Trojan bacteria cross blood-brain barrier for glioblastoma photothermal immunotherapy

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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Liposomes: Novel Drug Delivery Approach for Targeting Parkinson’s Disease

Current Pharmaceutical Design ◽

10.2174/1381612826666200128145124 ◽

2020 ◽

Vol 26 (37) ◽

pp. 4721-4737 ◽

Cited By ~ 4

Author(s):

Bhumika Kumar ◽

Mukesh Pandey ◽

Faheem H. Pottoo ◽

Faizana Fayaz ◽

Anjali Sharma ◽

...

Keyword(s):

Parkinson’S Disease ◽

Drug Delivery ◽

Parkinson's Disease ◽

Side Effects ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Brain Targeting ◽

Neural Cells ◽

Blood Brain ◽

The Brain

Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.

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Brain Drug Delivery: Overcoming the Blood-brain Barrier to Treat Tauopathies

Current Pharmaceutical Design ◽

10.2174/1381612826666200316130128 ◽

2020 ◽

Vol 26 (13) ◽

pp. 1448-1465 ◽

Cited By ~ 1

Author(s):

Jozef Hanes ◽

Eva Dobakova ◽

Petra Majerova

Keyword(s):

Drug Delivery ◽

Blood Brain Barrier ◽

Neurodegenerative Disorders ◽

Brain Barrier ◽

Neuronal Function ◽

Brain Drug Delivery ◽

Naturally Occurring ◽

Blood Brain ◽

Traditional Approaches ◽

The Brain

Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The application of potentially effective therapeutics for their successful treatment is hampered by the presence of a naturally occurring brain protection layer called the blood-brain barrier (BBB). BBB represents one of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders, where sufficient BBB penetration is inevitable. BBB is a heavily restricting barrier regulating the movement of molecules, ions, and cells between the blood and the CNS to secure proper neuronal function and protect the CNS from dangerous substances and processes. Yet, these natural functions possessed by BBB represent a great hurdle for brain drug delivery. This review is concentrated on summarizing the available methods and approaches for effective therapeutics’ delivery through the BBB to treat neurodegenerative disorders with a focus on tauopathies. It describes the traditional approaches but also new nanotechnology strategies emerging with advanced medical techniques. Their limitations and benefits are discussed.

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Potential Use of Nanomedicine for Drug Delivery Across the Blood-Brain Barrier in Healthy and Diseased Brain

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527315666160915112210 ◽

2016 ◽

Vol 15 (9) ◽

pp. 1079-1091 ◽

Cited By ~ 6

Author(s):

Barbara Ruozi ◽

Daniela Belletti ◽

Francesca Pederzoli ◽

Flavio Forni ◽

Maria Angela Vandelli ◽

...

Keyword(s):

Drug Delivery ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Blood Brain ◽

Potential Use

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Near-Infrared Radiation-Assisted Drug Delivery Nanoplatform to Realize Blood–Brain Barrier Crossing and Protection for Parkinsonian Therapy

ACS Applied Materials & Interfaces ◽

10.1021/acsami.1c12675 ◽

2021 ◽

Author(s):

Yao Liu ◽

Honghai Hong ◽

Jincheng Xue ◽

Jingshan Luo ◽

Qiao Liu ◽

...

Keyword(s):

Drug Delivery ◽

Blood Brain Barrier ◽

Infrared Radiation ◽

Near Infrared ◽

Brain Barrier ◽

Near Infrared Radiation ◽

Barrier Crossing ◽

Blood Brain

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PATH-04. THE BLOOD-BRAIN BARRIER IN DIFFUSE MIDLINE GLIOMA AND ITS IMPLICATIONS FOR DRUG DELIVERY

Neuro-Oncology ◽

10.1093/neuonc/noaa215.686 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii164-ii164

Author(s):

Rianne Haumann ◽

Fatma El-Khouly ◽

Marjolein Breur ◽

Sophie Veldhuijzen van Zanten ◽

Gertjan Kaspers ◽

...

Keyword(s):

Drug Delivery ◽

Blood Vessels ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Vascular Density ◽

Zonula Occludens ◽

Blood Brain ◽

Zonula Occludens 1 ◽

End Stage ◽

Diffuse Midline Glioma

Abstract INTRODUCTION Chemotherapy has been unsuccessful for pediatric diffuse midline glioma (DMG) most likely due to an intact blood-brain barrier (BBB). However, the BBB has not been characterized in DMG and therefore its implications for drug delivery are unknown. In this study we characterized the BBB in DMG patients and compared this to healthy controls. METHODS End-stage DMG pontine samples (n=5) were obtained from the VUmc diffuse intrinsic pontine glioma (DIPG) autopsy study and age-matched healthy pontine samples (n=22) were obtained from the NIH NeuroBioBank. Tissues were stained for BBB markers claudin-5, zonula occludens-1, laminin, and PDGFRβ. Claudin-5 stains were used to determine vascular density and diameter. RESULTS In DMG, expression of claudin-5 was reduced and dislocated to the abluminal side of endothelial cells. In addition, the expression of zonula occludens-1 was reduced. The basement membrane protein laminin expression was reduced at the glia limitans in both pre-existent vessels and neovascular proliferation. PDGFRβ expression was not observed in DMG but was present in healthy pons. Furthermore, the number of blood vessels in DMG was significantly (P< 0.01) reduced (13.9 ± 11.8/mm2) compared to healthy pons (26.3 ± 14.2/mm2). Markedly, the number of small blood vessels (< 10µm) was significantly lower (P< 0.01) while larger blood vessels (> 10µm) were not significantly different (P= 0.223). The mean vascular diameter was larger for DMG 9.3 ± 9.9µm compared to 7.7 ± 9.0µm for healthy pons (P= 0.016). CONCLUSION Both the BBB and the vasculature are altered at end-stage DMG. The reduced vascular density might have implications for several drug delivery methods such as focused ultrasound and convection enhanced delivery that are being explored for the treatment of DMG. The functional effects of the structurally altered BBB remain unknown and further research is needed to evaluate the BBB integrity at end-stage DMG

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Could Lipoxins Represent a New Standard in Ischemic Stroke Treatment?

International Journal of Molecular Sciences ◽

10.3390/ijms22084207 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4207

Author(s):

Nikola Tułowiecka ◽

Dariusz Kotlęga ◽

Andrzej Bohatyrewicz ◽

Małgorzata Szczuko

Keyword(s):

Ischemic Stroke ◽

Cardiovascular Diseases ◽

Blood Brain Barrier ◽

Inflammatory Cytokines ◽

The Body ◽

Brain Barrier ◽

Lipoxin A4 ◽

Stroke Treatment ◽

Blood Brain ◽

Anti Inflammatory

Introduction: Cardiovascular diseases including stroke are one of the most common causes of death. Their main cause is atherosclerosis and chronic inflammation in the body. An ischemic stroke may occur as a result of the rupture of unstable atherosclerotic plaque. Cardiovascular diseases are associated with uncontrolled inflammation. The inflammatory reaction produces chemical mediators that stimulate the resolution of inflammation. One of these mediators is lipoxins—pro-resolving mediators that are derived from the omega-6 fatty acid family, promoting inflammation relief and supporting tissue regeneration. Aim: The aim of the study was to review the available literature on the therapeutic potential of lipoxins in the context of ischemic stroke. Material and Methods: Articles published up to 31 January 2021 were included in the review. The literature was searched on the basis of PubMed and Embase in terms of the entries: ‘stroke and lipoxin’ and ‘stroke and atherosclerosis’, resulting in over 110 articles in total. Studies that were not in full-text English, letters to the editor, and conference abstracts were excluded. Results: In animal studies, the injection/administration of lipoxin A4 improved the integrity of the blood–brain barrier (BBB), decreased the volume of damage caused by ischemic stroke, and decreased brain edema. In addition, lipoxin A4 inhibited the infiltration of neutrophils and the production of cytokines and pro-inflammatory chemokines, such as interleukin (Il-1β, Il-6, Il-8) and tumor necrosis factor-α (TNF-α). The beneficial effects were also observed after introducing the administration of lipoxin A4 analog—BML-111. BML-111 significantly reduces the size of a stroke and protects the cerebral cortex, possibly by reducing the permeability of the blood–brain barrier. Moreover, more potent than lipoxin A4, it has an anti-inflammatory effect by inhibiting the production of pro-inflammatory cytokines and increasing the amount of anti-inflammatory cytokines. Conclusions: Lipoxins and their analogues may find application in reducing damage caused by stroke and improving the prognosis of patients after ischemic stroke.

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