Abstract
The localization of microbubbles to a treatment site has been shown to be essential to their effectiveness in therapeutic applications such as targeted drug delivery and gene therapy. A variety of different strategies for achieving localization has been investigated, including biochemical targeting, acoustic radiation force, and the incorporation of superparamagnetic nanoparticles into microbubbles to enable their manipulation using an externally applied magnetic field. The third of these strategies has the advantage of concentrating microbubbles in a target region without exposing them to ultrasound, and can be used in conjunction with biochemical targeting to achieve greater specificity. Magnetic microbubbles have been shown to be effective for therapeutic delivery in vitro and in vivo. Whether this technique can be successfully applied in humans however remains an open question. The aim of this study was to determine the range of flow conditions under which targeting could be achieved. In vitro results indicate that magnetic microbubbles can be retained using clinically acceptable magnetic fields, for both the high shear rates (approx. 104 s−1) found in human arterioles and capillaries, and the high flow rates (approx. 3.5 ml s−1) of human arteries. The potential for human in vivo microbubble retention was further demonstrated using a perfused porcine liver model.
Highlights
Advances in the development of new types of pharmaceutical product have resulted in rapidly growing demand for more effective delivery systems
The results of this study indicate that magnetic targeting of microbubbles can be achieved under flow conditions relevant to human physiology using magnetic fields that are safe for clinical use
With a maximum field of 0.2 T and gradient of 32 T m21, microbubbles were successfully retained in vessel phantoms with diameters ranging from 200 mm to 6 mm and at combinations of shear rates and flow rates corresponding to the larger capillaries, all veins and venules 11 and small arteries
Summary
Advances in the development of new types of pharmaceutical product have resulted in rapidly growing demand for more effective delivery systems. New delivery methods for existing products are being sought to mitigate the impact of patent expiration [1]. While systemic delivery of a drug, e.g. by intravenous or oral administration has significant advantages in terms of convenience and cost, it can lead to harmful side effects [2]. Conventional administration methods are not suitable for several classes of therapeutic compound. These include poorly soluble drugs and large molecules such as proteins, which often produce a negligible therapeutic effect when delivered orally or intravenously [3]. There are three criteria that any drug delivery system should fulfil to provide maximum therapeutic efficacy with minimal unwanted side effects: (i) that it prevents unwanted damage and degradation of the therapeutic material during circulation, (ii) that it ensures the majority of the material is maintained at the desired location(s), and (iii) that it promotes entry of the therapeutic compound into the target tissue [4]
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