Targeting the blood-brain barrier for the delivery of stroke therapies

D’Souza, Anisha A.; Dave, Kandarp M.; Stetler, R. Anne; Manickam, Devika S.

doi:10.1016/j.addr.2021.01.015

Cited by 78 publications

(46 citation statements)

References 274 publications

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“…The subtypes of EVs vary in particle diameters, among other factors, with the larger, 100-1000 nm microvesicles (MVs), and the smaller, 50 -150 nm exosomes (EXOs) being secreted via different biogenesis pathways [1,[6][7][8][12][13][14]. The lower immunogenicity of EVs, their increased stability in systemic circulation [15][16][17][18][19] and their ability to cross biological barriers make them attractive candidates for the delivery of biologics like nucleic acids and proteins [20][21][22]. Kanada et al loaded plasmid DNA [23] and minicircle DNA [24] in EVs.…”

Section: Introductionmentioning

confidence: 99%

“…Transfer of intact mitochondria via EVs to the recipient cells has been reported, especially during stress and injury [27] and the transferred mitochondria localize within the recipient's mitochondrial network [28], resulting in increased cellular ATP levels [29]. Depleted oxygen and nutrient supply decrease the overall cellular energy (ATP) levels and further generate reactive oxygen species resulting in mitochondrial dysfunction, decreased cell viability and trigger apoptotic endothelial and neuronal death during ischemic stroke [20,30].We sought to harness the innate EV mitochondrial load to increase cellular energetics in ischemic endothelial cells as a potent strategy to protect the blood-brain barrier (BBB), increase its cellular energetics and limit BBBinduced dysfunction post-stroke. We studied the effects of naïve EVs (EXOs and MVs) isolated from a brain endothelial-and macrophage cell lines on the resulting ATP levels in recipient BEC exposed to oxygen-glucose-deprived conditions, mimicking ischemic stroke-like conditions in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Microvesicles Transfer Mitochondria and Increase Mitochondrial Function in Brain Endothelial Cells

D’Souza

Burch

Dave

et al. 2021

Preprint

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Extracellular vesicles (EVs) such as exosomes (EXOs) and microvesicles (MVs) are promising carriers for the delivery of biologic drugs such as nucleic acids and proteins. We have demonstrated, for the first time, that EVs derived from hCMEC/D3: a human brain endothelial cell (BEC) line transfer polarized mitochondria to recipient BECs in culture and to neurons in mice acute brain cortical and hippocampal slices. This mitochondrial transfer increased ATP levels by 100 to 200-fold (relative to untreated cells) in the recipient BECs exposed to oxygen-glucose deprivation, an in vitro model of cerebral ischemia. Our previous studies suggested that EXOs, the smaller vesicle subpopulation, derived from a macrophage cell line (RAW264.7) load more exogenous plasmid DNA compared to the larger MVs and the RAW-derived EXOs also demonstrated greater transfection in the recipient BECs compared to EXOs derived from the homotypic hCMEC/D3 BECs. Proteomic analysis of EVs indicated that RAW-EVs are preferentially enriched with proteins that are involved in the trafficking of DNA-containing particles from the cytoplasm towards the nucleus. Intriguingly, although the heterotypic macrophage-derived EVs demonstrated increased transfection in the recipient BECs; the homotypic, BEC-derived EVs demonstrated a greater selectivity to transfer polarized mitochondria and increase endothelial cell survival under ischemic conditions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Microvesicles Transfer Mitochondria and Increase Mitochondrial Function in Brain Endothelial Cells

D’Souza

Burch

Dave

et al. 2021

Preprint

Self Cite

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“…BBB strictly limits the transcellular movement of drugs and nanoparticles from blood to brain (Gao, 2016). Macromolecules, small-molecules, proteins, antibodies, and nucleic acids are restricted by the BBB, which is a physical vascular barrier composed of brain endothelial cells, pericytes, and astrocytes, connected through tight junctions (Arvanitis et al, 2020;D'Souza et al, 2021). Changing characteristics or using delivery vehicles to breach the BBB has been considered more feasible than changing the permeability of BBB (Haumann et al, 2020).…”

Section: Bbbmentioning

confidence: 99%

“…In recent years, emerging efforts have been dedicated to developing biomimetic drug − delivery systems by using complex natural biological components or mimicking the structure (Parodi et al., 2013 ; Hu et al., 2015 ; Fang et al., 2018 ). For delivery of drugs for brain diseases therapy, biomimetic drug delivery systems may help increase biocompatibility, long − term circulation and more importantly, penetrate the BBB to increase drug concentration at the target site (Chen et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

From blood to brain: blood cell-based biomimetic drug delivery systems

Liu

et al. 2021

Drug Delivery

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Brain drug delivery remains a major difficulty for several challenges including the blood-brain barrier, lesion spot targeting, and stability during circulation. Blood cells including erythrocytes, platelets, and various subpopulations of leukocytes have distinct features such as long-circulation, natural targeting, and chemotaxis. The development of biomimetic drug delivery systems based on blood cells for brain drug delivery is growing fast by using living cells, membrane coating nanotechnology, or cell membrane-derived nanovesicles. Blood cell-based vehicles are superior delivery systems for their engineering feasibility and versatile delivery ability of chemicals, proteins, and all kinds of nanoparticles. Here, we focus on advances of blood cell-based biomimetic carriers for from blood to brain drug delivery and discuss their translational challenges in the future.

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“…The barrier is highly specialized and highly regulated to control the passage of substances between the luminal (blood-facing) side and the abluminal (brain-facing) side. BECs themselves are highly specialized, lacking fenestrations and having very low rates of transcytosis [ 7 ]. Furthermore, BECs form tight junctions utilizing occludin, claudin-5 and zonula occludens-1 (ZO-1) to prevent paracellular movement of water-soluble compounds [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Emerging Nano-Carrier Strategies for Brain Tumor Drug Delivery and Considerations for Clinical Translation

2021

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Treatment of brain tumors is challenging since the blood–brain tumor barrier prevents chemotherapy drugs from reaching the tumor site in sufficient concentrations. Nanomedicines have great potential for therapy of brain disorders but are still uncommon in clinical use despite decades of research and development. Here, we provide an update on nano-carrier strategies for improving brain drug delivery for treatment of brain tumors, focusing on liposomes, extracellular vesicles and biomimetic strategies as the most clinically feasible strategies. Finally, we describe the obstacles in translation of these technologies including pre-clinical models, analytical methods and regulatory issues.

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Targeting the blood-brain barrier for the delivery of stroke therapies

Cited by 78 publications

References 274 publications

Microvesicles Transfer Mitochondria and Increase Mitochondrial Function in Brain Endothelial Cells

Microvesicles Transfer Mitochondria and Increase Mitochondrial Function in Brain Endothelial Cells

From blood to brain: blood cell-based biomimetic drug delivery systems

Emerging Nano-Carrier Strategies for Brain Tumor Drug Delivery and Considerations for Clinical Translation

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