Sonopermeation to improve drug delivery to tumors: from fundamental understanding to clinical translation

ABSTRACT

Introduction: Ultrasound in combination with microbubbles can make cells and tissues more accessible for drugs, thereby achieving improved therapeutic outcomes. In this review, we introduce the term ‘sonopermeation’, covering mechanisms such as pore formation (traditional sonoporation), as well as the opening of intercellular junctions, stimulated endocytosis/transcytosis, improved blood vessel perfusion and changes in the (tumor) microenvironment. Sonopermeation has gained a lot of interest in recent years, especially for delivering drugs through the otherwise impermeable blood-brain barrier, but also to tumors.

Areas covered: In this review, we summarize various in vitro assays and in vivo setups that have been employed to unravel the fundamental mechanisms involved in ultrasound-enhanced drug delivery, as well as clinical trials that are ongoing in patients with brain, pancreatic, liver and breast cancer. We summarize the basic principles of sonopermeation, describe recent findings obtained in (pre-) clinical trials, and discuss future directions.

Expert Opinion: We suggest that an improved mechanistic understanding, and microbubbles and ultrasound equipment specialized for drug delivery (and not for imaging) are key aspects to create more effective treatment regimens by sonopermeation. Real-time feedback and tools to predict therapeutic outcome and which tumors/patients will benefit from sonopermeation-based interventions will be important to promote clinical translation.

KEYWORDS:

• Sonopermeation
• sonoporation
• ultrasound
• microbubbles
• drug delivery
• drug targeting
• nanomedicine
• cancer
• blood-brain barrier

Article highlights

• We suggest ‘sonopermeation’ as a new term to describe improved drug delivery resulting from the combined use of ultrasound and microbubbles.

• Specialized microbubbles and ultrasound transducers are being developed for drug delivery and therapeutic applications.

• As sonopermeation is being established as one of many treatment options, it will be important to develop tools to stratify tumors and patients, to include only those who are most likely to respond in (initial) clinical trials.

• Protocols enabling real-time feedback on sonopermeation efficacy would be a major step forward towards safe and effective treatment regimens.

• Understanding the underlying mechanisms of sonopermeation will be crucial to optimize efficacy and safety during clinical translation.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors were supported by The Central Norway Regional Health Authority (S Snipstad, E Sulheim), the EU-EuroNanoMed-III project NSC4DIPG (CMoonen, R Schmid, T Lammers), the partnership Program of KWF and STW ‘Technology for Oncology’ (C Moonen, G Storm) and the German Research Foundation (KI1072/11-1, LA2937/1-2, GRK 2375) (F Kiessling, T Lammers).