Ultrasound-Responsive Cavitation Nuclei for Therapy and Drug Delivery

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Abstract

Therapeutic ultrasound strategies that harness the mechanical activity of cavitation nuclei for beneficial tissue bio-effects are actively under development. The mechanical oscillations of circulating microbubbles, the most widely investigated cavitation nuclei, which may also encapsulate or shield a therapeutic agent in the bloodstream, trigger and promote localized uptake. Oscillating microbubbles can create stresses either on nearby tissue or in surrounding fluid to enhance drug penetration and efficacy in the brain, spinal cord, vasculature, immune system, biofilm or tumors. This review summarizes recent investigations that have elucidated interactions of ultrasound and cavitation nuclei with cells, the treatment of tumors, immunotherapy, the blood–brain and blood–spinal cord barriers, sonothrombolysis, cardiovascular drug delivery and sonobactericide. In particular, an overview of salient ultrasound features, drug delivery vehicles, therapeutic transport routes and pre-clinical and clinical studies is provided. Successful implementation of ultrasound and cavitation nuclei-mediated drug delivery has the potential to change the way drugs are administered systemically, resulting in more effective therapeutics and less-invasive treatments.

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Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress.

Twan Lammers, Fabian Kiessling, Wim E Hennink … (2012)

Many different systems and strategies have been evaluated for drug targeting to tumors over the years. Routinely used systems include liposomes, polymers, micelles, nanoparticles and antibodies, and examples of strategies are passive drug targeting, active drug targeting to cancer cells, active drug targeting to endothelial cells and triggered drug delivery. Significant progress has been made in this area of research both at the preclinical and at the clinical level, and a number of (primarily passively tumor-targeted) nanomedicine formulations have been approved for clinical use. Significant progress has also been made with regard to better understanding the (patho-) physiological principles of drug targeting to tumors. This has led to the identification of several important pitfalls in tumor-targeted drug delivery, including I) overinterpretation of the EPR effect; II) poor tumor and tissue penetration of nanomedicines; III) misunderstanding of the potential usefulness of active drug targeting; IV) irrational formulation design, based on materials which are too complex and not broadly applicable; V) insufficient incorporation of nanomedicine formulations in clinically relevant combination regimens; VI) negligence of the notion that the highest medical need relates to metastasis, and not to solid tumor treatment; VII) insufficient integration of non-invasive imaging techniques and theranostics, which could be used to personalize nanomedicine-based therapeutic interventions; and VIII) lack of (efficacy analyses in) proper animal models, which are physiologically more relevant and more predictive for the clinical situation. These insights strongly suggest that besides making ever more nanomedicine formulations, future efforts should also address some of the conceptual drawbacks of drug targeting to tumors, and that strategies should be developed to overcome these shortcomings. Copyright © 2011 Elsevier B.V. All rights reserved.

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Clinical trial of blood-brain barrier disruption by pulsed ultrasound.

Alexandre Carpentier, Michael Canney, Alexandre Vignot … (2016)

The blood-brain barrier (BBB) limits the delivery of systemically administered drugs to the brain. Methods to circumvent the BBB have been developed, but none are used in standard clinical practice. The lack of adoption of existing methods is due to procedural invasiveness, serious adverse effects, and the complications associated with performing such techniques coincident with repeated drug administration, which is customary in chemotherapeutic protocols. Pulsed ultrasound, a method for disrupting the BBB, was shown to effectively increase drug concentrations and to slow tumor growth in preclinical studies. We now report the interim results of an ultrasound dose-escalating phase 1/2a clinical trial using an implantable ultrasound device system, SonoCloud, before treatment with carboplatin in patients with recurrent glioblastoma (GBM). The BBB of each patient was disrupted monthly using pulsed ultrasound in combination with systemically injected microbubbles. Contrast-enhanced magnetic resonance imaging (MRI) indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic (MRI) or clinical examination. Our preliminary findings indicate that repeated opening of the BBB using our pulsed ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain.

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Understanding ultrasound induced sonoporation: definitions and underlying mechanisms.

Chrit Moonen, Colomban de Vargas, Roel Deckers … (2014)

In the past two decades, research has underlined the potential of ultrasound and microbubbles to enhance drug delivery. However, there is less consensus on the biophysical and biological mechanisms leading to this enhanced delivery. Sonoporation, i.e. the formation of temporary pores in the cell membrane, as well as enhanced endocytosis is reported. Because of the variety of ultrasound settings used and corresponding microbubble behavior, a clear overview is missing. Therefore, in this review, the mechanisms contributing to sonoporation are categorized according to three ultrasound settings: i) low intensity ultrasound leading to stable cavitation of microbubbles, ii) high intensity ultrasound leading to inertial cavitation with microbubble collapse, and iii) ultrasound application in the absence of microbubbles. Using low intensity ultrasound, the endocytotic uptake of several drugs could be stimulated, while short but intense ultrasound pulses can be applied to induce pore formation and the direct cytoplasmic uptake of drugs. Ultrasound intensities may be adapted to create pore sizes correlating with drug size. Small molecules are able to diffuse passively through small pores created by low intensity ultrasound treatment. However, delivery of larger drugs such as nanoparticles and gene complexes, will require higher ultrasound intensities in order to allow direct cytoplasmic entry. Copyright © 2013 Elsevier B.V. All rights reserved.

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Author and article information

Contributors

Klazina Kooiman

Journal

Journal ID (nlm-ta): Ultrasound Med Biol

Journal ID (iso-abbrev): Ultrasound Med Biol

Title: Ultrasound in Medicine & Biology

Publisher: Pergamon Press

ISSN (Print): 0301-5629

ISSN (Electronic): 1879-291X

Publication date PMC-release: 1 June 2020

Publication date (Print): June 2020

Volume: 46

Issue: 6

Pages: 1296-1325

Affiliations

[* ]Department of Biomedical Engineering, Thoraxcenter, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands

[† ]Ghent Research Group on Nanomedicines, Lab for General Biochemistry and Physical Pharmacy, Department of Pharmaceutical Sciences, Ghent University, Ghent, Belgium

[‡ ]Department of Biomedical Engineering, College of Engineering and Applied Sciences, University of Cincinnati, Cincinnati, OH, USA

[§ ]Laboratory for Molecular and Cellular Therapy, Medical School of the Vrije Universiteit Brussel, Jette, Belgium

[¶ ]Cancer Research Institute Ghent (CRIG), Ghent University Hospital, Ghent University, Ghent, Belgium

[║ ]Physical Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada

[# ]Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

[** ]UMR 1253, iBrain, Université de Tours, Inserm, Tours, France

[†† ]Laboratory of Acoustical Wavefield Imaging, Faculty of Applied Sciences, Delft University of Technology, Delft, The Netherlands

[‡‡ ]Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada

[§§ ]Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, United Kingdom

[¶¶ ]Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, Cincinnati, OH, USA

Author notes

[1 ]Address correspondence to: Klazina Kooiman, Office Ee2302, PO Box 2040, 3000 CA Rotterdam, The Netherlands. k.kooiman@ 123456erasmusmc.nl

Article

Publisher ID: S0301-5629(20)30004-1

DOI: 10.1016/j.ultrasmedbio.2020.01.002

PMC ID: 7189181

PubMed ID: 32165014

SO-VID: 03228c46-bf11-40b7-ab27-6f590a95fdbf

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 2 October 2019

Date revision received : 20 December 2019

Date accepted : 7 January 2020

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Ultrasound-Responsive Cavitation Nuclei for Therapy and Drug Delivery

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RNA drug delivery

Most cited references 266

Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress.

Clinical trial of blood-brain barrier disruption by pulsed ultrasound.

Understanding ultrasound induced sonoporation: definitions and underlying mechanisms.

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Cited by 90

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