The Trigeminal Pathway Dominates the Nose-to-Brain Transportation of Intact Polymeric Nanoparticles: Evidence from Aggregation-Caused Quenching Probes

Li, Ye; Wang, Chunliu; Zong, Shiyu; Qi, Jianping; Dong, Xiaochun; Zhao, Weili; Wu, Wei; Fu, Qiang; Lü, Yi; Chen, Zhongjian

doi:10.1166/jbn.2019.2724

Cited by 43 publications

(29 citation statements)

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“…Subsequent analyses, elaborated here, reveal that trace element contaminants of AP may be a likely source of its neurotoxic consequences, based on the presence of known elemental neurotoxicants in the exposures and in excess in brain following such exposures. The increases in these elements, which can be taken up into brain from bloodstream but also via the olfactory and trigeminal nerves, 66 -68 moreover, suggest specific mechanisms of CAP-induced neurotoxicity via ferroptosis, as schematized in Figure 1, and their actions in brain would be likely to influence pathways consistent with reported biomarkers of neurodevelopmental disorders. 69 -75 In addition, data across different exposures were utilized to determine preliminary concentration–effect functions for various outcomes where available.…”

Section: Introductionmentioning

confidence: 70%

“…In addition, sensory nerves in the upper and lower respiratory tract can translocate particles 128 that reach for example, the trigeminal ganglion or the vagal nerve. 66,68,129,130 As Fe regulatory proteins 1 and 2, and Fe transporters such as the transferrin receptor and divalent metal transporter-1, critical to tight brain regulation of Fe levels, are not fully expressed until PNDs 15 to 20 in rodents, 131,132 an extended window is open during which excess Fe or S can reach and directly influence brain development. Similarly, homeostatic regulation of Fe absorption appears in human infants at about 6 to 9 months of age.…”

Section: Discussionmentioning

confidence: 99%

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The Impact of Inhaled Ambient Ultrafine Particulate Matter on Developing Brain: Potential Importance of Elemental Contaminants

et al. 2019

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Epidemiological studies report associations between air pollution (AP) exposures and several neurodevelopmental disorders including autism, attention deficit disorder, and cognitive delays. Our studies in mice of postnatal (human third trimester brain equivalent) exposures to concentrated ambient ultrafine particles (CAPs) provide biological plausibility for these associations, producing numerous neuropathological and behavioral features of these disorders, including male-biased vulnerability. These findings raise questions about the specific components of AP that underlie its neurotoxicity, which our studies suggest could involve trace elements as candidate neurotoxicants. X-ray fluorescence analyses of CAP chamber filters confirm contamination of AP exposures by multiple elements, including iron (Fe) and sulfur (S). Correspondingly, laser ablation inductively coupled plasma mass spectrometry of brains of male mice indicates marked postexposure elevations of Fe and S and other elements. Elevations of brain Fe and S in particular are consistent with potential ferroptotic, oxidative stress, and altered antioxidant capacity-based mechanisms of CAPs-induced neurotoxicity, supported by observations of increased serum oxidized glutathione and increased neuronal cell death in nucleus accumbens with no corresponding significant increase in caspase-3, in male brains following postnatal CAP exposures. Understanding the role of trace element contaminants of particulate matter AP as a source of neurotoxicity is critical for public health protection.

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Section: Introductionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

The Impact of Inhaled Ambient Ultrafine Particulate Matter on Developing Brain: Potential Importance of Elemental Contaminants

et al. 2019

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“…There has been some evidence to suggest intact nanocarriers have capacity to transport along an intact trigeminal nerve. In a recent study, Li and colleagues utilized aggregation-caused quenching probes to track the in vivo fate of PCL nanoparticles, and reporting slow transport of intact nanoparticles along the trigeminal nerve to the brain stem, but not along the olfactory nerve [45]. Ahmed and collegaues also detected some presence of 100nm vehicle in the trigeminal nerve, though model cargoes DiR and C6 were ultimately delivered to the brain in free form [46].…”

Section: Discussionmentioning

confidence: 99%

Targeting Small Molecule Delivery to the Brain and Spinal Cord via Intranasal Administration of Rabies Virus Glycoprotein (RVG29)-Modified PLGA Nanoparticles

et al. 2020

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Alternative routes of administration are one approach that could be used to bypass the blood–brain barrier (BBB) for effective drug delivery to the central nervous system (CNS). Here, we focused on intranasal delivery of polymer nanoparticles. We hypothesized that surface modification of poly(lactic-co-glycolic acid) (PLGA) nanoparticles with rabies virus glycoprotein (RVG29) would increase residence time and exposure of encapsulated payload to the CNS compared to non-targeted nanoparticles. Delivery kinetics and biodistribution were analyzed by administering nanoparticles loaded with the carbocyanine dye 1,1′-Dioctadecyl-3,3,3′,3′-Tetramethylindotricarbocyanine Iodide (DiR) to healthy mice. Intranasal administration yielded minimal exposure of nanoparticle payload to most peripheral organs and rapid, effective delivery to whole brain. Regional analysis of payload delivery within the CNS revealed higher delivery to tissues closest to the trigeminal nerve, including the olfactory bulb, striatum, midbrain, brainstem, and cervical spinal cord. RVG29 surface modifications presented modest targeting benefits to the striatum, midbrain, and brainstem 2 h after administration, although targeting was not observed 30 min or 6 h after administration. Payload delivery to the trigeminal nerve was 3.5× higher for targeted nanoparticles compared to control nanoparticles 2 h after nanoparticle administration. These data support a nose-to-brain mechanism of drug delivery that closely implicates the trigeminal nerve for payload delivery from nanoparticles via transport of intact nanoparticles and eventual diffusion of payload. Olfactory and CSF routes are also observed to play a role. These data advance the utility of targeted nanoparticles for nose-to-brain drug delivery of lipophilic payloads and provide mechanistic insight to engineer effective delivery vectors to treat disease in the CNS.

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“…Therefore, the trigeminal nerve could provide an effective pathway for the nose-to-brain transport of intact NPs. [230] An in situ gel formulation for the intranasal delivery of tacrine (THA) in adult male SD rats as an animal model was reported by Qian and co-workers. [231] For this purpose, the thermosensitive Figure 5.…”

Section: Peg-coated Nanoparticlesmentioning

confidence: 99%

“…Therefore, the trigeminal nerve could provide an effective pathway for the nose‐to‐brain transport of intact NPs. [ 230 ]…”

Section: Use Of Polymeric Nanocarriers For Ad Drug Delivery Via the Nmentioning

confidence: 99%

Polymeric Nanoparticles for Nasal Drug Delivery to the Brain: Relevance to Alzheimer's Disease

Rabiee

Ahmadi

Afshari

et al. 2020

Advanced Therapeutics

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Currently, Alzheimer's disease (AD) accounts for more than half of all dementia cases. Although genetics, age, and environmental factors affect the disease, the cause of AD is not yet fully known. Various drugs have been proposed for the prevention and treatment of AD, but the delivery of these therapeutic agents to the brain is difficult. The blood-brain barrier prevents systemic drugs from accessing the central nervous system and designing a suitable system to overcome this barrier has attracted much attention. The intranasal pathway, given its proximity to the brain, provides a great opportunity for drug delivery. Understanding the physiological characteristics of the nose can be useful in selecting the appropriate carrier and material. Some of the emerging vehicles used for nose-to-brain delivery of anti-AD drugs are natural (such as chitosan) and polymeric (such as poly(lactic-co-glycolic acid) and polyethylene glycol) nanoparticles (NPs). This review discusses the hypotheses for AD pathogenesis and highlights recent advances in the applications of natural and polymeric NPs for treatment. The fundamental and applied aspects of this approach for nasal drug delivery to the brain are reviewed here with thoughts on what is needed for the field to mature also provided.

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The Trigeminal Pathway Dominates the Nose-to-Brain Transportation of Intact Polymeric Nanoparticles: Evidence from Aggregation-Caused Quenching Probes

Cited by 43 publications

References 0 publications

The Impact of Inhaled Ambient Ultrafine Particulate Matter on Developing Brain: Potential Importance of Elemental Contaminants

The Impact of Inhaled Ambient Ultrafine Particulate Matter on Developing Brain: Potential Importance of Elemental Contaminants

Targeting Small Molecule Delivery to the Brain and Spinal Cord via Intranasal Administration of Rabies Virus Glycoprotein (RVG29)-Modified PLGA Nanoparticles

Polymeric Nanoparticles for Nasal Drug Delivery to the Brain: Relevance to Alzheimer's Disease

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