Monocyte Trafficking, Engraftment, and Delivery of Nanoparticles and an Exogenous Gene into the Acutely Inflamed Brain Tissue – Evaluations on Monocyte-Based Delivery System for the Central Nervous System

Tong, Hsin-I; Wen, Kai; Davy, Philip; Shi, Yunfan; Sun, Si; Allsopp, Richard; Lu, Yuanan

doi:10.1371/journal.pone.0154022

Cited by 50 publications

(28 citation statements)

References 38 publications

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“…The BBB is notoriously difficult to cross; the microvascular endothelial cells that form the neurovascular unit are characterized by several restrictive features, including the expression of tight junction complexes, a lack of fenestrations, and low pinocytic activity . As a result, there has been significant research into methods for improving nanoparticle transport through the BBB, using ideas ranging from physically disrupting the endothelium using ultrasound combined with microbubbles, to coating nanoparticles with ligands that enhance transcytosis, to using live cells as delivery vehicles . While there has been some investigation into how nanoparticle properties modulate transport into the brain, overall very little is known about how these differences affect their biological performance.…”

Section: Introductionmentioning

confidence: 99%

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

Nowak

Brown

Graham

et al. 2019

Bioengineering & Transla Med

137

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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: Introductionmentioning

confidence: 99%

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

Nowak

Brown

Graham

et al. 2019

Bioengineering & Transla Med

137

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“…In the present study we showed that some homing genes were downregulated by Dex microparticle treatment while others were upregulated, but these results are likely confounded by the fact that we analyzed the cells after their differentiation into macrophages, which is known to inhibit homing capacity relative to monocytes 62 .…”

Section: Discussionmentioning

confidence: 64%

“…Moreover, we chose dexamethasone for proof of concept, but a drug that promotes a more regenerative macrophage phenotype would be a better choice for studying therapeutic efficacy. Finally, within this paper we have not characterized the effect of microparticle-loading on the homing capacity of monocytes, although other groups have completed similar characterizations 52,53,62 , but this will be important if monocytes are to be administered systemically.…”

Section: Discussionmentioning

confidence: 99%

Non-Genetic Reprogramming of Monocytes via Microparticle Phagocytosis for Sustained Modulation of Macrophage Phenotype

Wofford

Singh

Cullen

et al. 2019

Preprint

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Monocyte-derived macrophages orchestrate tissue regeneration by homing to sites of injury, phagocytosing pathological debris, and stimulating other cell types to repair the tissue. Accordingly, monocytes have been investigated as a translational and potent source for cell therapy, but their utility has been hampered by their rapid acquisition of a pro-inflammatory phenotype in response to the inflammatory injury microenvironment. To overcome this problem, we designed a cell therapy strategy where we collect and exogenously reprogram monocytes by intracellularly loading the cells with biodegradable microparticles containing an anti-inflammatory drug in order to modulate and maintain an anti-inflammatory phenotype over time. To test this concept, poly(lactic-co-glycolic) acid microparticles were loaded with the anti-inflammatory drug dexamethasone (Dex) and administered to primary human monocytes for four hours to facilitate phagocytic uptake. After removal of non-phagocytosed microparticles, microparticle-loaded monocytes differentiated into macrophages and stored the microparticles intracellularly for several weeks in vitro, releasing drug into the extracellular environment over time. Cells loaded with intracellular Dex microparticles showed decreased expression and secretion of inflammatory factors even in the presence of pro-inflammatory stimuli up to 7 days after microparticle uptake compared to untreated cells or cells loaded with blank microparticles. This study represents a new strategy for long-term maintenance of anti-inflammatory macrophage phenotype using a translational monocyte-based cell therapy strategy without the use of genetic modification. Because of the ubiquitous nature of monocytederived macrophage involvement in pathology and regeneration, this strategy holds potential as a treatment for a vast number of diseases and disorders. RESULTS Microparticle Characteristics and Intracellular StabilityPoly(lactic-co-glycolic) acid (PLGA) microparticles were fabricated with dexamethasone (Dex) or with tetramethylrhodamine (TRITC) as a fluorescent model drug. Microparticles ranged in diameter from 0.98 to 2.05 µm with polydispersity indices between 0.08 and 0.28 ( Fig. 2A).Microparticles were administered to primary human monocytes for 4 hours followed by removal of non-phagocytosed microparticles. Thereafter, monocytes were cultured in macrophage colony stimulating factor (MCSF)-containing media to induce differentiation into macrophages and were imaged at regular intervals (Fig. 2B). Cell area increased over time for both untreated and microparticle-loaded cells, indicating that that monocyte-to-macrophage differentiation was not hindered by intracellular microparticle loading (Fig. 2C). Intracellular fluorescent microparticles were detected for up to 16 days in vitro (detection and quantification methods outlined in Sup. Fig. 1). Interestingly, the number of microparticles ( Fig. 2D) and their intensity per cell ( Fig. 2E) increased in the first three days, which may be due to cell death, phagocytosi...

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“…The study shows good permeation behavior. 25,26 Some other similar studies also demonstrated the application of monocytes for drug cargo to the brain. Although, cell-mediated transport has major disadvantages like early release of the freight, failure to reach the particular site of action and poor drug loading ability.…”

Section: Adsorptive Mediated Transcytosis (Amt)mentioning

confidence: 86%

<p>Recent expansions of novel strategies towards the drug targeting into the brain</p>

Alexander¹,

Agrawal²,

Uddin³

et al. 2019

IJN

124

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The treatment of central nervous system (CNS) disorders always remains a challenge for the researchers. The presence of various physiological barriers, primarily the blood–brain barrier (BBB) limits the accessibility of the brain and hinders the efficacy of various drug therapies. Hence, drug targeting to the brain, particularly to the diseased cells by circumventing the physiological barriers is essential to develop a promising therapy for the treatment of brain disorders. Presently, the investigations emphasize the role of different nanocarrier systems or surface modified target specific novel carrier system to improve the efficiency and reduce the side effects of the brain therapeutics. Such approaches supposed to circumvent the BBB or have the ability to cross the barrier function and thus increases the drug concentration in the brain. Although the efficacy of novel carrier system depends upon various physiological factors like active efflux transport, protein corona of the brain, stability, and toxicity of the nanocarrier, physicochemical properties, patient-related factors and many more. Hence, to develop a promising carrier system, it is essential to understand the physiology of the brain and BBB and also the other associated factors. Along with this, some alternative route like direct nose-to-brain drug delivery can also offer a better means to access the brain without exposure of the BBB. In this review, we have discussed the role of various physiological barriers including the BBB and blood-cerebrospinal fluid barrier (BCSFB) on the drug therapy and the mechanism of drug transport across the BBB. Further, we discussed different novel strategies for brain targeting of drug including, polymeric nanoparticles, lipidic nanoparticles, inorganic nanoparticles, liposomes, nanogels, nanoemulsions, dendrimers, quantum dots, etc. along with the intranasal drug delivery to the brain. We have also illustrated various factors affecting the drug targeting efficiency of the developed novel carrier system.

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Monocyte Trafficking, Engraftment, and Delivery of Nanoparticles and an Exogenous Gene into the Acutely Inflamed Brain Tissue – Evaluations on Monocyte-Based Delivery System for the Central Nervous System

Cited by 50 publications

References 38 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

Non-Genetic Reprogramming of Monocytes via Microparticle Phagocytosis for Sustained Modulation of Macrophage Phenotype

<p>Recent expansions of novel strategies towards the drug targeting into the brain</p>

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