Review of Current Strategies for Delivering Alzheimer’s Disease Drugs across the Blood-Brain Barrier

Wong, Ka Hong; Riaz, Muhammad Kashif; Xie, Yangyang; Zhang, Xue; Qiang, Liu; Chen, Huoji; Bian, Zhaoxiang; Chen, Xiaoyu; Lü, Aiping; Yang, Zhijun

doi:10.3390/ijms20020381

Cited by 161 publications

(111 citation statements)

References 143 publications

(53 reference statements)

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“…The Coulomb interactions favor the adsorption of positively charged species, for instance, arginine residues. Also of note is that due to the positively charged nature, arginine has been found to enhance the cellular uptake of peptides 18 and promote the therapeutic delivery of peptides across the blood-brain barrier for Alzheimer's disease 19 . Therefore, the observed drops in the RBD-ACE2 binding energy for mutants 1 and 2 could be primarily ascribed to a change in (long-range) Coulomb interactions between ACE2 and the spike protein (Table S2), even though the polybasic cleavage sites are around 10 nm away from the RBD and ACE2.…”

Section: Demonstrated Inmentioning

confidence: 99%

The Distal Polybasic Cleavage Sites of SARS-CoV-2 Spike Protein Enhance Spike Protein-ACE2 Binding

Qiao

Cruz

2020

Preprint

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The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein plays a crucial role in binding the human cell receptor ACE2 that is required for viral entry. Many studies have been conducted to target the structures of RBD-ACE2 binding and to design RBD-targeting vaccines and drugs. Nevertheless, mutations distal from the SARS-CoV-2 RBD also impact its transmissibility and antibody can target non-RBD regions, suggesting the incomplete role of the RBD region in the spike protein-ACE2 binding. Here, in order to elucidate distant binding mechanisms, we analyze complexes of ACE2 with the wild type spike protein and with key mutants via large-scale all-atom explicit solvent molecular dynamics simulations. We find that though distributed approximately 10 nm away from the RBD, the SARS-CoV-2 polybasic cleavage sites enhance, via electrostatic interactions and hydration, the RBD-ACE2 binding affinity. A negatively charged tetrapeptide (GluGluLeuGlu) is then designed to neutralize the positively charged arginine on the polybasic cleavage sites. We find that the tetrapeptide GluGluLeuGlu binds to one of the three polybasic cleavage sites of the SARS-CoV-2 spike protein lessening by 34% the RBD-ACE2 binding strength. This significant binding energy reduction demonstrates the feasibility to neutralize RBD-ACE2 binding by targeting this specific polybasic cleavage site. Our work enhances understanding of the binding mechanism of SARS-CoV-2 to ACE2, which may aid the design of therapeutics for COVID-19 infection. TOC:The SARS-CoV-2 spike protein-ACE2 complex showing the polybasic cleavage sites

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Section: Demonstrated Inmentioning

confidence: 99%

The Distal Polybasic Cleavage Sites of SARS-CoV-2 Spike Protein Enhance Spike Protein-ACE2 Binding

Qiao

Cruz

2020

Preprint

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“…11 NPs are employed for diverse applications, including sitespecific and targeted drug delivery in cancer, 12 as the leaky and defective architecture of tumour allows interstitial access to NPs which is popularly known as enhanced permeation and retention. 13,14 These are explored for drug delivery through different routes of administration including oral, 15 pulmonary, 16 nasal, parenteral, 17 ocular, 18 brain 19 and dermal-transdermal routes. 20,21 The reports focused on cyclodextrin (CD) which discusses its role in oral cancer therapy, 22 pharmaceutical and biomedical applications of CD-based nanogels 23 and in drug and gene delivery are available.…”

Section: Introductionmentioning

confidence: 99%

Cyclodextrin Based Nanoparticles for Drug Delivery and Theranostics

Gadade

Pekamwar

2020

Adv Pharm Bull

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Colloidal nanoparticulate technology has been described in the literature as a versatile drug delivery system. But it possesses some inherent lacunae in their formulation. Cyclodextrins (CDs) have been extensively reported for the solubility enhancement of poorly water-soluble drugs. The CDs can cause intervention in aspects related to nanoparticles (NPs) that include improving drug loading in nano-system, improving stability, site-specific/targeted drug delivery, improving solubility profile and absorption of the drug in nanosystem with consequent improvement in bioavailability, with the possibility of controlled release, safety and efficacy. They find application in for simultaneous diagnosis and therapeutics for better treatment procedures. The current communication is focused on the application of CDs to overcome troubles in nanoparticulate formulation and enhancement of their performance. It also envisages the theranostic aspects of CDs.

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“…BBB structure is not the focus of this review, hence some essential key points about this topic are given and the reader is suggested to eventually look through other papers that better present its structure, physiological, immunological and pathological characteristics and BBB overcoming strategies. 9,12,13 In summary, BBB is composed by brain microvascular endothelial cells, pericytes, astrocytes, tight junctions, neurons, and basal membrane that create a continuous barrier whose functions are the protection of the brain and the strict control of the passage of solutes. 14 Molecules that can overcome the BBB through passive diffusion should be liposoluble and generally not charged at physiological pH, should have a <500 Da molecular weight and a partition coefficient between 0.5 and 6.0.…”

Section: Blood-brain Barriermentioning

confidence: 99%

<p>Innovative Therapies and Nanomedicine Applications for the Treatment of Alzheimer’s Disease: A State-of-the-Art (2017–2020)</p>

Binda¹,

Murano²,

Rivolta³

2020

IJN

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The field of nanomedicine is constantly expanding. Since the first work dated in 1999, almost 28 thousand articles have been published, and more and more are published every year: just think that only in the last five years 20,855 have come out (source PUBMED) including original research and reviews. The goal of this review is to present the current knowledge about nanomedicine in Alzheimer's disease, a widespread neurodegenerative disorder in the over 60 population that deeply affects memory and cognition. Thus, after a brief introduction on the pathology and on the state-of-the-art research for NPs passing the BBB, special attention is placed to new targets that can enter the interest of nanoparticle designers and to new promising therapies. The authors performed a literature review limited to the last three years (2017-2020) of available studies with the intention to present only novel formulations or approaches where at least in vitro studies have been performed. This choice was made because, while limiting the sector to nanotechnology applied to Alzheimer, an organic census of all the relevant news is difficult to obtain.

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Review of Current Strategies for Delivering Alzheimer’s Disease Drugs across the Blood-Brain Barrier

Cited by 161 publications

References 143 publications

The Distal Polybasic Cleavage Sites of SARS-CoV-2 Spike Protein Enhance Spike Protein-ACE2 Binding

The Distal Polybasic Cleavage Sites of SARS-CoV-2 Spike Protein Enhance Spike Protein-ACE2 Binding

Cyclodextrin Based Nanoparticles for Drug Delivery and Theranostics

<p>Innovative Therapies and Nanomedicine Applications for the Treatment of Alzheimer’s Disease: A State-of-the-Art (2017–2020)</p>

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