The Effect of Nanoparticle Size on the Ability to Cross the Blood–Brain Barrier: An
            <i>In Vivo</i>
            Study

Betzer, Oshra; Shilo, Malka; Opochinsky, Renana; Barnoy, Eran; Motiei, Menachem; Okun, Eitan; Yadid, Gal; Popovtzer, Rachela

doi:10.2217/nnm-2017-0022

Cited by 237 publications

(157 citation statements)

References 52 publications

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“…These transport data are in qualitative agreement with transport of silica nanoparticles through a static coculture rat BBB model, which showed that 100 nm spherical particles crossed more than 400 nm spherical particles, although transport for intermediate sizes was not reported . Literature data on the dependence of nanoparticle accumulation in the brain in vivo do not have sufficient granularity to quantitatively distinguish between endothelial accumulation and transport into the parenchyma . Further, these in vivo nanoparticle accumulation data are confounded by size‐dependent persistence of nanoparticles in the blood.…”

Section: Resultssupporting

confidence: 64%

Size, shape, and flexibility influence nanoparticle transport across brain endothelium under flow

Nowak

Brown

Graham

et al. 2019

Bioengineering & Transla Med

136

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Nanoparticle-based therapeutic formulations are being increasingly explored for the treatment of various ailments. Despite numerous advances, the success of nanoparticle-based technologies in treating brain diseases has been limited. Translational hurdles of nanoparticle therapies are attributed primarily to their limited ability to cross the blood-brain barrier (BBB), which is one of the body's most exclusive barriers. Several efforts have been focused on developing affinity-based agents and using them to increase nanoparticle accumulation at the brain endothelium. Very little is known about the role of fundamental physical parameters of nanoparticles such as size, shape, and flexibility in determining their interactions with and penetration across the BBB. Using a three-dimensional human BBB microfluidic model (μHuB), we investigate the impact of these physical parameters on nanoparticle penetration across the BBB. To gain insights into the dependence of transport on nanoparticle properties, two separate parameters were measured: the number of nanoparticles that fully cross the BBB and the number that remain associated with the endothelium. Association of nanoparticles with the brain endothelium was substantially impacted by their physical characteristics. Hard particles associate more with the endothelium compared to soft particles, as do small particles compared to large particles, and spherical particles compared to rod-shaped particles. Transport across the BBB also exhibited a dependence on nanoparticle properties. A nonmonotonic dependence on size was observed, where 200 nm particles exhibited higher BBB transport compared to 100 and 500 nm spheres. Rod-shaped particles exhibited higher BBB transport when normalized by endothelial association and soft particles exhibited comparable transport to hard particles when normalized by endothelial association. Tuning nanoparticles' physical parameters could potentially enhance their ability to cross the BBB for therapeutic applications. K E Y W O R D S

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Section: Resultssupporting

confidence: 64%

Size, shape, and flexibility influence nanoparticle transport across brain endothelium under flow

Nowak

Brown

Graham

et al. 2019

Bioengineering & Transla Med

136

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“…The optimal size of a NP also depends on the specific location and type of targeted tissue [70], for example, most tumors have a vascular pore cutoff size between 380 and 780 nm [71]. However, Kang et al have shown that for a gold NP has to be around 10 to 20 nm in diameter to effectively cross the BBB, while particles around 50 and 100 nm diameter were not distributed well enough into the brain [72,73]. nanospheres and nanorods [110].…”

Section: Nanocarriers Nanoparticles and Vectorsmentioning

confidence: 99%

Overcoming the Blood–Brain Barrier. Challenges and Tricks for CNS Drug Delivery

2019

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Treatment of certain central nervous system disorders, including different types of cerebral malignancies, is limited by traditional oral or systemic administrations of therapeutic drugs due to possible serious side effects and/or lack of the brain penetration and, therefore, the efficacy of the drugs is diminished. During the last decade, several new technologies were developed to overcome barrier properties of cerebral capillaries. This review gives a short overview of the structural elements and anatomical features of the blood–brain barrier. The various in vitro (static and dynamic), in vivo (microdialysis), and in situ (brain perfusion) blood–brain barrier models are also presented. The drug formulations and administration options to deliver molecules effectively to the central nervous system (CNS) are presented. Nanocarriers, nanoparticles (lipid, polymeric, magnetic, gold, and carbon based nanoparticles, dendrimers, etc.), viral and peptid vectors and shuttles, sonoporation and microbubbles are briefly shown. The modulation of receptors and efflux transporters in the cell membrane can also be an effective approach to enhance brain exposure to therapeutic compounds. Intranasal administration is a noninvasive delivery route to bypass the blood–brain barrier, while direct brain administration is an invasive mode to target the brain region with therapeutic drug concentrations locally. Nowadays, both technological and mechanistic tools are available to assist in overcoming the blood–brain barrier. With these techniques more effective and even safer drugs can be developed for the treatment of devastating brain disorders.

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“…Ultrafine particles are expected to be deposited in the deepest part of the respiratory tract (Chow and Watson 2007;Hinds 1999). The smallest nanoparticles (<50 nm) can even cross the blood-brain barrier (Betzer et al 2017;Oberdorster et al 2004). To compare the potential health impact of ultrafine particles measured for hookah and cigarette mainstream smoke inhaled into the respiratory tract, the particle concentration for different size ranges was determined.…”

Section: Size Distribution Of Particles In Mainstream Smokementioning

confidence: 99%

Chemical characterization of nanoparticles and volatiles present in mainstream hookah smoke

Perraud

Lawler

Malecha

et al. 2019

Aerosol Science and Technology

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Waterpipe smoking is becoming more popular worldwide and there is a pressing need to better characterize the exposure of smokers to chemical compounds present in the mainstream smoke. We report real-time measurements of mainstream smoke for carbon monoxide, volatile organic compounds and nanoparticle size distribution and chemical composition using a custom dilution flow tube. A conventional tobacco mixture, a dark leaf unwashed tobacco, and a nicotine-free herbal tobacco were studied. Results show that carbon monoxide is present in the mainstream smoke and originates primarily from the charcoal used to heat the tobacco. Online measurements of volatile organic compounds in mainstream smoke showed an overwhelming contribution from glycerol and its decomposition products. Gas phase analysis also showed that very little filtration of the gas phase products is provided by the percolation of mainstream smoke through water. Waterpipe smoking generated high concentrations of 4-100 nm nanoparticles, which were mainly composed of sugar derivatives and especially abundant in the first 10 min of the smoking session. These measured emissions of volatiles and particles are compared with those from a reference cigarette (3R4F) and represent the equivalent of the emission of one or more entire cigarettes for a single puff of hookah smoke. Considerations related to the health impacts of waterpipe smoking are discussed.

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The Effect of Nanoparticle Size on the Ability to Cross the Blood–Brain Barrier: An In Vivo Study

Abstract: These findings promote the optimization of nanovehicles for transport of drugs through the BBB. The insulin coating of the particles enabled targeting of specific brain regions, suggesting the potential use of INS-GNPs for delivery of various treatments for brain-related disorders.

Cited by 237 publications

References 52 publications

Size, shape, and flexibility influence nanoparticle transport across brain endothelium under flow

Size, shape, and flexibility influence nanoparticle transport across brain endothelium under flow

Overcoming the Blood–Brain Barrier. Challenges and Tricks for CNS Drug Delivery

Chemical characterization of nanoparticles and volatiles present in mainstream hookah smoke

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