Study results of a research team led by scientists at the Massachusetts General Hospital (MGH), Boston, Massachusetts, shows, for the first time, the mechanisms underlying the use of Focused Ultrasound (FUS) to improve the delivery of anti-cancer drugs across the blood brain barrier into brain tumors.

The blood?brain/blood?tumor barriers (BBB and BTB) and interstitial transport constitute major obstacles to the transport of therapeutics agents in brain tumors.

The report, published in the September 2018 issue of the Proceedings of the National Academy of Sciences (PNAS), shows how scientists uses advanced microscopy techniques and mathematical modeling to track the potential of this promising, minimally invasive treatment approach in an animal model of breast cancer brain metastasis.[1]

The team of scientists also included investigators from Georgia Institute of Technology, the University of Edinburgh and Brigham and Women’s Hospital.

Blood-brain barrier
“The blood brain barrier is a challenge in the treatment of brain malignancies, as it can hinder drug delivery,” expained co-corresponding and co-lead author Costas Arvanitis, PhD.

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Photo 1.0: Costas D. Arvanitis, Ph.D, assistant professor at the George W. Woodruff School of Mechanical Engineering Wallace H. Coulter Dept. of Biomedical Engineering Georgia Institute of Technology and Emory University

“Even when a drug reaches the brain’s circulation, abnormal blood vessels in and around tumors lead to non-uniform drug delivery, with low concentrations in some areas of the tumor. If a drug makes it to a region of the tumor and crosses the abnormal blood vessel wall, it encounters dense tissue within the tumor that can block access to malignant cells. We sought to use a new methodology that may improve these abnormal transport properties to enhance drug delivery and efficacy throughout a brain tumor,” he added.

Arvanitis, an assistant professor at Georgia Institute of Technology, worked on this study at? both the Edwin L. Steele Laboratories for Tumor Biology in the MGH Department of Radiation Oncology and in his new Biomedical Acoustics and Image-Guided Therapy laboratory at Georgia Tech.

Focused ultrasound
Focused ultrasound is an early-stage, non-invasive therapeutic technology which?concentrates multiple beams of high-intensity ultrasound energy on a single spot within the body. The technology has the potential to transform the treatment of medical disorders, including cancer, by targeting tissue deep in the body without incisions or radiation.

The study shows how scientists examined the impact of focused ultrasound (FUS) in combination with microbubbles on the transport of two relevant chemotherapy-based anticancer agents in breast cancer brain metastases.

Microbubbles, originally developed in the 1990s to enhance ultrasound scans, are tiny lipid bubbles that vibrate in response to ultrasound signals – injected into the circulation. They resonate in an ultrasound beam, contracting and expanding as pressure changes occur in the ultrasound wave.

Different types of microbubbles possess unique properties that can be leveraged and adjusted for specialized functions and scientists are now using microbubbles for the targeted release of drugs. As a result, patient can be treated with significantly smaller doses than when a chemotherapic drugs is used alone.

Another benefit is that the shell of the microbubble can also prevent the drug from damaging healthy cells. Clinical trials have shown that using microbubbles in this way is significantly more beneficial to patients, who experience dramatically reduced side effects and recover much more rapidly.

Microbubbles are also being investigated as a potential technique for the noninvasive identification of newly forming abdominal adhesions (deposits of fibrous scar tissue) after surgery. These bands of fibrous scar tissue, bridging apposing tissues/organs that form in the abdomen following surgery, can cause significant morbidity and mortality, but also can also cause chronic abdominal or pelvic pain, infertility in women, and potentially fatal intestinal obstructions [2][3][4]

In one study, using microbubbles based on targetable Hybrid Polymerized Liposomal Nanoparticles (HPLN; Nanovalent), scientists, developing noninvasive adhesion treatments, have demonstrated that monodisperse, targeted microbubbles, excited by ultrasound, can be used in a therapeutic mode to breakup soft, fibrinous early-stage adhesions in an animal model.[5][6]

Another use of microbubbles is the delivery of drugs past the blood-brain barrier. One of the unique benefits of using microbubbles is that they can temporarily breach the blood brain barrier at the target site. Although this approach has been studied in animal models with promising results – leading to Phase I clinical trials in conditions including primary brain tumors such as glioblastoma – the underlying mechanisms have not been well understood.

Better understanding
To learn more about and better understand the properties of focused ultrasound treatment of brain tumors, the team of scientists employed advanced microscopy techniques in live mice that had received implants of HER2-positive breast cancer cells in their brains.

In their experiments, the researchers explored the ability of focused ultrasound to enhance delivery of two types of anti-cancer agents – the common chemotherapy drug doxorubicin (Doxil?;?Janssen Products) and the targeted antibody-drug conjugate ado-trastuzumab emtansine or T-DM1 (Kadcyla?; Roche/Genentech) which combines the HER2-antibody-based drug trastuzumab (Herceptin?; Roche/Genentech) with the cytotoxic, tubulin inhibitor DM1 (also known as mertansine and, in some of its forms, emtansine), a thiol-containing maytansinoid.

This approach improved the delivery of both drugs across blood vessel walls, with even greater improvement for the smaller doxorubicin molecule, and it also improved the distribution of both drugs within tumor tissue.

The study, for the first time, showed that focused ultrasound enhanced the permeability of the endothelial cells that line tumor blood vessels, leading those cells to take up doxorubicin.

“Evidence of increased cellular transmembrane transport and uptake of doxorubicin by focused ultrasound was largely unknown until now,” explained co-lead author Vasileios Askoxylakis, MD, PhD, of the Steele Labs at the Massachusetts General Hospital.

“And while focused ultrasound with microbubbles also increased the penetration of? ado-trastuzumab emtansine into tumors, that improvement diminished five days after drug administration, supporting the hypothesis that the accumulation of?ado-trastuzumab emtansine is a result of transiently increased permeability of tumor blood vessels.”

High-resolution imaging allowed the investigators to demonstrate increased flow of the interstitial fluid between cells within a tumor after the application of ultrasound and to reveal its role in improving drug delivery.

Using this approach, the scientists were able to show show significant increases in the extravasation of both therapeutic agents (sevenfold and twofold for doxorubicin and ado-trastuzumab emtansine, respectively), and we provide evidence of increased drug penetration (>100 vs. <20 ?m and 42 ? 7 vs. 12 ? 4 ?m for doxorubicin and ado-trastuzumab emtansine, respectively) after the application of focused ultrasound compared with control (non-FUS).

Mathematical modeling
Mathematical modeling enabled the investigators to quantify focused-ultrasound-induced changes in tissues and cellular transport properties and to identify optimal conditions for improved drug delivery. These results could provide a framework for the development of new strategies and the design of clinical trials that combine promising therapeutics with focused ultrasound.

“By explaining and underscoring the potential of combining focused ultrasound with different drugs for the treatment of brain metastases, our findings provide important scientific principles for the optimal clinical use of the technology,” explained senior author Rakesh Jain, PhD, director of the Steele Labs for Tumor Biology and the Cook Professor of Radiation Oncology at Harvard Medical School.

“In particular, they may allow identification of specific administration protocols for improved drug uptake – such as slow infusion rather than bolus administration – and support the hypothesis that the approach needs to be tested individually for different drugs,” Jain further explained.

“By laying the groundwork for more rational design and deeper understanding of focused-ultrasound-based treatment, our work could help improve treatment of any brain tumor – primary or metastatic – and could also revolutionize approaches to immunotherapy of tumors by improving localized delivery of tumor-killing immune cells,” he concluded.

[1] Arvanitis CD, Askoxylakis V, Guo Y, Datta M, Kloepper J, Ferraro GB, Bernabeu MO, Fukumura D, McDannold N, Jain RK. Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood-tumor barrier disruption. Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):E8717-E8726. doi: 10.1073/pnas.1807105115. Epub 2018 Aug 27.
[2] Lyell DJ, Caughey AB, Hu E, Daniels K. Peritoneal closure at primary cesarean delivery and adhesions. Obstet Gynecol. 2005 Aug;106(2):275-80.
[3] Duron JJ. Postoperative intraperitoneal adhesion pathophysiology. Colorectal Dis. 2007 Oct;9 Suppl 2:14-24
[4] Scott FI, Mamtani R, Haynes K, Goldberg DS, Mahmoud NN, Lewis JD. Validation of a coding algorithm for intra-abdominal surgeries and adhesion-related complications in an electronic medical records database. Pharmacoepidemiol Drug Saf. 2016 Apr;25(4):405-12. doi: 10.1002/pds.3974. Epub 2016 Feb 10.
[5] Ward BC, Panitch A. Abdominal adhesions: current and novel therapies. J Surg Res. 2011 Jan;165(1):91-111. doi: 10.1016/j.jss.2009.09.015. Epub 2009 Oct 2.

Last Editorial Review: December 24, 2018

Featured Image: Brain Cancer. Courtesy: ? 2010 ? 2018 Fotolia. Used with permission. Photo 1.0:?Costas D. Arvanitis, Ph.D, assistant professor at the George W. Woodruff School of Mechanical Engineering, Wallace H. Coulter Dept. of Biomedical Engineering Georgia Institute of Technology and Emory University Courtesy:? ? 2010 ? 2018 George W. Woodruff School of Mechanical Engineering . Used with permission.

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