Driving delivery vehicles with ultrasound

Abstract

Therapeutic applications of ultrasound have been considered for over 40 years, with the mild hyperthermia and associated increases in perfusion produced by ultrasound harnessed in many of the earliest treatments. More recently, new mechanisms for ultrasound-based or ultrasound-enhanced therapies have been described, and there is now great momentum and enthusiasm for the clinical translation of these techniques. This dedicated issue of Advanced Drug Delivery Reviews, entitled "Ultrasound for Drug and Gene Delivery," addresses the mechanisms by which ultrasound can enhance local drug and gene delivery and the applications that have been demonstrated at this time. In this commentary, the identified mechanisms, delivery vehicles, applications and current bottlenecks for translation of these techniques are summarized. KeywordsUltrasound; Therapy; Drug delivery; Gene delivery; Sonoporation; Cavitation As an imaging modality, ultrasound is widely employed and valued for its real time applications, low cost, simplicity, and safety. Waves of alternating increased and decreased pressure propagate from the transducer, typically resulting in a maximum intensity in a focal region chosen by the operator. The dimensions of the focal region can vary from tens of microns for high frequency ultrasound to centimeters for an unfocused therapeutic beam. Most clinical instruments are engineered to effectively image from the body surface to 24 or more centimeters in depth. The ability to locally control and maximize energy deposition deep within the body facilitates a broad range of clinical opportunities for ultrasound imaging and therapy. Developing over four decades, clinical and commercial application of ultrasonic therapies spans hyperthermia, drug delivery, lipoplasty, and thrombolysis [1,2]. A complete and precise summary of the potential applications for ultrasonic enhancement of drug and gene delivery remains challenging as the mechanisms are multiple and not fully characterized. From an engineering viewpoint, the methods by which ultrasound facilitates drug and gene delivery can be summarized as direct changes in the biological or physiological properties of tissues facilitating transport, direct changes in the drug or vehicle increasing bioavailability or enhancing efficacy, and indirect effects by which ultrasound acts on the vehicle to produce changes in the surrounding tissue. While there are common mechanisms between these methods, the engineering challenges associated with the optimization of ultrasound systems and drug and vehicle design are unique for each method. Promising examples of each of these methods can be identified at this time and are addressed below.☆ This commentary is part of the Advanced Drug Delivery Reviews theme issue on "Ultrasound in Drug and Gene Delivery".

Acoustic Cluster Therapy (ACT) — pre-clinical proof of principle for local drug delivery and enhanced uptake

“…In brief, local US insonation of a pathologic condition (e.g. tumor) containing microbubbles in vascular compartments induces bubble oscillations (stable or inertial cavitation) which lead to a variety of biomechanical effects that enhance extravasation and distribution of drug molecules to target tissue [9][10][11][12][13][14]. This approach may hence be explored to improve on the local specificity of a drug, either co-injected with, or attached to microbubbles.…”

Sonosensitive dioleoylphosphatidylethanolamine-containing liposomes with prolonged blood circulation time of doxorubicin

“…Several studies have shown that gas-containing particles are highly sonosensitive (Huang et al, 2008;Unger et al, 1998;Huang and MacDonald., 2004). Unfortunately, gas-filled liposomes are micron-sized and thus too large to allow for effective extravasation into tumour tissue (Ferrara, 2008;Maeda et al, 2000). Another limitation of such particles is the rapid dissolution of the entrapped gas in blood circulation with consequent loss of sonosensitivity (Unger et al, 1998;Ferrara, 2008).…”

Gene Delivery Systems: Recent Progress in Viral and Non-Viral Therapy

“…Ultrasound has many clinical advantages as a gene delivery system, due its easy and reliable procedure (Pitt et al, 2004;Ferrara, 2010). In recent years, it was found that microbubbles applied by ultrasound increased gene expression.…”