Bubbling up: Introducing a new drug delivery method, microbubbles

In this article, Dr Malcolm Haddrick (Medicines Discovery Catapult) and Professor Steve Evans (University of Leeds) highlight the exciting and innovative new method of drug delivery — microbubbles.

A current challenge across the pharmaceutical industry is how to improve the rate of attrition in the delivery of new medicines to patients.¹Innovative drug delivery technologies have the potential to address this challenge by overcoming the cell permeability limitations of promising novel therapeutics (e.g., PROTACs) or by ‘rescuing’ existing drugs with poor solubility or those with a low therapeutic index. Investment in therapeutic delivery platforms has the potential to be broadly impactful across multiple drug modalities that can be applied to a wide range of disease areas.

The Medicines Discovery Catapult, a not-for-profit research company established to support UK drug discovery, is collaborating with the University of Leeds to evaluate microbubble technology as a new drug delivery system. Microbubbles are safe and well tolerated, they are currently in use in the clinic as a contrast-enhancing reagent for ultrasound imaging scans²and have useful properties to exploit as vectors for therapeutic agents.

Microbubbles are micron-sized gas filled phospholipid bubbles which can be manipulated or destroyed by ultrasound energy. They are generated on-chip in a microfluidic production platform³and form the core that enables the assembly of therapeutic microbubble drug complexes.

Drugs, or other modalities, are encapsulated into nanoparticles, such as liposomes, which are attached to the microbubble, achieving high drug loading levels while stabilising the bubbles. Targeting to specific cell surface molecules can also be achieved by the incorporation of antibodies to the bubble and liposome lipids. Post injection into the body, the microbubble complex travels through the circulation and accumulates at the target site, for example a tumour. The drug cargo is then delivered in a controlled way by ultrasound-triggered microbubble destruction which simultaneously generates transient micropores in the cell membrane, enabling drug penetration and activity in cells.

The aim of the Medicines Discovery Catapult and Leeds collaboration is to develop the Horizon microbubble production platform to be suitable for first-in-human trials to treat colorectal cancer within two years. This will include validation of production technology, optimisation of microbubble/drug carrier assembly, pre-clinical assessment of the efficacy of ultrasound enhanced drug delivery and establish safety profiles in multiple drug and disease combinations.

Therefore, microbubble technology can deliver multiple modalities in a targeted way, drug payloads may be ‘masked’ into nanoparticles and activity controlled by ultrasound. This technology is ideally placed to minimise the issues associated with chemotherapy treatments for cancer.⁴The ability to enhance local concentration and the non-invasive nature of the delivery may enable treatment into pharmacological sanctuaries like the blood brain barrier.⁵This is an innovative and exciting new technology option for drug delivery.

References:

1. Waring, M., et al., Nature Reviews Drug Discovery, 2015;14:475–486.
2. Foster, A., et al., Cancer Metastasis Rev., 2000;19(1–2):131–138.
3. Peyman, S.A., et al., Lab Chip 2012;12:4544–4552
4. Ibsen, S., et al., Drug Design, Development and Therapy, 2013;7:375–388.
5. Liu, H.L., et al., Theranostics, 2014;4(4):432–444.