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Nucleation, mapping and control of cavitation for drug delivery

Nature Reviews Physics volume 1, pages 495–509 (2019)Cite this article

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Abstract

Acoustically driven bubbles produce a range of mechanical, thermal and chemical effects that can be exploited in drug delivery applications. Significant improvements in the targeting, distribution and efficacy of both current and emerging therapeutics can be achieved, from small molecules to biologics and nucleic-acid-based drugs. This Review describes how specially designed cavitation nuclei in the form of solid, liquid or gas particles can enable the triggered release of drugs, promote the permeabiliziation of challenging biological barriers and enhance drug delivery through tissue regions where diffusion alone is inadequate. Scalable strategies for mapping and controlling cavitation activity to harness its therapeutic potential at depth within the body are discussed, alongside current and emerging applications for the treatment of diseases, including cancer and stroke.

Key points

  • A major challenge in the treatment of diseases such as cancer and stroke is achieving a sufficient concentration of a drug throughout the target region without producing toxic side effects elsewhere in the body.

  • Oscillating microbubbles driven by ultrasound produce a range of mechanical, thermal and chemical effects that can be used to enable both localized delivery and improved distribution of drugs in tissue.

  • This approach can be used to deliver both conventional small-molecule drugs and more recent biological therapeutics to areas of the body that are normally inaccessible, including across the blood–brain barrier and into solid tumours.

  • Ultrasound-responsive microparticles and nanoparticles can either be used as drug carriers or co-administered with a free drug into the bloodstream, providing cavitation nuclei that reduce the ultrasound pressures required to achieve effective drug delivery.

  • The production of strong acoustic emissions during cavitation-enhanced delivery enables acoustic localization and mapping of bubble activity in real time for treatment monitoring.

The term cavitation encompasses bubble formation produced by changes in fluid pressure (hydrodynamic cavitation), heat (boiling), pressure waves (acoustic cavitation) and absorption of radiation (particle cavitation). Its usage also includes the dynamic behaviour of bubbles, in particular their expansion and collapse. Since the nineteenth century, cavitation has been investigated in fields as diverse as the hunting strategies of marine creatures1, accelerating chemical reactions2 and drug delivery3. Acoustic cavitation produced by ultrasound has been studied extensively in biological systems. Initially, this was to establish standards for the safe use of ultrasound in medical applications4,5. However, it was also recognized that cavitation could have beneficial effects, for example, in the treatment of kidney stones using lithotripsy6, in high-intensity focused ultrasound (HIFU) surgery7 and in the intracellular delivery of molecules8.

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Fig. 1: Schematic of barriers to drug delivery from the tissue to the intracellular scale.
Fig. 2: Illustration of key cavitation-mediated phenomena exploited in drug delivery.
Fig. 3: Schematic of the different mechanisms of cavitation nucleation.
Fig. 4: Oncological, brain, cardiovascular and transdermal applications of microbubble-enhanced drug delivery.
Fig. 5: Challenges and future directions for applications of acoustic cavitation.

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Acknowledgements

The authors thank The Engineering and Physical Sciences Research Council for supporting their work through grants EP/ EP/L024012/1 and EP/L024012.

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Authors and Affiliations

  1. Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, UK

    Eleanor Stride & Constantin Coussios

  2. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK

    Eleanor Stride

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  1. Eleanor Stride
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All authors researched data for the article, discussed the content, wrote the manuscript, and reviewed and edited it before submission.

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Correspondence to Eleanor Stride.

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Competing interests

C.C. is a named inventor on several patents pertaining to cavitation nucleation, mapping, monitoring and control, and a founder, director, shareholder and consultant receiving consultancy income from OxSonics Ltd, a spin-out from the University of Oxford developing a commercial product to enable the clinical translation of cavitation-mediated drug delivery. E.S. is a named inventor on two patents relating to the use of microbubbles for therapeutic applications and a founder of SonoTarg Ltd, a spin-out company developing oxygen-loaded microbubbles for cancer treatment.

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Glossary

Lithotripsy

A medical procedure involving the physical destruction of solid masses such as kidney stones.

High-intensity focused ultrasound

In medicine, this refers to ultrasound with intensities typically exceeding 1,000 W cm−2 used for thermal ablation of tissue, for example, for cancer treatment.

Vascular

Relating to vessels, typically blood vessels.

Endothelium

The layer of cells lining the interior surface of blood or lymphatic vessels.

Microstreaming

The microscale circulation of a viscous fluid produced by an oscillating structure.

Tissue phantoms

Synthetic objects whose physical properties are similar to those of tissue, enabling experiments to be conducted in a realistic environment.

Transcytosis

A process by which material is transported through the interior of a cell by encapsulation within vesicles that are formed on one side of the cell and ejected on the other.

Secondary radiation force

The force generated between two objects as a result of their oscillation, which may be attractive or repulsive.

Echogenicity

Ability to produce strong echoes — reflections or scattering — of an incident ultrasound field.

Superharmonic focusing

The process by which a small acoustically responsive object acts as a lens focusing the high-frequency components of a nonlinearly propagated ultrasound wave.

Extravasation

The leakage of a fluid out of its container; in the context of drug delivery, the transport of material out of the bloodstream into the surrounding tissue.

Beamform

To combine signals with suitable delays to amplify information coming from the region of interest.

Stromal layer

A region of tissue containing cells that are not part of the specific function of the organ in which they reside. In a tumour, this layer consists of cells that are not themselves malignant but present a dense barrier to the diffusion of drugs.

Erythrocyte

Red blood cell whose primary function is the transport of oxygen throughout the bloodstream.

Ischaemic

Referring to restricted blood supply and hence a shortage of oxygen.

Recanalization

The process of restoring flow to a blocked vessel.

Epicardial

Referring to the membrane constituting the outer layer of the heart.

Langerhans cells

Immune cells present in all layers of the epidermis and stimulated during vaccination.

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Stride, E., Coussios, C. Nucleation, mapping and control of cavitation for drug delivery. Nat Rev Phys 1, 495–509 (2019). https://doi.org/10.1038/s42254-019-0074-y

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