scholarly journals A review of potential applications of MR-guided focused ultrasound for targeting brain tumor therapy

2018 ◽  
Vol 44 (2) ◽  
pp. E10 ◽  
Author(s):  
Layton Lamsam ◽  
Eli Johnson ◽  
Ian D. Connolly ◽  
Max Wintermark ◽  
Melanie Hayden Gephart
Keyword(s):  
Drug Delivery ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Focused Ultrasound ◽  
Tumor Therapy ◽  
Survival Times ◽  
Potential Applications ◽  
Animal Tumor ◽  
Antitumor Chemotherapy ◽  
Systemic Drug Delivery

Magnetic resonance–guided focused ultrasound (MRgFUS) has been used extensively to ablate brain tissue in movement disorders, such as essential tremor. At a lower energy, MRgFUS can disrupt the blood-brain barrier (BBB) to allow passage of drugs. This focal disruption of the BBB can target systemic medications to specific portions of the brain, such as for brain tumors. Current methods to bypass the BBB are invasive, as the BBB is relatively impermeable to systemically delivered antineoplastic agents. Multiple healthy and brain tumor animal models have suggested that MRgFUS disrupts the BBB and focally increases the concentration of systemically delivered antitumor chemotherapy, immunotherapy, and gene therapy. In animal tumor models, combining MRgFUS with systemic drug delivery increases median survival times and delays tumor progression. Liposomes, modified microbubbles, and magnetic nanoparticles, combined with MRgFUS, more effectively deliver chemotherapy to brain tumors. MRgFUS has great potential to enhance brain tumor drug delivery, while limiting treatment toxicity to the healthy brain.

scholarly journals Focused ultrasound in neuro-oncology: the role of the Focused Ultrasound Foundation in driving adoption and innovation

2021 ◽  
Author(s):  
Emily C. Whipple ◽  
Camille A. Favero ◽  
Neal F. Kassell
Keyword(s):  
Drug Delivery ◽  
Brain Tumors ◽  
Focused Ultrasound ◽  
Clinical Evidence ◽  
Neurological Injury ◽  
High Concentration ◽  
Potential Applications ◽  
Tumor Agent

Abstract Introduction Intra-arterial (lA) delivery of therapeutic agents across the blood-brain barrier (BBB) is an evolving strategy which enables the distribution of high concentration therapeutics through a targeted vascular territory, while potentially limiting systemic toxicity. Studies have demonstrated lA methods to be safe and efficacious for a variety of therapeutics. However, further characterization of the clinical efficacy of lA therapy for the treatment of brain tumors and refinement of its potential applications are necessary. Methods We have reviewed the preclinical and clinical evidence supporting superselective intraarterial cerebral infusion (SSJACI) with BBB disruption for the treatment of brain tumors. In addition, we review ongoing clinical trials expanding the applicability and investigating the efficacy of lA therapy for the treatment of brain tumors. Results Trends in recent studies have embraced the use of SSIACI and less neurotoxic chemotherapies. The majority of trials continue to use mannitol as the preferred method of hyperosmolar BBB disruption. Recent preclinical and preliminary human investigations into the lA delivery of Bevacizumab have demonstrated its safety and efficacy as an anti-tumor agent both alone and in combination with chemotherapy. Conclusion lA drug delivery may significantly affect the way treatment are delivered to patients with brain tumors, and in particular GBM. With refinement and standardization of the techniques of lA drug delivery, improved drug selection and formulations, and the development of methods to minimize treatment-related neurological injury, lA therapy may offer significant benefits for the treatment of brain tumors.

Enhanced therapeutic agent delivery through magnetic resonance imaging–monitored focused ultrasound blood-brain barrier disruption for brain tumor treatment: an overview of the current preclinical status

2012 ◽  
Vol 32 (1) ◽  
pp. E4 ◽  
Author(s):  
Hao-Li Liu ◽  
Hung-Wei Yang ◽  
Mu-Yi Hua ◽  
Kuo-Chen Wei
Keyword(s):  
Drug Delivery ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Therapeutic Agent ◽  
Brain Barrier ◽  
Term Survival ◽  
Blood Brain ◽  
The Brain

Malignant glioma is a severe primary CNS cancer with a high recurrence and mortality rate. The current strategy of surgical debulking combined with radiation therapy or chemotherapy does not provide good prognosis, tumor progression control, or improved patient survival. The blood-brain barrier (BBB) acts as a major obstacle to chemotherapeutic treatment of brain tumors by severely restricting drug delivery into the brain. Because of their high toxicity, chemotherapeutic drugs cannot be administered at sufficient concentrations by conventional delivery methods to significantly improve long-term survival of patients with brain tumors. Temporal disruption of the BBB by microbubble-enhanced focused ultrasound (FUS) exposure can increase CNS-blood permeability, providing a promising new direction to increase the concentration of therapeutic agents in the brain tumor and improve disease control. Under the guidance and monitoring of MR imaging, a brain drug-delivery platform can be developed to control and monitor therapeutic agent distribution and kinetics. The success of FUS BBB disruption in delivering a variety of therapeutic molecules into brain tumors has recently been demonstrated in an animal model. In this paper the authors review a number of critical studies that have demonstrated successful outcomes, including enhancement of the delivery of traditional clinically used chemotherapeutic agents or application of novel nanocarrier designs for actively transporting drugs or extending drug half-lives to significantly improve treatment efficacy in preclinical animal models.

Chemotherapy Delivery Issues in Central Nervous System Malignancy: A Reality Check

2007 ◽  
Vol 25 (16) ◽  
pp. 2295-2305 ◽  
Author(s):  
Leslie L. Muldoon ◽  
Carole Soussain ◽  
Kristoph Jahnke ◽  
Conrad Johanson ◽  
Tali Siegal ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Tumor Therapy ◽  
Reality Check ◽  
Current State ◽  
Biologic Effect ◽  
Prospective Trials ◽  
Cns Lymphomas ◽  
Alternative Delivery

PurposeThis review assesses the current state of knowledge regarding preclinical and clinical pharmacology for brain tumor chemotherapy and evaluates relevant brain tumor pharmacology studies before October 2006.ResultsChemotherapeutic regimens in brain tumor therapy have often emerged from empirical clinical studies with retrospective pharmacologic explanations, rather than prospective trials of rational chemotherapeutic approaches. Brain tumors are largely composed of CNS metastases of systemic cancers. Primary brain tumors, such as glioblastoma multiforme or primary CNS lymphomas, are less common. Few of these tumors have well-defined optimal treatment. Brain tumors are protected from systemic chemotherapy by the blood-brain barrier (BBB) and by intrinsic properties of the tumors. Pharmacologic studies of delivery of conventional chemotherapeutics and novel therapeutics showing actual tumor concentrations and biologic effect are lacking.ConclusionIn this article, we review drug delivery across the BBB, as well as blood-tumor and –cerebrospinal fluid (CSF) barriers, and mechanisms to increase drug delivery to CNS and CSF tumors. Because of the difficulty in treating CNS tumors, innovative treatments and alternative delivery techniques involving brain/cord capillaries, choroid plexus, and CSF are needed.

scholarly journals Focused Ultrasound Strategies for Brain Tumor Therapy

2019 ◽  
Vol 19 (1) ◽  
pp. 9-18 ◽  
Author(s):  
Adomas Bunevicius ◽  
Nathan Judson McDannold ◽  
Alexandra J Golby
Keyword(s):  
Brain Tumors ◽  
Viral Vectors ◽  
Focused Ultrasound ◽  
Tumor Therapy ◽  
Drug Distribution ◽  
Low Frequency ◽  
Tissue Level ◽  
Chemotherapeutic Agents ◽  
Promising Tool ◽  
Investigational Agents

Abstract BACKGROUND A key challenge in the medical treatment of brain tumors is the limited penetration of most chemotherapeutic agents across the blood–brain barrier (BBB) into the tumor and the infiltrative margin around the tumor. Magnetic resonance-guided focused ultrasound (MRgFUS) is a promising tool to enhance the delivery of chemotherapeutic agents into brain tumors. OBJECTIVE To review the mechanism of FUS, preclinical evidence, and clinical studies that used low-frequency FUS for a BBB opening in gliomas. METHODS Literature review. RESULTS The potential of externally delivered low-intensity ultrasound for a temporally and spatially precise and predictable disruption of the BBB has been investigated for over a decade, yielding extensive preclinical literature demonstrating that FUS can disrupt the BBB in a spatially targeted and temporally reversible manner. Studies in animal models documented that FUS enhanced the delivery of numerous chemotherapeutic and investigational agents across the BBB and into brain tumors, including temozolomide, bevacizumab, 1,3-bis (2-chloroethyl)-1-nitrosourea, doxorubicin, viral vectors, and cells. Chemotherapeutic interventions combined with FUS slowed tumor progression and improved animal survival. Recent advances of MRgFUS systems allow precise, temporally and spatially controllable, and safe transcranial delivery of ultrasound energy. Initial clinical evidence in glioma patients has shown the efficacy of MRgFUS in disrupting the BBB, as demonstrated by an enhanced gadolinium penetration. CONCLUSION Thus far, a temporary disruption of the BBB followed by the administration of chemotherapy has been both feasible and safe. Further studies are needed to determine the actual drug delivery, including the drug distribution at a tissue-level scale, as well as effects on tumor growth and patient prognosis.

Recent Advances in Brain Tumor Therapy: Local Intracerebral Drug Delivery by Polymers

2004 ◽  
Vol 22 (1) ◽  
pp. 27-37 ◽  
Author(s):  
Christopher Guerin ◽  
Alessandro Olivi ◽  
Jon D. Weingart ◽  
H. Christopher Lawson ◽  
Henry Brem
Keyword(s):  
Drug Delivery ◽  
Brain Tumor ◽  
Tumor Therapy ◽  
Recent Advances ◽  
Brain Tumor Therapy

scholarly journals Pharmacodynamic Analysis of Magnetic Resonance Imaging-Monitored Focused Ultrasound-Induced Blood-Brain Barrier Opening for Drug Delivery to Brain Tumors

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Po-Chun Chu ◽  
Wen-Yen Chai ◽  
Han-Yi Hsieh ◽  
Jiun-Jie Wang ◽  
Shiaw-Pyng Wey ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Small Molecule ◽  
Focused Ultrasound ◽  
Therapeutic Agents ◽  
Tumor Treatment ◽  
Target Region ◽  
Pharmacodynamic Analysis ◽  
The Brain ◽  
Bbb Opening

Microbubble-enhanced focused ultrasound (FUS) can enhance the delivery of therapeutic agents into the brain for brain tumor treatment. The purpose of this study was to investigate the influence of brain tumor conditions on the distribution and dynamics of small molecule leakage into targeted regions of the brain after FUS-BBB opening. A total of 34 animals were used, and the process was monitored by 7T-MRI. Evans blue (EB) dye as well as Gd-DTPA served as small molecule substitutes for evaluation of drug behavior. EB was quantified spectrophotometrically. Spin-spin (R1) relaxometry and area under curve (AUC) were measured by MRI to quantify Gd-DTPA. We found that FUS-BBB opening provided a more significant increase in permeability with small tumors. In contrast, accumulation was much higher in large tumors, independent of FUS. The AUC values of Gd-DTPA were well correlated with EB delivery, suggesting that Gd-DTPA was a good indicator of total small-molecule accumulation in the target region. The peripheral regions of large tumors exhibited similar dynamics of small-molecule leakage after FUS-BBB opening as small tumors, suggesting that FUS-BBB opening may have the most significant permeability-enhancing effect on tumor peripheral. This study provides useful information toward designing an optimized FUS-BBB opening strategy to deliver small-molecule therapeutic agents into brain tumors.

scholarly journals Status Quo and Trends of Intra-Arterial Therapy for Brain Tumors: A Bibliometric and Clinical Trials Analysis

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1885
Author(s):  
Julian S. Rechberger ◽  
Frederic Thiele ◽  
David J. Daniels
Keyword(s):  
Drug Delivery ◽  
Clinical Trials ◽  
Brain Tumors ◽  
Phase 1 ◽  
Citation Count ◽  
Tumor Therapy ◽  
The United States ◽  
Blood Brain Barrier Disruption ◽  
Current State ◽  
Brain Barrier Disruption

Intra-arterial drug delivery circumvents the first-pass effect and is believed to increase both efficacy and tolerability of primary and metastatic brain tumor therapy. The aim of this update is to report on pertinent articles and clinical trials to better understand the research landscape to date and future directions. Elsevier’s Scopus and ClinicalTrials.gov databases were reviewed in August 2021 for all possible articles and clinical trials of intra-arterial drug injection as a treatment strategy for brain tumors. Entries were screened against predefined selection criteria and various parameters were summarized. Twenty clinical trials and 271 articles satisfied all inclusion criteria. In terms of articles, 201 (74%) were primarily clinical and 70 (26%) were basic science, published in a total of 120 different journals. Median values were: publication year, 1986 (range, 1962–2021); citation count, 15 (range, 0–607); number of authors, 5 (range, 1–18). Pertaining to clinical trials, 9 (45%) were phase 1 trials, with median expected start and completion years in 2011 (range, 1998–2019) and 2022 (range, 2008–2025), respectively. Only one (5%) trial has reported results to date. Glioma was the most common tumor indication reported in both articles (68%) and trials (75%). There were 215 (79%) articles investigating chemotherapy, while 13 (65%) trials evaluated targeted therapy. Transient blood–brain barrier disruption was the commonest strategy for articles (27%) and trials (60%) to optimize intra-arterial therapy. Articles and trials predominately originated in the United States (50% and 90%, respectively). In this bibliometric and clinical trials analysis, we discuss the current state and trends of intra-arterial therapy for brain tumors. Most articles were clinical, and traditional anti-cancer agents and drug delivery strategies were commonly studied. This was reflected in clinical trials, of which only a single study had reported outcomes. We anticipate future efforts to involve novel therapeutic and procedural strategies based on recent advances in the field.

SPIO-conjugated, doxorubicin-loaded microbubbles for concurrent MRI and focused-ultrasound enhanced brain-tumor drug delivery

Biomaterials ◽  
2013 ◽  
Vol 34 (14) ◽  
pp. 3706-3715 ◽  
Author(s):  
Ching-Hsiang Fan ◽  
Chien-Yu Ting ◽  
Han-Jung Lin ◽  
Chung-Hsin Wang ◽  
Hao-Li Liu ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Brain Tumor ◽  
Focused Ultrasound ◽  
Tumor Drug Delivery

The New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium: Organization, Objectives, and Activities

1998 ◽  
Vol 5 (2) ◽  
pp. 107-114 ◽  
Author(s):  
Stuart A. Grossman ◽  
Joy D. Fisher ◽  
Steven Piantadosi ◽  
Henry Brem
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Clinical Research ◽  
Tumor Therapy ◽  
Laboratory Research ◽  
Primary Brain Tumors ◽  
Large Numbers ◽  
Neuro Imaging ◽  
Important Drug

Background: Despite advances in neuro-imaging, neurosurgery, radiation therapy, and chemotherapy, limited progress has been made in the treatment of patients with high-grade astrocytomas. The National Cancer Institute has attempted to speed advances in this field by funding CNS consortia to conduct innovative clinical trials in this patient population since 1994. Methods: The NABTT CNS Consortium is composed of a consortium headquarters and nine member institutions with outstanding multidisciplinary expertise, clinical and laboratory research capabilities, and access to large numbers of patients with brain tumors. Results: The objectives of the NABTT Consortium are to improve the therapeutic outcome for adults with primary brain tumors, to conduct basic science and clinical research, and to improve the care and quality of life of adults with primary brain tumors. NABTT's clinical studies have discovered important drug interactions between anticonvulsant and antineoplastic agents, defined the activity of paclitaxel and 9-aminocamptothecin in glioblastoma multiforme, tested a novel dose escalation strategy for brain tumor trials, and established new protocol “classes” to expedite and standardize clinical research in this field. Conclusions: Significant progress in the care of patients with primary brain tumors is likely to result from the highly focused and multidisciplinary efforts of the NIH-funded CNS consortia.

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