scholarly journals Targeted Delivery of Liposomal Temozolomide Enhanced Anti-Glioblastoma Efficacy through Ultrasound-Mediated Blood–Brain Barrier Opening

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1270
Author(s):  
Zhuqing Song ◽  
Xiuxian Huang ◽  
Jieqiong Wang ◽  
Feiyan Cai ◽  
Ping Zhao ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Targeted Delivery ◽  
Primary Brain Tumor ◽  
Brain Barrier ◽  
Therapeutic Drugs ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Novel Strategy ◽  
Bbb Opening ◽  
Blood Brain Barrier Opening

Glioblastoma (GBM) is the commonest form of primary brain tumor in the central nervous system, with median survival below 15 months and only a 25% two-year survival rate for patients. One of the major clinical challenges in treating GBM is the presence of the blood–brain barrier (BBB), which greatly limits the availability of therapeutic drugs to the tumor. Ultrasound-mediated BBB opening provides a promising approach to help deliver drugs to brain tumors. The use of temozolomide (TMZ) in the clinical treatment of GBM has been shown to be able to increase survival in patients with GBM, but this improvement is still trivial. In this study, we developed a liposomal temozolomide formulation (TMZ-lipo) and locally delivered these nanoparticles into GBM through ultrasound-mediated BBB opening technology, significantly suppressing tumor growth and prolonging tumor-bearing animal survival. No significant side effects were observed in comparison with control rats. Our study provides a novel strategy to improve the efficacy of TMZ against GBM.

scholarly journals BOT-01 BLOOD-BRAIN BARRIER OPENING USING 220-KHZ TRANSCRANIAL MRI-GUIDED FOCUSED ULTRASOUND AND MICROBUBBLES IN MOUSE AND RAT

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii12-ii12
Author(s):  
Michiharu Yoshida ◽  
Kazuo Maruyama ◽  
Yasutaka Kato ◽  
Rachmilevitch Itay ◽  
Syuji Suzuki ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Brain Barrier ◽  
Maximum Temperature ◽  
Non Invasive ◽  
Therapeutic Drugs ◽  
Blood Brain ◽  
Mri Guided ◽  
Bbb Opening

Abstract OBJECTIVE In neuro-oncology, it is believed that one major obstacle to effective chemotherapy is the high vascularity and heterogenous permeability of brain tumors. Focused ultrasound (FUS) exposure with the microbubbles has been shown to transiently open the blood-brain barrier (BBB) without depositing thermal energy, and thus may enhance the delivery of various therapeutic drugs into brain tumors. The aim of this study was to evaluate the BBB opening using 220-kHz transcranial MRI-guided FUS (TcMRgFUS) device and microbubbles in mouse and rat. METHODS The experiments were performed with the 220-kHz ExAblate Neuro TcMRgFUS system (InSightec) and novel lipid bubbles (LB, Teikyo Univ.). Normal mouse and rat brains were irradiated with TcMRgFUS (output power, 5W; duration of irradiation, 30 s; duty cycle 100%) following intravenous injection of 6x107 LB per mouse and rat, respectively. On irradiation, target temperature rise & cavitation signal were monitored by MR thermometry and cavitation receiver, respectively. Immediately after irradiation, BBB opening and complications were detected based on T1, T2, T2*, and Gadolinium (Gd) enhanced T1-weighted images. RESULTS The maximum temperature of brain tissue was under 42 C. There were no risky-cavitation signals causing hemorrhage. The FUS-LB exposure induced successful BBB opening effect in both mouse and rat, confirmed by Gd enhancement in the target region, lateral ventricles, and sulcus. In addition, there were no complications such as edema, coagulation, and hemorrhage. CONCLUSIONS Although there remain many conditions to be optimized, BBB opening using a 220-kHz TcMRgFUS device and LB can offer a non-invasive and feasible drug delivery for brain malignancies.

scholarly journals Endothelial Unc5B controls blood-brain barrier integrity

2021 ◽  
Author(s):  
Kevin Boyé ◽  
Luiz Henrique Medeiros Geraldo ◽  
Jessica furtado ◽  
Laurence Pibouin-fragner ◽  
Mathilde Poulet ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Proper Function ◽  
Downstream Signaling ◽  
Adult Mice ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Specific Deletion ◽  
Blood Brain Barrier Integrity ◽  
Bbb Opening

Blood-brain barrier (BBB) integrity is critical for proper function of the central nervous system (CNS). Here, we showed that the endothelial Netrin1 receptor Unc5B controls BBB integrity by maintaining Wnt/β-catenin signaling. Inducible endothelial-specific deletion of Unc5B in adult mice led to region and size-selective BBB opening. Loss of Unc5B decreased BBB Wnt/β-catenin signaling, and β-catenin overexpression rescued Unc5B mutant BBB defects. Mechanistically, Netrin1 enhanced Unc5B interaction with the Wnt co-receptor LRP6, induced its phosphorylation and activated Wnt/β-catenin downstream signaling. Intravenous delivery of antibodies blocking Netrin1 binding to Unc5B caused a transient disruption of Wnt signaling and BBB breakdown, followed by neurovascular barrier resealing. These data identify Netrin-Unc5B signaling as a novel regulator of BBB integrity with potential therapeutic utility for CNS diseases.

scholarly journals Feedback control of microbubble cavitation for ultrasound-mediated blood–brain barrier disruption in non-human primates under magnetic resonance guidance

2018 ◽  
Vol 39 (7) ◽  
pp. 1191-1203 ◽  
Author(s):  
Hermes AS Kamimura ◽  
Julien Flament ◽  
Julien Valette ◽  
Andrea Cafarelli ◽  
Romina Aron Badin ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Feedback Control ◽  
Blood Brain Barrier ◽  
Targeted Delivery ◽  
Pulse Length ◽  
Brain Barrier ◽  
Mr Images ◽  
Blood Brain ◽  
Combining Data ◽  
Bbb Opening

Focused ultrasound (FUS) in combination with microbubbles is capable of noninvasive, site-targeted delivery of drugs through the blood–brain barrier (BBB). Although acoustic parameters are reproducible in small animals, their control remains challenging in primates due to skull heterogeneity. This study describes a 7-T magnetic resonance (MR)-guided FUS system designed for BBB disruption in non-human primates (NHP) with a robust feedback control based on passive cavitation detection (PCD). Contrast enhanced T1-weighted MR images confirmed the BBB opening in NHP sonicated during 2 min with 500-kHz frequency, pulse length of 10 ms, and pulse repetition frequency of 5 Hz. The safe acoustic pressure range from 185 ± 22 kPa to 266 ± 4 kPa in one representative case was estimated from combining data from the acoustic beam profile with the BBB opening and hemorrhage profiles obtained from MR images. A maximum amount of MR contrast agent at focus was observed at 30 min after sonication with a relative contrast enhancement of 67% ± 15% (in comparison to that found in muscles). The feedback control based on PCD using relative spectra was shown to be robust, allowing comparisons across animals and experimental sessions. Finally, we also demonstrated that PCD can test acoustic coupling conditions, which improves the efficacy and safety of ultrasound transmission into the brain.

scholarly journals Ultrasound-Induced Blood-Brain-Barrier Opening Enhances Anticancer Efficacy in the Treatment of Glioblastoma: Current Status and Future Prospects

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Zhiting Deng ◽  
Zonghai Sheng ◽  
Fei Yan
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Targeted Delivery ◽  
Brain Barrier ◽  
Current Status ◽  
Normal Brain ◽  
Anticancer Efficacy ◽  
Blood Brain ◽  
Delivery Technique ◽  
Bbb Opening

Glioblastoma multiforme (GBM) diffusely infiltrates normal brain tissue. The presence of the blood-brain barrier (BBB) poses difficulties for targeted delivery of currently available antitumor drugs. Novel brain drug delivery strategies are far from satisfactory for glioma treatment. Recently, focused ultrasound (FUS) combined with microbubbles presents a transient, reversible, and noninvasive approach for local induction of BBB opening. This strategy demonstrated its potential to increase local concentrations of both diagnostic and therapeutic agents in glioma therapy. Current status and related physic mechanisms of this drug delivery technique are discussed in this review. Delivery efficiency enhancement in many preclinical glioma models was obtained by FUS-BBB opening combined with various nanoparticles. And, the clinical translational status of FUS-BBB will be discussed.

scholarly journals Can Natural Products Exert Neuroprotection without Crossing the Blood–Brain Barrier?

2021 ◽  
Vol 22 (7) ◽  
pp. 3356
Author(s):  
Manon Leclerc ◽  
Stéphanie Dudonné ◽  
Frédéric Calon
Keyword(s):  
Natural Products ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Omega 3 ◽  
Indirect Pathway ◽  
Brain Functions ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Peripheral Metabolism

The scope of evidence on the neuroprotective impact of natural products has been greatly extended in recent years. However, a key question that remains to be answered is whether natural products act directly on targets located in the central nervous system (CNS), or whether they act indirectly through other mechanisms in the periphery. While molecules utilized for brain diseases are typically bestowed with a capacity to cross the blood–brain barrier, it has been recently uncovered that peripheral metabolism impacts brain functions, including cognition. The gut–microbiota–brain axis is receiving increasing attention as another indirect pathway for orally administered compounds to act on the CNS. In this review, we will briefly explore these possibilities focusing on two classes of natural products: omega-3 polyunsaturated fatty acids (n-3 PUFAs) from marine sources and polyphenols from plants. The former will be used as an example of a natural product with relatively high brain bioavailability but with tightly regulated transport and metabolism, and the latter as an example of natural compounds with low brain bioavailability, yet with a growing amount of preclinical and clinical evidence of efficacy. In conclusion, it is proposed that bioavailability data should be sought early in the development of natural products to help identifying relevant mechanisms and potential impact on prevalent CNS disorders, such as Alzheimer’s disease.

scholarly journals Dual Roles of Astrocyte-Derived Factors in Regulation of Blood-Brain Barrier Function after Brain Damage

2019 ◽  
Vol 20 (3) ◽  
pp. 571 ◽  
Author(s):  
Shotaro Michinaga ◽  
Yutaka Koyama
Keyword(s):  
Brain Damage ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain ◽  
Secondary Damage ◽  
The Central Nervous System ◽  
Bbb Permeability ◽  
Novel Therapeutic Strategies ◽  
Glial Derived Neurotrophic Factor ◽  
Endothelial Growth Factors

The blood-brain barrier (BBB) is a major functional barrier in the central nervous system (CNS), and inhibits the extravasation of intravascular contents and transports various essential nutrients between the blood and the brain. After brain damage by traumatic brain injury, cerebral ischemia and several other CNS disorders, the functions of the BBB are disrupted, resulting in severe secondary damage including brain edema and inflammatory injury. Therefore, BBB protection and recovery are considered novel therapeutic strategies for reducing brain damage. Emerging evidence suggests key roles of astrocyte-derived factors in BBB disruption and recovery after brain damage. The astrocyte-derived vascular permeability factors include vascular endothelial growth factors, matrix metalloproteinases, nitric oxide, glutamate and endothelin-1, which enhance BBB permeability leading to BBB disruption. By contrast, the astrocyte-derived protective factors include angiopoietin-1, sonic hedgehog, glial-derived neurotrophic factor, retinoic acid and insulin-like growth factor-1 and apolipoprotein E which attenuate BBB permeability resulting in recovery of BBB function. In this review, the roles of these astrocyte-derived factors in BBB function are summarized, and their significance as therapeutic targets for BBB protection and recovery after brain damage are discussed.

scholarly journals 17-β-Estradiol: A Powerful Modulator of Blood–Brain Barrier BCRP Activity

2010 ◽  
Vol 30 (10) ◽  
pp. 1742-1755 ◽  
Author(s):  
Anika MS Hartz ◽  
Anne Mahringer ◽  
David S Miller ◽  
Björn Bauer
Keyword(s):  
Blood Brain Barrier ◽  
Ex Vivo ◽  
Brain Barrier ◽  
Cancer Resistance ◽  
Transport Activity ◽  
Brain Capillaries ◽  
Therapeutic Drugs ◽  
Blood Brain ◽  
Capillary Membranes ◽  
Blood Brain Barrier Model

The ATP-driven efflux transporter, breast cancer resistance protein (BCRP), handles many therapeutic drugs, including chemotherapeutics, limiting their ability to cross the blood–brain barrier. This study provides new insight into rapid, nongenomic regulation of BCRP transport activity at the blood–brain barrier. Using isolated brain capillaries from rats and mice as an ex vivo blood–brain barrier model, we show that BCRP protein is highly expressed in brain capillary membranes and functionally active in intact capillaries. We show that nanomolar concentrations of 17-β-estradiol (E2) rapidly reduced BCRP transport activity in the brain capillaries. This E2-mediated effect occurred within minutes and did not involve transcription, translation, or proteasomal degradation, indicating a nongenomic mechanism. Removing E2 after 1 h fully reversed the loss of BCRP activity. Experiments using agonists and antagonists for estrogen receptor (ER)α and ERβ and brain capillaries from ERα and ERβ knockout mice demonstrated that E2 could signal through either receptor to reduce BCRP transport function. We speculate that this nongenomic E2-signaling pathway could potentially be used for targeting BCRP at the blood–brain barrier, in brain tumors, and in brain tumor stem cells to improve chemotherapy of the central nervous system.

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