Transcytosis to Cross the Blood Brain Barrier, New Advancements and Challenges

Pulgar, Víctor M.

doi:10.3389/fnins.2018.01019

Cited by 325 publications

(254 citation statements)

References 104 publications

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“…This natural strategy exploits the various transporters and receptors expressed at the BBB, as well as the physiological properties of the BBB (e.g., charge and lipid composition) ( Figure 2) [41][42][43]. These translocation mechanisms are fundamental for the uptake of essential substances to maintain brain homeostasis.…”

Section: Physiological Approachmentioning

confidence: 99%

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Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

et al. 2020

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The incidence of brain metastases (BM) in cancer patients is increasing. After diagnosis, overall survival (OS) is poor, elicited by the lack of an effective treatment. Monoclonal antibody (mAb)-based therapy has achieved remarkable success in treating both hematologic and non-central-nervous system (CNS) tumors due to their inherent targeting specificity. However, the use of mAbs in the treatment of CNS tumors is restricted by the blood–brain barrier (BBB) that hinders the delivery of either small-molecules drugs (sMDs) or therapeutic proteins (TPs). To overcome this limitation, active research is focused on the development of strategies to deliver TPs and increase their concentration in the brain. Yet, their molecular weight and hydrophilic nature turn this task into a challenge. The use of BBB peptide shuttles is an elegant strategy. They explore either receptor-mediated transcytosis (RMT) or adsorptive-mediated transcytosis (AMT) to cross the BBB. The latter is preferable since it avoids enzymatic degradation, receptor saturation, and competition with natural receptor substrates, which reduces adverse events. Therefore, the combination of mAbs properties (e.g., selectivity and long half-life) with BBB peptide shuttles (e.g., BBB translocation and delivery into the brain) turns the therapeutic conjugate in a valid approach to safely overcome the BBB and efficiently eliminate metastatic brain cells.

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Section: Physiological Approachmentioning

confidence: 99%

“…Another interesting strategy to deliver drugs into the brain exploiting RMT is the use of nanoparticles (NPs) coupled with mAbs or peptides that recognize these receptors [43,56,57]. NPs are colloidal carriers of natural or synthetic origin with a size varying from 1 to 1000 nm.…”

Section: Physiological Approachmentioning

confidence: 99%

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

et al. 2020

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“…For further reading on these and other potential ligands, please refer to the review by Lajoie et al [194]. This described mechanism seems to be one of the most secure and most efficient methods of targeting drugs to the CNS, and it is perceived to be one of the strategies most likely to succeed [197], as demonstrated in previous sections. Also, the BBB carrier-mediated transporters control the changes of small hydrophilic molecules induced by the linkage to the respective ligands, such as the glucose transporter GLUT1 and the amino acid carrier LAT1 [185,194].…”

Section: Blood-brain Barriermentioning

confidence: 84%

Breaking Barriers: Bioinspired Strategies for Targeted Neuronal Delivery to the Central Nervous System

et al. 2020

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Central nervous system (CNS) disorders encompass a vast spectrum of pathological conditions and represent a growing concern worldwide. Despite the high social and clinical interest in trying to solve these pathologies, there are many challenges to bridge in order to achieve an effective therapy. One of the main obstacles to advancements in this field that has hampered many of the therapeutic strategies proposed to date is the presence of the CNS barriers that restrict the access to the brain. However, adequate brain biodistribution and neuronal cells specific accumulation in the targeted site also represent major hurdles to the attainment of a successful CNS treatment. Over the last few years, nanotechnology has taken a step forward towards the development of therapeutics in neurologic diseases and different approaches have been developed to surpass these obstacles. The versatility of the designed nanocarriers in terms of physical and chemical properties, and the possibility to functionalize them with specific moieties, have resulted in improved neurotargeted delivery profiles. With the concomitant progress in biology research, many of these strategies have been inspired by nature and have taken advantage of physiological processes to achieve brain delivery. Here, the different nanosystems and targeting moieties used to achieve a neuronal delivery reported in the open literature are comprehensively reviewed and critically discussed, with emphasis on the most recent bioinspired advances in the field. Finally, we express our view on the paramount challenges in targeted neuronal delivery that need to be overcome for these promising therapeutics to move from the bench to the bedside.

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“…A general issue for new single-or multi-modal imaging probes that target the brain and that have to be taken into account is the permeability of the blood-brain barrier, a complex multicellular structure that protect CNS by external neurotoxic substances and which functions are assured also by astrocytic endfeet (Poupot et al, 2018). A possible solution is represented by the use of physiological transfer existing across the barrier, like the use of specific carriers or the transcytosis phenomenon (Pulgar, 2019).…”

Section: Bimodal Probes As Future Perspectivesmentioning

confidence: 99%

Gliosis and Neurodegenerative Diseases: The Role of PET and MR Imaging

Cavaliere

Tramontano

Fiorenza

et al. 2020

Front. Cell. Neurosci.

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Glial activation characterizes most neurodegenerative and psychiatric diseases, often anticipating clinical manifestations and macroscopical brain alterations. Although imaging techniques have improved diagnostic accuracy in many neurological conditions, often supporting diagnosis, prognosis prediction and treatment outcome, very few molecular imaging probes, specifically focused on microglial and astrocytic activation, have been translated to a clinical setting. In this context, hybrid positron emission tomography (PET)/magnetic resonance (MR) scanners represent the most advanced tool for molecular imaging, combining the functional specificity of PET radiotracers (e.g., targeting metabolism, hypoxia, and inflammation) to both high-resolution and multiparametric information derived by MR in a single imaging acquisition session. This simultaneity of findings achievable by PET/MR, if useful for reciprocal technical adjustments regarding temporal and spatial cross-modal alignment/synchronization, opens still debated issues about its clinical value in neurological patients, possibly incompliant and highly variable from a clinical point of view. While several preclinical and clinical studies have investigated the sensitivity of PET tracers to track microglial (mainly TSPO ligands) and astrocytic (mainly MAOB ligands) activation, less studies have focused on MR specificity to this topic (e.g., through the assessment of diffusion properties and T2 relaxometry), and only few exploiting the integration of simultaneous hybrid acquisition. This review aims at summarizing and critically review the current state about PET and MR imaging for glial targets, as well as the potential added value of hybrid scanners for characterizing microglial and astrocytic activation.

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Transcytosis to Cross the Blood Brain Barrier, New Advancements and Challenges

Cited by 325 publications

References 104 publications

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

Breaking Barriers: Bioinspired Strategies for Targeted Neuronal Delivery to the Central Nervous System

Gliosis and Neurodegenerative Diseases: The Role of PET and MR Imaging

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