity and inflammation. We have previously shown that the enzyme glutamate carboxypeptidase (GCPII) is overexpressed in activated microglia in the presence of inflammation in fetal/newborn rabbit brain. We assessed the therapeutic utility of a GCPII enzyme inhibitor called 2-(3-Mercaptopropyl) pentanedioic acid (2MPPA) attached to a dendrimer (D-2MPPA), in order to target activated microglia in an experimental neonatal hypoxia-ischemia (HI) model using superoxide dismutase transgenic (SOD) mice that are often more injured after hypoxia-ischemia than wildtype animals. SOD overexpressing and wild type (WT) mice underwent permanent ligation of the left common carotid artery followed by 50 min of asphyxiation (10% O 2 ) to induce HI injury on postnatal day 9 (P9). Cy5-labeled dendrimers were administered to the mice at 6 h, 24 h or 72 h after HI and brains were evaluated by immunoflu orescence analysis 24 h after the injection to visualize microglial localization and uptake over time. Expression of GCPII enzyme was analyzed in microglia 24 h after the HI injury. The expression of pro- and anti-inflammatory cytokines were analyzed 24 h and 72 h post-HI. Brain damage was analyzed histologically 7 days post-HI in the three randomly assigned groups: control (C); hypoxic-ischemic (HI); and HI mice who received a single dose of D-2MPPA 6 h post-HI (HI+D-2MPPA). First, we found that GCPII was overexpressed in activated microglia 24 h after HI in the SOD overexpressing mice. Also, there was an increase in microglial activation 24 h after HI in the ipsilateral hippocampus which was most visible in the SOD+HI group. Dendrimers were mostly taken up by microglia by 24 h post-HI; uptake was more prominent in the SOD+HI mice than in the WT+HI. The inflammatory profile showed significant increase in expression of KC/GRO following injury in SOD mice compared to WT at 24 and 72 h. A greater and significant decrease in KC/GRO was seen in the SOD mice following treatment with D-2MPPA. Seven days after HI, D-2MPPA treatment decreased brain injury in the SOD+HI group, but not in WT+HI. This reduced damage was mainly seen in hippocampus and cortex. Our data indicate that the best time point to administer D-2MPPA is 6 h post-HI in order to suppress the expression of GCPII by 24 h after the damage since dendrimer localization in microglia is seen as early as 6 h with the peak of GCPII upregulation in activated microglia seen at 24 h post-HI. Ultimately, treatment with D-2MPPA

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“…By using the theories of network control, the designing strategies for the innovation of nanotheranostic to cure cognitive disorders can accomplish in nanotherapy. Therefore, the need to highlight and outline the effectiveness of nanotechnology-enabled procedures and techniques 122 (electrophysiology and intracellular sampling) to understand the brain and its components are there 123 . Implementing nanotheranostics techniques to interrupt the brain, explore breakthroughs to get single-cell resolution, for better diagnosis, and monitoring of neurological diseases.…”

Section: Dysfunction Of Neuronal Network In Brain Functionmentioning

confidence: 99%

Review of nanotheranostics for molecular mechanisms underlying psychiatric disorders and commensurate nanotherapeutics for neuropsychiatry: The mind knockout

Kumar¹,

Chhikara²,

Gulia³

et al. 2021

Nanotheranostics

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Bio-neuronal led psychiatric abnormalities transpired by the loss of neuronal structure and function (neurodegeneration), pro-inflammatory cytokines, microglial dysfunction, altered neurotransmission, toxicants, serotonin deficiency, kynurenine pathway, and excessively produced neurotoxic substances. These uncontrolled happenings in the etiology of psychiatric disorders initiate further changes in neurotransmitter metabolism, pathologic microglial, cell activation, and impaired neuroplasticity. Inflammatory cytokines, the outcome of dysfunctional mitochondria, dysregulation of the immune system, and under stress functions of the brain are leading biochemical factors for depression and anxiety. Nanoscale drug delivery platforms, inexpensive diagnostics using nanomaterials, nano-scale imaging technologies, and ligand-conjugated nanocrystals used for elucidating the molecular mechanisms and foremost cellular communications liable for such disorders are highly capable features to study for efficient diagnosis and therapy of the mental illness. These theranostic tools made up of multifunctional nanomaterials have the potential for effective and accurate diagnosis, imaging of psychiatric disorders, and are at the forefront of leading technologies in nanotheranostics openings field as they can collectively and efficiently target the stimulated territories of the cerebellum (cells and tissues) through molecular-scale interactions with higher bioavailability, and bio-accessibility. Specifically, the nanoplatforms based neurological changes are playing a significant role in the diagnosis of psychiatric disorders and portraying the routes of functional restoration of mental disorders by newer imaging tools at nano-level in all directions. Because of these nanotherapeutic platforms, the molecules of nanomedicine can penetrate the Blood-Brain Barrier with an increased half-life of drug molecules. The discoveries in nanotheranostics and nanotherapeutics inbuilt unique multi-functionalities are providing the best multiplicities of novel nanotherapeutic potentialities with no toxicity concerns at the level of nano range.

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Leveraging the interplay of nanotechnology and neuroscience: Designing new avenues for treating central nervous system disorders

Cited by 33 publications

References 236 publications

Nanoparticle‐microglial interaction in the ischemic brain is modulated by injury duration and treatment

Nanoparticle‐microglial interaction in the ischemic brain is modulated by injury duration and treatment

Neuroprotective effects of a dendrimer-based glutamate carboxypeptidase inhibitor on superoxide dismutase transgenic mice after neonatal hypoxic-ischemic brain injury

Review of nanotheranostics for molecular mechanisms underlying psychiatric disorders and commensurate nanotherapeutics for neuropsychiatry: The mind knockout

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