Strategies to enhance the distribution of nanotherapeutics in the brain

Zhang, Clark; Mastorakos, Panagiotis; Sobral, Miguel C.; Berry, Sneha; Song, Eric; Nance, Elizabeth; Eberhart, Charles G.; Suk, Jung Soo

doi:10.1016/j.jconrel.2017.07.028

Cited by 25 publications

(30 citation statements)

References 51 publications

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“…26 13,70,71 Nanoparticle diffusive ability also plays a role in reaching target microglial cells and in achieving maximal therapeutic impact. 72,73 As evidenced by the MPT results after OGD, PS-PEG nanoparticles exhibited more than 16-fold higher diffusive ability compared to the NC condition. In this study, we directly confirmed diffusivity of PS-PEG, but PEGylated QDs and PAMAM dendrimers have also been shown to move effectively within the brain parenchyma.…”

Section: Discussionmentioning

confidence: 94%

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: 94%

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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“…Therefore, more BSA/Mal‐SPIONs would stay in the extracellular circulation system and diffuse to other brain areas through the perivascular flow pathway. Because of their decreased nonspecific cell internalization, BSA/Mal‐SPIONs are more likely to be removed by the efflux pump that exists in blood‐brain barrier (BBB) (Jia et al, ) to maintain and regulate the homeostatic balance in the brain (Iliff et al, ; Zhang et al, ). On the other hand, albumin that is not naturally found in brain parenchyma has been reported to induce immunoreactivity in the brain (Kozai, Jaquins‐Gerstl, Vazquez, Michael, & Cui, ), and some BSA/Mal‐SPIONs are found in glial cells in the present work.…”

Section: Discussionmentioning

confidence: 99%

Subcellular distributions of iron oxide nanoparticles in rat brains affected by different surface modifications

Wang

Zhang

et al. 2019

J Biomedical Materials Res

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The impact of the surface modification on the subcellular distribution of nanoparticles in the brain remains elusive. The nanoparticles prepared by conjugating polyethylene glycol and maleic anhydride‐coated superparamagnetic iron oxide nanoparticles (Mal‐SPIONs) with bovine serum albumin (BSA/Mal‐SPIONs) and with Arg–Gly–Asp peptide (RGD/Mal‐SPIONs) were injected into the rat substantia nigra. Observation of transmission electron microscopy (TEM) samples obtained 24 h after perfusion showed that abundant RGD/Mal‐SPIONs accumulated in the myelin sheath, dendrites, axon terminals and mitochondria, and on cell membranes in the brain tissue near the injection site. For rats injected with BSA/Mal‐SPIONs, a few nanoparticles accumulated in the myelin sheath, axon terminals, endoplasmic reticulum, mitochondria, Golgi, and lysosomes of neurons and glial cells while least SPIONs in rats injected with Mal‐SPIONs were found. TEM pictures showed some Mal‐SPIONs were expelled out of the brain. RGD/Mal‐SPIONs diffused extensively to the thalamus, frontal cortex, temporal lobe, olfactory bulb, and brain stem after injection. Only a few BSA/Mal‐SPIONs diffused to the afore‐mentioned brain areas. This work reveals different surface modifications on the iron oxide nanoparticles play crucial roles in their distribution and diffusion in the rat brains.

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“…hydrophobic and negatively charged) and steric diffusional barrier, and established design criteria for engineering nanoparticle-based therapeutic delivery systems that can efficiently spread through the ECM [5][6][7]. Specifically, we found that nanoparticles with diameters small enough (≤ ~110 nm) to fit through the ECM pores while possessing non-adhesive dense surface polyethylene glycol (PEG) coatings rapidly penetrated rodent and human brain tissues [5,[8][9][10].…”

Section: Introductionmentioning

confidence: 97%

Widespread gene transfer to malignant gliomas with In vitro-to-In vivo correlation

Negron

Khalasawi

et al. 2019

Journal of Controlled Release

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Gene therapy of malignant gliomas has shown a lack of clinical success to date due in part to inability of conventional gene vectors to achieve widespread gene transfer throughout highly disseminated tumor areas within the brain. Here, we demonstrate that newly engineered polymerbased DNA-loaded nanoparticles (DNA-NP) possessing small particle diameters (~50 nm) and non-adhesive surface polyethylene glycol (PEG) coatings efficiently penetrate brain tumor tissue as well as healthy brain parenchyma. Specifically, this brain-penetrating nanoparticle (BPN), following intracranial administration via convection enhanced delivery (CED), provides widespread transgene expression in heathy rodent striatum and an aggressive brain tumor tissue established orthotopically in rats. The ability of BPN to efficiently traverse both tissues is of great

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Strategies to enhance the distribution of nanotherapeutics in the brain

Cited by 25 publications

References 51 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

Subcellular distributions of iron oxide nanoparticles in rat brains affected by different surface modifications

Widespread gene transfer to malignant gliomas with In vitro-to-In vivo correlation

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