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Article ; Online: Interstitial chemotherapy for malignant glioma

Antonella Mangraviti / Betty Tyler / Henry Brem

Surgical Neurology International, Vol 6, Iss 2, Pp 78-

Future prospects in the era of multimodal therapy

2015 Volume 84

Abstract: The advent of interstitial chemotherapy has significantly increased therapeutic options for patients with malignant glioma. Interstitial chemotherapy can deliver high concentrations of chemotherapeutic agents, directly at the site of the brain tumor ... ...

Abstract	The advent of interstitial chemotherapy has significantly increased therapeutic options for patients with malignant glioma. Interstitial chemotherapy can deliver high concentrations of chemotherapeutic agents, directly at the site of the brain tumor while bypassing systemic toxicities. Gliadel, a locally implanted polymer that releases the alkylating agent carmustine, given alone and in combination with various other antitumor and resistance modifying therapies, has significantly increased the median survival for patients with malignant glioma. Convection enhanced delivery, a technique used to directly infuse drugs into brain tissue, has shown promise for the delivery of immunotoxins, monoclonal antibodies, and chemotherapeutic agents. Preclinical studies include delivery of chemotherapeutic and immunomodulating agents by polymer and microchips. Interstitial chemotherapy was shown to maximize local efficacy and is an important strategy for the efficacy of any multimodal approach.
Keywords	Carmustine ; Gliadel ® ; glioblastoma multiforme ; interstitial chemotherapy ; malignant glioma ; Medicine ; R ; Surgery ; RD1-811 ; Internal medicine ; RC31-1245 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Neurology. Diseases of the nervous system ; RC346-429
Subject code	610
Publishing date	2015-01-01T00:00:00Z
Publisher	Medknow Publications
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Nanobiotechnology-based delivery strategies: New frontiers in brain tumor targeted therapies

Mangraviti, Antonella / Betty Tyler / David Gullotti / Henry Brem

Journal of Controlled Release. 2016 Oct. 28, v. 240

2016

Abstract: Despite recent technological advancements and promising preclinical experiments, brain tumor patients are still met with limited treatment options. Some of the barriers to clinical improvements include the systemic toxicity of cytotoxic compounds, the ... ...

Abstract	Despite recent technological advancements and promising preclinical experiments, brain tumor patients are still met with limited treatment options. Some of the barriers to clinical improvements include the systemic toxicity of cytotoxic compounds, the impedance of the blood brain barrier (BBB), and the lack of therapeutic agents that can selectively target the intracranial tumor environment. To overcome such barriers, a number of chemotherapeutic agents and nucleic acid-based therapies are rapidly being synthesized and tested as new brain tumor-targeted delivery strategies. Novel carriers include liposomal and polymeric nanoparticles, wafers, microchips, microparticle-based nanoplatforms and cells-based vectors. Strong preclinical results suggest that these nanotechnologies are set to transform the therapeutic paradigm for brain tumor treatment. In addition to new tumoricidal agents, parallel work is also being conducted on the BBB front. Preclinical testing of chemical and physical modulation strategies is yielding improved intracranial concentrations. New diagnostic and therapeutic imaging techniques, such as high-intensity focused ultrasound and MRI-guided focused ultrasound, are being used to modulate the BBB in a more precise and non-invasive manner. This review details some of the tremendous advances that are being explored in current brain tumor targeted therapies, including local implant development, nanobiotechnology-based delivery strategies, and techniques of BBB manipulation.
Keywords	blood-brain barrier ; brain ; cytotoxicity ; drug therapy ; image analysis ; impedance ; nanoparticles ; patients
Language	English
Dates of publication	2016-1028
Size	p. 443-453.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2016.03.031
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Emerging Insights into Barriers to Effective Brain Tumor Therapeutics

GraemeFWoodworth / GavinPDunn / ElizabethANance / HenryBrem

Frontiers in Oncology, Vol

2014 Volume 4

Abstract: There is great promise that ongoing advances in the delivery of therapeutics to the central nervous system (CNS) combined with rapidly expanding knowledge of brain tumor patho-biology will provide new, more effective therapies. Brain tumors that form ... ...

Abstract	There is great promise that ongoing advances in the delivery of therapeutics to the central nervous system (CNS) combined with rapidly expanding knowledge of brain tumor patho-biology will provide new, more effective therapies. Brain tumors that form from brain cells, as opposed to those that come from other parts of the body, rarely metastasize outside of the central nervous system. Instead, the tumor cells invade deep into the brain itself, causing disruption in brain circuits, blood vessel and blood flow changes, and tissue swelling. Patients with the most common and deadly form, glioblastoma (GBM) rarely live more than 2 years even with the most aggressive treatments and often with devastating neurological consequences. Current treatments include maximal safe surgical removal or biopsy followed by radiation and chemotherapy to address the residual tumor mass and invading tumor cells. However, delivering effective and sustained treatments to these invading cells without damaging healthy brain tissue is a major challenge and focus of the emerging fields of nanomedicine and viral and cell-based therapies. New treatment strategies, particularly those directed against the invasive component of this devastating CNS disease, are sorely needed. In this review, we (1) discuss the history and evolution of treatments for GBM, (2) define and explore three critical barriers to improving therapeutic delivery to invasive brain tumors, specifically, the neurovascular unit as it relates to the blood brain barrier, the extracellular space in regard to the brain penetration barrier, and the tumor genetic heterogeneity and instability in association with the treatment efficacy barrier, and (3) identify promising new therapeutic delivery approaches that have the potential to address these barriers and create sustained, meaningful efficacy against GBM.
Keywords	Glioblastoma ; Glioma ; Immunotherapy ; Nanomedicine ; Nanotechnology ; Drug delivery ; brain cancer ; malignant glioma ; Blood Brain Barrier (BBB) ; advanced therapeutic ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R
Subject code	610
Language	English
Publishing date	2014-07-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Multi-layered core-sheath fiber membranes for controlled drug release in the local treatment of brain tumor

Daewoo Han / Riccardo Serra / Noah Gorelick / Umailla Fatima / Charles G. Eberhart / Henry Brem / Betty Tyler / Andrew J. Steckl

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 12

Abstract: Abstract Interstitial chemotherapy plays a pivotal role in the treatment of glioblastoma multiforme (GBM), an aggressive form of primary brain cancer, by enhancing drug biodistribution to the tumor and avoiding systemic toxicities. The use of new polymer ...

Abstract	Abstract Interstitial chemotherapy plays a pivotal role in the treatment of glioblastoma multiforme (GBM), an aggressive form of primary brain cancer, by enhancing drug biodistribution to the tumor and avoiding systemic toxicities. The use of new polymer structures that extend the release of cytotoxic agents may therefore increase survival and prevent recurrence. A novel core-sheath fiber loaded with the drug carmustine (BCNU) was evaluated in an in vivo brain tumor model. Three-dimensional discs were formed from coaxially electrospun fiber membranes and in vitro BCNU release kinetics were measured. In vivo survival was assessed following implantation of discs made of compressed core-sheath fibers (NanoMesh) either concurrently with or five days after intracranial implantation of 9L gliosarcoma. Co-implantation of NanoMesh and 9L gliosarcoma resulted in statistically significant long-term survival (>150 days). Empty control NanoMesh confirmed the safety of these novel implants. Similarly, Day 5 studies showed significant median, overall, and long-term survival rates, suggesting optimal control of tumor growth, confirmed with histological and immunohistochemical analyses. Local chemotherapy by means of biodegradable NanoMesh implants is a new treatment paradigm for the treatment for brain tumors. Drug delivery with coaxial core-sheath structures benefits from high drug loading, controlled long-term release kinetics, and slow polymer degradation. This represents a promising evolution for the current treatment of GBM.
Keywords	Medicine ; R ; Science ; Q
Subject code	660
Language	English
Publishing date	2019-11-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model.

Riccardo Serra / Tianna Zhao / Sakibul Huq / Noah Leviton Gorelick / Joshua Casaos / Arba Cecia / Antonella Mangraviti / Charles Eberhart / Renyuan Bai / Alessandro Olivi / Henry Brem / Eric M Jackson / Betty Tyler

PLoS ONE, Vol 16, Iss 11, p e

2021 Volume 0251957

Abstract: Background Medulloblastoma (MB) is the most common brain malignancy in children, and is still responsible for significant mortality and morbidity. The aim of this study was to assess the safety and efficacy of Disulfiram (DSF), an FDA-approved inhibitor ... ...

Abstract	Background Medulloblastoma (MB) is the most common brain malignancy in children, and is still responsible for significant mortality and morbidity. The aim of this study was to assess the safety and efficacy of Disulfiram (DSF), an FDA-approved inhibitor of Aldehyde-Dehydrogenase (ALDH), and Copper (Cu++) in human SSH-driven and Group 3 MB. The molecular mechanisms, effect on cancer-stem-cells (CSC) and DNA damage were investigated in xenograft models. Methods The cytotoxic and anti-CSC effects of DSF/Cu++ were evaluated with clonogenic assays, flow-cytometry, immunofluorescence, western-blotting. ONS76, UW228 (SHH-driven with Tp53m), D425med, D283 and D341 (Group 3) cell-lines were used. In vivo survival and nuclear protein localization protein-4 (NPL4), Ki67, Cleaved-Caspase-3, GFAP and NeuN expression were assessed in two Group 3 MB xenografts with immunohistochemistry and western-blotting. Results Significant in vitro cytotoxicity was demonstrated at nanomolar concentrations. DSF/Cu++ induced cell-death through NPL4 accumulation in cell-nucleus and buildup of poly-ubiquitylated proteins. Flow-cytometry demonstrated a significant decrease in ALDH+, Nestin+ and CD133+ following treatment, anti-CSC effect was confirmed in vitro and in vivo. DSF/Cu++ prolonged survival, and increased nuclear NPL4 expression in vivo. Conclusions Our data suggest that this combination may serve as a novel treatment, as monotherapy or in combination with existing therapies, for aggressive subtypes of pediatric MB.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model

PLoS ONE, Vol 16, Iss

2021 Volume 11

Abstract	Background Medulloblastoma (MB) is the most common brain malignancy in children, and is still responsible for significant mortality and morbidity. The aim of this study was to assess the safety and efficacy of Disulfiram (DSF), an FDA-approved inhibitor of Aldehyde-Dehydrogenase (ALDH), and Copper (Cu++) in human SSH-driven and Group 3 MB. The molecular mechanisms, effect on cancer-stem-cells (CSC) and DNA damage were investigated in xenograft models. Methods The cytotoxic and anti-CSC effects of DSF/Cu++ were evaluated with clonogenic assays, flow-cytometry, immunofluorescence, western-blotting. ONS76, UW228 (SHH-driven with Tp53m), D425med, D283 and D341 (Group 3) cell-lines were used. In vivo survival and nuclear protein localization protein-4 (NPL4), Ki67, Cleaved-Caspase-3, GFAP and NeuN expression were assessed in two Group 3 MB xenografts with immunohistochemistry and western-blotting. Results Significant in vitro cytotoxicity was demonstrated at nanomolar concentrations. DSF/Cu++ induced cell-death through NPL4 accumulation in cell-nucleus and buildup of poly-ubiquitylated proteins. Flow-cytometry demonstrated a significant decrease in ALDH+, Nestin+ and CD133+ following treatment, anti-CSC effect was confirmed in vitro and in vivo. DSF/Cu++ prolonged survival, and increased nuclear NPL4 expression in vivo. Conclusions Our data suggest that this combination may serve as a novel treatment, as monotherapy or in combination with existing therapies, for aggressive subtypes of pediatric MB.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Intraoperative Laser Speckle Contrast Imaging For Real-Time Visualization of Cerebral Blood Flow in Cerebrovascular Surgery

Antonella Mangraviti / Francesco Volpin / Jaepyeong Cha / Samantha I. Cunningham / Karan Raje / M. Jason Brooke / Henry Brem / Alessandro Olivi / Judy Huang / Betty M. Tyler / Abhishek Rege

Scientific Reports, Vol 10, Iss 1, Pp 1-

Results From Pre-Clinical Studies

2020 Volume 13

Abstract: Abstract Cerebrovascular surgery can benefit from an intraoperative system that conducts continuous monitoring of cerebral blood flow (CBF). Such a system must be handy, non-invasive, and directly integrated into the surgical workflow. None of the ... ...

Abstract	Abstract Cerebrovascular surgery can benefit from an intraoperative system that conducts continuous monitoring of cerebral blood flow (CBF). Such a system must be handy, non-invasive, and directly integrated into the surgical workflow. None of the currently available techniques, considered alone, meets all these criteria. Here, we introduce the SurgeON™ system: a newly developed non-invasive modular tool which transmits high-resolution Laser Speckle Contrast Imaging (LSCI) directly onto the eyepiece of the surgical microscope. In preclinical rodent and rabbit models, we show that this system enabled the detection of acute perfusion changes as well as the recording of temporal response patterns and degrees of flow changes in various microvascular settings, such as middle cerebral artery occlusion, femoral artery clipping, and complete or incomplete cortical vessel cautery. During these procedures, a real-time visualization of vasculature and CBF was available in high spatial resolution through the eyepiece as a direct overlay on the live morphological view of the surgical field. Upon comparison with indocyanine green angiography videoangiography (ICG-VA) imaging, also operable via SurgeON, we found that direct-LSCI can produce greater information than ICG-VA and that continuous display of data is advantageous for performing immediate LSCI-guided adjustments in real time.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: MCP-1/CCR2 axis inhibition sensitizes the brain microenvironment against melanoma brain metastasis progression

JCI Insight, Vol 7, Iss

2022 Volume 17

Abstract: Development of resistance to chemo- and immunotherapies often occurs following treatment of melanoma brain metastasis (MBM). The brain microenvironment (BME), particularly astrocytes, cooperate toward MBM progression by upregulating secreted factors, ... ...

Abstract	Development of resistance to chemo- and immunotherapies often occurs following treatment of melanoma brain metastasis (MBM). The brain microenvironment (BME), particularly astrocytes, cooperate toward MBM progression by upregulating secreted factors, among which we found that monocyte chemoattractant protein-1 (MCP-1) and its receptors, CCR2 and CCR4, were overexpressed in MBM compared with primary lesions. Among other sources of MCP-1 in the brain, we show that melanoma cells altered astrocyte secretome and evoked MCP-1 expression and secretion, which in turn induced CCR2 expression in melanoma cells, enhancing in vitro tumorigenic properties, such as proliferation, migration, and invasion of melanoma cells. In vivo pharmacological blockade of MCP-1 or molecular knockout of CCR2/CCR4 increased the infiltration of cytotoxic CD8+ T cells and attenuated the immunosuppressive phenotype of the BME as shown by decreased infiltration of Tregs and tumor-associated macrophages/microglia in several models of intracranially injected MBM. These in vivo strategies led to decreased MBM outgrowth and prolonged the overall survival of the mice. Our findings highlight the therapeutic potential of inhibiting interactions between BME and melanoma cells for the treatment of this disease.
Keywords	Oncology ; Therapeutics ; Medicine ; R
Subject code	570
Language	English
Publishing date	2022-10-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: P-selectin axis plays a key role in microglia immunophenotype and glioblastoma progression

Eilam Yeini / Paula Ofek / Sabina Pozzi / Nitzan Albeck / Dikla Ben-Shushan / Galia Tiram / Sapir Golan / Ron Kleiner / Ron Sheinin / Sahar Israeli Dangoor / Shlomit Reich-Zeliger / Rachel Grossman / Zvi Ram / Henry Brem / Thomas M. Hyde / Prerna Magod / Dinorah Friedmann-Morvinski / Asaf Madi / Ronit Satchi-Fainaro

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 22

Abstract: Glioma-associated microglia/macrophages are central drivers of brain tumor pathology. Here the authors characterize the role of the P-selectin/PSGL-1 axis in the cross-talk between glioblastoma cells and microglia/macrophages and show that the ... ...

Abstract	Glioma-associated microglia/macrophages are central drivers of brain tumor pathology. Here the authors characterize the role of the P-selectin/PSGL-1 axis in the cross-talk between glioblastoma cells and microglia/macrophages and show that the therapeutic targeting of P-selectin limits glioblastoma progression in preclinical models.
Keywords	Science ; Q
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Convection enhanced delivery of cisplatin-loaded brain penetrating nanoparticles cures malignant glioma in rats

Zhang, Clark / Betty Tyler / Charles Eberhart / Elizabeth A. Nance / Henry Brem / Jane Chisholm / Jung Soo Suk / Justin Hanes / Panagiotis Mastorakos / Sneha Berry

Journal of Controlled Release. 2017,

2017

Abstract: Glioblastoma multiforme (GBM) is highly invasive and uniformly fatal, with median survival<20months after diagnosis even with the most aggressive treatment that includes surgery, radiation, and systemic chemotherapy. Cisplatin is a particularly potent ... ...

Abstract	Glioblastoma multiforme (GBM) is highly invasive and uniformly fatal, with median survival<20months after diagnosis even with the most aggressive treatment that includes surgery, radiation, and systemic chemotherapy. Cisplatin is a particularly potent chemotherapeutic agent, but its use to treat GBM is limited by severe systemic toxicity and inefficient penetration of brain tumor tissue even when it is placed directly in the brain within standard delivery systems. We describe the development of cisplatin-loaded nanoparticles that are small enough (70nm in diameter) to move within the porous extracellular matrix between cells and that possess a dense polyethylene glycol (PEG) corona that prevents them from being trapped by adhesion as they move through the brain tumor parenchyma. As a result, these âbrain-penetrating nanoparticlesâ penetrate much deeper into brain tumor tissue compared to nanoparticles without a dense PEG corona following local administration by either bolus injection or convection enhanced delivery. The nanoparticles also provide controlled release of cisplatin in effective concentrations to kill the tumor cells that they reach without causing toxicity-related deaths that were observed when cisplatin was infused into the brain without a delivery system. Median survival time of rats bearing orthotopic glioma was significantly enhanced when cisplatin was delivered in brain penetrating nanoparticles (median survival not reached; 80% long-term survivors) compared to cisplatin in conventional un-PEGylated particles (median survival=40days), cisplatin alone (median survival=12days) or saline-treated controls (median survival=28days).
Keywords	adhesion ; brain ; brain neoplasms ; cisplatin ; convection ; drug therapy ; extracellular matrix ; nanoparticles ; neoplasm cells ; polyethylene glycol ; rats ; surgery ; toxicity ; covid19
Language	English
Size	p. .
Publishing place	Elsevier B.V.
Document type	Article
Note	Pre-press version
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2017.03.007
Database	NAL-Catalogue (AGRICOLA)

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