Neuroinflammation: A Common Pathway in CNS Diseases as Mediated at the Blood-Brain Barrier

AbstractAlthough nanomedicine have greatly developed and human life span has been extended, we have witnessed the soared incidence of central nervous system (CNS) diseases including neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease), ischemic stroke, and brain tumors, which have severely damaged the quality of life and greatly increased the economic and social burdens. Moreover, partial small molecule drugs and almost all large molecule drugs (such as recombinant protein, therapeutic antibody, and nucleic acid) cannot cross the blood–brain barrier. Therefore, it is especially important to develop a drug delivery system that can effectively deliver therapeutic drugs to the central nervous system for the treatment of central nervous system diseases. Cell penetrating peptides (CPPs) provide a potential strategy for the transport of macromolecules through the blood–brain barrier. This study analyzed and summarized the progress of CPPs in CNS diseases from three aspects: CPPs, the conjugates of CPPs and drug, and CPPs modified nanoparticles to provide scientific basis for the application of CPPs for CNS diseases.

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Brain penetrating peptides and peptide–drug conjugates to overcome the blood–brain barrier and target CNS diseases

Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology ◽

10.1002/wnan.1695 ◽

2021 ◽

Author(s):

Xue Zhou ◽

Quentin R. Smith ◽

Xinli Liu

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Peptide Drug ◽

Cns Diseases ◽

Drug Conjugates ◽

Blood Brain ◽

Peptide Drug Conjugates

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Trojan bacteria cross blood-brain barrier for glioblastoma photothermal immunotherapy

10.21203/rs.3.rs-1114519/v1 ◽

2021 ◽

Author(s):

Rong Sun ◽

Mingzhu Liu ◽

Jianping Lu ◽

Binbin Chu ◽

Yunmin Yang ◽

...

Keyword(s):

Drug Delivery ◽

Blood Brain Barrier ◽

Silicon Nanoparticles ◽

The Body ◽

Brain Barrier ◽

Bacterial Cells ◽

Cns Diseases ◽

Blood Brain ◽

Innovative Therapies ◽

Photothermal Effects

Abstract Bacteria can bypass the blood-brain barrier (BBB) transcellularly, paracellularly and/or in infected phagocytes, suggesting the possibility of employment of bacteria for combating central nervous system (CNS) diseases. However, the bacteria-based drug delivery vehicle crossing the BBB is still vacant up to present. Herein, we develop an innovative bacteria-based drug delivery system (dubbed Trojan bacteria) for glioblastoma (GBM) photothermal immunotherapy. Typically, Trojan bacteria are made of therapeutics internalized into bacteria (e.g., attenuated Salmonella typhimurium, Escherichia coli). The therapeutics are composed of glucose polymer (GP) (e.g., poly[4-O-(α-D-glucopyranosyl)-D-glucopyranose])-conjugated and indocyanine green (ICG)-loaded silicon nanoparticles (GP-ICG-SiNPs). The GP-ICG-SiNPs can be selectively and robustly internalized into the bacterial intracellular volume through the bacteria-specific ATP-binding cassette (ABC) transporter. In an orthotopic GBM mouse model, we demonstrate that the intravenously injected Trojan bacteria could take therapeutics together not only to bypass the BBB, but also to target and penetrate GBM tissues. Under 808 nm-laser irradiation, the photothermal effects (PTT) produced by ICG allow the destruction of Trojan bacterial cells and the adjacent tumour cells. Furthermore, the bacterial debris as well as the tumour-associated antigens would promote antitumor immune responses that prolong the survival of GBM-bearing mice. Moreover, we demonstrate the residual Trojan bacteria could be effectively eliminated from the body due to the distinct photothermal effects. We anticipate the proposed Trojan bacteria system would catalyze innovative therapies for various CNS diseases.

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Design and Development of Nanomaterial-Based Drug Carriers to Overcome the Blood–Brain Barrier by Using Different Transport Mechanisms

International Journal of Molecular Sciences ◽

10.3390/ijms221810118 ◽

2021 ◽

Vol 22 (18) ◽

pp. 10118

Author(s):

Jisu Song ◽

Chao Lu ◽

Jerzy Leszek ◽

Jin Zhang

Keyword(s):

Drug Delivery ◽

Blood Brain Barrier ◽

Drug Carriers ◽

Brain Barrier ◽

Transport Mechanisms ◽

Cns Diseases ◽

Routes Of Administration ◽

Neurotropic Viruses ◽

Blood Brain ◽

Novel Drug

Central nervous system (CNS) diseases are the leading causes of death and disabilities in the world. It is quite challenging to treat CNS diseases efficiently because of the blood–brain barrier (BBB). It is a physical barrier with tight junction proteins and high selectivity to limit the substance transportation between the blood and neural tissues. Thus, it is important to understand BBB transport mechanisms for developing novel drug carriers to overcome the BBB. This paper introduces the structure of the BBB and its physiological transport mechanisms. Meanwhile, different strategies for crossing the BBB by using nanomaterial-based drug carriers are reviewed, including carrier-mediated, adsorptive-mediated, and receptor-mediated transcytosis. Since the viral-induced CNS diseases are associated with BBB breakdown, various neurotropic viruses and their mechanisms on BBB disruption are reviewed and discussed, which are considered as an alternative solution to overcome the BBB. Therefore, most recent studies on virus-mimicking nanocarriers for drug delivery to cross the BBB are also reviewed and discussed. On the other hand, the routes of administration of drug-loaded nanocarriers to the CNS have been reviewed. In sum, this paper reviews and discusses various strategies and routes of nano-formulated drug delivery systems across the BBB to the brain, which will contribute to the advanced diagnosis and treatment of CNS diseases.

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Modulating the Blood–Brain Barrier: A Comprehensive Review

Pharmaceutics ◽

10.3390/pharmaceutics13111980 ◽

2021 ◽

Vol 13 (11) ◽

pp. 1980

Author(s):

Rory Whelan ◽

Grainne C. Hargaden ◽

Andrew J. S. Knox

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Cns Diseases ◽

Diverse Range ◽

Advantages And Disadvantages ◽

Drug Access ◽

Blood Brain ◽

Future Drug ◽

The Brain ◽

Insight Into

The highly secure blood–brain barrier (BBB) restricts drug access to the brain, limiting the molecular toolkit for treating central nervous system (CNS) diseases to small, lipophilic drugs. Development of a safe and effective BBB modulator would revolutionise the treatment of CNS diseases and future drug development in the area. Naturally, the field has garnered a great deal of attention, leading to a vast and diverse range of BBB modulators. In this review, we summarise and compare the various classes of BBB modulators developed over the last five decades—their recent advancements, advantages and disadvantages, while providing some insight into their future as BBB modulators.

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High Mobility Group Box-1 and Blood–Brain Barrier Disruption

Cells ◽

10.3390/cells9122650 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2650

Author(s):

Masahiro Nishibori ◽

Dengli Wang ◽

Daiki Ousaka ◽

Hidenori Wake

Keyword(s):

Endothelial Cells ◽

Blood Brain Barrier ◽

Brain Injuries ◽

Inflammatory Responses ◽

High Mobility ◽

Brain Inflammation ◽

High Mobility Group ◽

Brain Barrier ◽

Cns Diseases ◽

Blood Brain

Increasing evidence suggests that inflammatory responses are involved in the progression of brain injuries induced by a diverse range of insults, including ischemia, hemorrhage, trauma, epilepsy, and degenerative diseases. During the processes of inflammation, disruption of the blood–brain barrier (BBB) may play a critical role in the enhancement of inflammatory responses and may initiate brain damage because the BBB constitutes an interface between the brain parenchyma and the bloodstream containing blood cells and plasma. The BBB has a distinct structure compared with those in peripheral tissues: it is composed of vascular endothelial cells with tight junctions, numerous pericytes surrounding endothelial cells, astrocytic endfeet, and a basement membrane structure. Under physiological conditions, the BBB should function as an important element in the neurovascular unit (NVU). High mobility group box-1 (HMGB1), a nonhistone nuclear protein, is ubiquitously expressed in almost all kinds of cells. HMGB1 plays important roles in the maintenance of chromatin structure, the regulation of transcription activity, and DNA repair in nuclei. On the other hand, HMGB1 is considered to be a representative damage-associated molecular pattern (DAMP) because it is translocated and released extracellularly from different types of brain cells, including neurons and glia, contributing to the pathophysiology of many diseases in the central nervous system (CNS). The regulation of HMGB1 release or the neutralization of extracellular HMGB1 produces beneficial effects on brain injuries induced by ischemia, hemorrhage, trauma, epilepsy, and Alzheimer’s amyloidpathy in animal models and is associated with improvement of the neurological symptoms. In the present review, we focus on the dynamics of HMGB1 translocation in different disease conditions in the CNS and discuss the functional roles of extracellular HMGB1 in BBB disruption and brain inflammation. There might be common as well as distinct inflammatory processes for each CNS disease. This review will provide novel insights toward an improved understanding of a common pathophysiological process of CNS diseases, namely, BBB disruption mediated by HMGB1. It is proposed that HMGB1 might be an excellent target for the treatment of CNS diseases with BBB disruption.

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