Delivery of Therapeutic Agents to the Central Nervous System and the Promise of Extracellular Vesicles

René, Charlotte A.; Parks, Robin J.

doi:10.3390/pharmaceutics13040492

Cited by 31 publications

(19 citation statements)

References 151 publications

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“…The BBB is a highly selective and regulated filter that controls and limits the passage of molecules from the bloodstream into the brain parenchyma and vice versa. Many drugs directed against CNS targets suffer from a very high rate of failure due to the BBB, limiting the entry of xenobiotics into the brain [139,140]. In contrast to conventional immunoglobulins, which are described as BBB impenetrable when the barrier is intact, some nanobodies can cross through the BBB or be easily modified to favor their penetration.…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Transportation of Single-Domain Antibodies through the Blood–Brain Barrier

Ruiz-López

Schuhmacher

2021

Biomolecules

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Single-domain antibodies derive from the heavy-chain-only antibodies of Camelidae (camel, dromedary, llama, alpaca, vicuñas, and guananos; i.e., nanobodies) and cartilaginous fishes (i.e., VNARs). Their small size, antigen specificity, plasticity, and potential to recognize unique conformational epitopes represent a diagnostic and therapeutic opportunity for many central nervous system (CNS) pathologies. However, the blood–brain barrier (BBB) poses a challenge for their delivery into the brain parenchyma. Nevertheless, numerous neurological diseases and brain pathologies, including cancer, result in BBB leakiness favoring single-domain antibodies uptake into the CNS. Some single-domain antibodies have been reported to naturally cross the BBB. In addition, different strategies and methods to deliver both nanobodies and VNARs into the brain parenchyma can be exploited when the BBB is intact. These include device-based and physicochemical disruption of the BBB, receptor and adsorptive-mediated transcytosis, somatic gene transfer, and the use of carriers/shuttles such as cell-penetrating peptides, liposomes, extracellular vesicles, and nanoparticles. Approaches based on single-domain antibodies are reaching the clinic for other diseases. Several tailoring methods can be followed to favor the transport of nanobodies and VNARs to the CNS, avoiding the limitations imposed by the BBB to fulfill their therapeutic, diagnostic, and theragnostic promises for the benefit of patients suffering from CNS pathologies.

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Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Transportation of Single-Domain Antibodies through the Blood–Brain Barrier

Ruiz-López

Schuhmacher

2021

Biomolecules

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“…Several EV characteristics are particularly appealing for their application as drug delivery vehicle in a broad range of CNS diseases [ 60 , 61 ]. They encompass factors such as endogenous biocompatibility, natural biological cargo protection, low immunogenicity and an ability to cross biological barriers [ 60 , 61 ], all factors that are still limiting the success of synthetic delivery systems [ 14 ]. However, the exact barrier crossing mechanisms whereby EVs can cross the brain barriers still need to be fully elucidated.…”

Section: Extracellular Vesicles As Drug Delivery Vehiclementioning

confidence: 99%

Special delEVery: Extracellular Vesicles as Promising Delivery Platform to the Brain

2021

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The treatment of central nervous system (CNS) pathologies is severely hampered by the presence of tightly regulated CNS barriers that restrict drug delivery to the brain. An increasing amount of data suggests that extracellular vesicles (EVs), i.e., membrane derived vesicles that inherently protect and transfer biological cargoes between cells, naturally cross the CNS barriers. Moreover, EVs can be engineered with targeting ligands to obtain enriched tissue targeting and delivery capacities. In this review, we provide a detailed overview of the literature describing a natural and engineered CNS targeting and therapeutic efficiency of different cell type derived EVs. Hereby, we specifically focus on peripheral administration routes in a broad range of CNS diseases. Furthermore, we underline the potential of research aimed at elucidating the vesicular transport mechanisms across the different CNS barriers. Finally, we elaborate on the practical considerations towards the application of EVs as a brain drug delivery system.

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“…There is evidence that EV transport across the BBB mainly occurs via transcellular pathways, which can be receptor-mediated transcytosis (via specific ligand–receptor binding) or adsorptive-mediated transcytosis (via nonspecific interaction with membrane cationic proteins or peptides) [ 103 ]. This provides a foundation for the concept of active targeting: to modify the nanoparticle surface to richly express certain moieties that mediate or accelerate transcytosis processes at the BBB.…”

Section: Potentials Of Msc-evs As a Cell-free Platform Of Therapeutic Delivery To The Brainmentioning

confidence: 99%

“…Non-infectious neuropathologies of the brain consist of distinct entities such as neuroinflammatory and neurodegenerative disorders, ischemic and traumatic injuries, primary and secondary neoplasms, etc. Since EVs emerged as a potential therapeutic platform in this field, many preclinical models have achieved desirable EV distributions in the brain for effective drug delivery [ 94 , 95 , 103 , 116 , 117 ]. At present, more than 200 studies involving the use of EVs or exosomes are registered on clinicaltrials.gov (accessed on 1 September 2021).…”

Section: Current Status Of Msc-ev Therapeutic Applications In the Brainmentioning

confidence: 99%

Application of Mesenchymal Stem Cells in Targeted Delivery to the Brain: Potential and Challenges of the Extracellular Vesicle-Based Approach for Brain Tumor Treatment

Duy

Kurniawati

Hsieh

et al. 2021

IJMS

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Treating brain tumors presents enormous challenges, and there are still poor prognoses in both adults and children. Application of novel targets and potential drugs is hindered by the function of the blood-brain barrier, which significantly restricts therapeutic access to the tumor. Mesenchymal stem cells (MSCs) can cross biological barriers, migrate to sites of injuries to exert many healing effects, and be engineered to incorporate different types of cargo, making them an ideal vehicle to transport anti-tumor agents to the central nervous system. Extracellular vesicles (EVs) produced by MSCs (MSC-EVs) have valuable innate properties from parent cells, and are being exploited as cell-free treatments for many neurological diseases. Compared to using MSCs, targeted delivery via MSC-EVs has a better pharmacokinetic profile, yet avoids many critical issues of cell-based systems. As the field of MSC therapeutic applications is quickly expanding, this article aims to give an overall picture for one direction of EV-based targeting of brain tumors, with updates on available techniques, outcomes of experimental models, and critical challenges of this concept.

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Delivery of Therapeutic Agents to the Central Nervous System and the Promise of Extracellular Vesicles

Cited by 31 publications

References 151 publications

Transportation of Single-Domain Antibodies through the Blood–Brain Barrier

Transportation of Single-Domain Antibodies through the Blood–Brain Barrier

Special delEVery: Extracellular Vesicles as Promising Delivery Platform to the Brain

Application of Mesenchymal Stem Cells in Targeted Delivery to the Brain: Potential and Challenges of the Extracellular Vesicle-Based Approach for Brain Tumor Treatment

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