Promising Approaches to Circumvent the Blood–Brain Barrier: Progress, Pitfalls and Clinical Prospects in Brain Cancer

Papademetriou, Iason T.; Porter, Tyrone M.

doi:10.4155/tde.15.48

Cited by 50 publications

(52 citation statements)

References 262 publications

(314 reference statements)

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“…The BBB restricts the delivery of therapeutics to the brain. Overall, 98% of sMDs and probably all TPs cannot cross the barrier by free diffusion [31][32][33]. In the last decade, intense investigation allowed the discovery of new strategies to increase brain penetration of existing therapeutics (invasive, pharmacological, and physiological) [34][35][36].…”

Section: Strategies To Overcome the Bbbmentioning

confidence: 99%

“…The pharmacological approach relies on the observation that some molecules freely enter the brain owing to their molecular weight (<500 Da), charge (low hydrogen bonding capabilities), and lipophilicity [40]. Thus, researchers started modifying, through medicinal chemistry, molecules that are active against CNS diseases or BM to enable them to get into the brain [31]. Although it has enormous potential, the modifications may result in loss of pharmacological activity.…”

Section: Pharmacological 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: Strategies To Overcome the Bbbmentioning

confidence: 99%

Section: Pharmacological Approachmentioning

confidence: 99%

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

et al. 2020

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“…O-linked glycosylation was shown to improve the BBB penetration of an opioid peptide as well as markedly increasing the serum and brain stability of that peptide [70,71]. In the future, BBB-penetrating glycans could be used to help target infections of the nervous system, facilitating elimination of persistent infections and improving therapeutic bioavailability [72].…”

Section: Rational Design Of Antimicrobial Peptidesmentioning

confidence: 99%

The importance of the glycosylation of antimicrobial peptides: natural and synthetic approaches

Bednarska

Wren

Willcocks

2017

Drug Discovery Today

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Glycosylation is one of the most prevalent post-translational modifications of a protein, with a defining impact on its structure and function. Many of the proteins involved in the innate or adaptive immune response, including cytokines, chemokines, and antimicrobial peptides (AMPs), are glycosylated, contributing to their myriad activities. The current availability of synthetic coupling and glycoengineering technology makes it possible to customise the most beneficial glycan modifications for improved AMP stability, microbicidal potency, pathogen specificity, tissue or cell targeting, and immunomodulation.

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“…[35] For instance, the LDL receptor family can be targeted via aprotinin, ApoE3 mimetic, angiopep-2, and p97 (melanotransferrin). [36][37][38] Angiopep-2, a 19-amino-acid peptide, is one of the promising vectors designed to target the LDLr-related protein to mediate transcytosis across the BBB. [39] Angiochem Inc., in partnership with Geron Inc., developed ANG1005 (also known as GRN 1005), an Angiopep-2-PTX conjugate for treating primary (glioblastoma) and metastatic brain tumors.…”

Section: Receptor Mediated Transcytosismentioning

confidence: 99%

Tailored nanocarriers and bioconjugates for combating glioblastoma and other brain tumors

ElAmrawy¹,

Othman²,

Adkins³

et al. 2016

JCMT

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Worldwide, the incidence of primary brain tumors is on the rise. Unfortunately, noninvasive drug therapy is hampered by poor access of most drugs to the brain due to the insurmountable blood-brain barrier (BBB). Nanotechnology holds great promise for noninvasive therapy of severe brain diseases. Furthermore, recent bioconjugation strategies have enabled the invasion of the BBB via tailored-designed bioconjugates either with targeting moieties or alterations in the physicochemical and/or the pharmacokinetic parameters of central nervous system (CNS) active pharmaceutical ingredients. Multifunctional systems and new entities are being developed to target brain cells and tumor cells to resist the progression of brain tumors. Direct conjugation of an FDA-approved drug with a targeting moiety, diagnostic moiety, or pharmacokinetic-modifying moiety represents another current approach in combating brain tumors and metastases. Finally, genetic engineering, stem cells, and vaccinations are innovative nontraditional approaches described in different patents for the management of brain tumors and metastases. This review summarizes the recent technologies and patent applications in the past five years for the noninvasive treatment of glioblastoma and other brain tumors. Till now, there has been no optimal strategy to deliver therapeutic agents to the CNS for the treatment of brain tumors and metastases. Intensive research efforts are ongoing to bring novel CNS delivery systems to potential clinical application.

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Promising Approaches to Circumvent the Blood–Brain Barrier: Progress, Pitfalls and Clinical Prospects in Brain Cancer

Cited by 50 publications

References 262 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?

The importance of the glycosylation of antimicrobial peptides: natural and synthetic approaches

Tailored nanocarriers and bioconjugates for combating glioblastoma and other brain tumors

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