Healing sound: the use of ultrasound in drug delivery and other therapeutic applications

Ultrasound, which is routinely used for diagnostic imaging applications, is now being adopted in various drug delivery and other therapeutic applications. Ultrasound has been shown to facilitate the delivery of drugs across the skin, promote gene therapy to targeted tissues, deliver chemotherapeutic drugs into tumours and deliver thrombolytic drugs into blood clots. In addition, ultrasound has also been shown to facilitate the healing of wounds and bone fractures. This article reviews the principles and current status of ultrasound-based treatments.     

Driving delivery vehicles with ultrasound

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.     

Dermal and transdermal drug delivery systems: current and future prospects

The protective function of human skin imposes physicochemical limitations to the type of permeant that can traverse the barrier. For a drug to be delivered passively via the skin it needs to have adequate lipophilicity and also a molecular weight <500 Da. These requirements have limited the number of commercially available products based on transdermal or dermal delivery. Various strategies have emerged over recent years to optimize delivery and these can be categorized into passive and active methods. The passive approach entails the optimization of formulation or drug carrying vehicle to increase skin permeability. Passive methods, however do not greatly improve the permeation of drugs with molecular weights >500 Da. In contrast active methods that normally involve physical or mechanical methods of enhancing delivery have been shown to be generally superior. Improved delivery has been shown for drugs of differing lipophilicity and molecular weight including proteins, peptides, and oligonucletides using electrical methods (iontophoresis, electroporation), mechanical (abrasion, ablation, perforation), and other energy-related techniques such as ultrasound and needless injection. However, for these novel delivery methods to succeed and compete with those already on the market, the prime issues that require consideration include device design and safety, efficacy, ease of handling, and cost-effectiveness. This article provides a detailed review of the next generation of active delivery technologies.     

Application of ultrasound energy as a new drug delivery system

Ultrasound is frequently used in medicine for diagnostic purposes. Recently, there have been numerous reports on application of ultrasound energy for controlling drug release or targeting. This new concept of therapeutic ultrasound combined with drugs has induced excitement in various areas. Ultrasound energy can enhance effects of thrombolytic agents as urokinase. Ultrasound emitting catheters are currently being developed for cardiovascular diseases. Device with ultrasound transducers implanted in transdermal drug patches are also being evaluated for possible delivery of insulin through the skin. Chemical activation of drugs by ultrasound energy for treatment of cancers is another new field recently termed as "Sonodynamic Therapy". Various examples of application of ultrasound for drug delivery systems are discussed.     

Dermal and Transdermal Drug Delivery Systems: Current and Future Prospects

The protective function of human skin imposes physicochemical limitations to the type of permeant that can traverse the barrier. For a drug to be delivered passively via the skin it needs to have adequate lipophilicity and also a molecular weight <500 Da. These requirements have limited the number of commercially available products based on transdermal or dermal delivery. Various strategies have emerged over recent years to optimize delivery and these can be categorized into passive and active methods. The passive approach entails the optimization of formulation or drug carrying vehicle to increase skin permeability. Passive methods, however do not greatly improve the permeation of drugs with molecular weights >500 Da. In contrast active methods that normally involve physical or mechanical methods of enhancing delivery have been shown to be generally superior. Improved delivery has been shown for drugs of differing lipophilicity and molecular weight including proteins, peptides, and oligonucletides using electrical methods (iontophoresis, electroporation), mechanical (abrasion, ablation, perforation), and other energy-related techniques such as ultrasound and needless injection. However, for these novel delivery methods to succeed and compete with those already on the market, the prime issues that require consideration include device design and safety, efficacy, ease of handling, and cost-effectiveness. This article provides a detailed review of the next generation of active delivery technologies.     

Novel Central Nervous System Drug Delivery Systems

For decades, biomedical and pharmaceutical researchers have worked to devise new and more effective therapeutics to treat diseases affecting the central nervous system. The blood–brain barrier effectively protects the brain, but poses a profound challenge to drug delivery across this barrier. Many traditional drugs cannot cross the blood–brain barrier in appreciable concentrations, with less than 1% of most drugs reaching the central nervous system, leading to a lack of available treatments for many central nervous system diseases, such as stroke, neurodegenerative disorders, and brain tumors. Due to the ineffective nature of most treatments for central nervous system disorders, the development of novel drug delivery systems is an area of great interest and active research. Multiple novel strategies show promise for effective central nervous system drug delivery, giving potential for more effective and safer therapies in the future. This review outlines several novel drug delivery techniques, including intranasal drug delivery, nanoparticles, drug modifications, convection‐enhanced infusion, and ultrasound‐mediated drug delivery. It also assesses possible clinical applications, limitations, and examples of current clinical and preclinical research for each of these drug delivery approaches. Improved central nervous system drug delivery is extremely important and will allow for improved treatment of central nervous system diseases, causing improved therapies for those who are affected by central nervous system diseases.     

Liposomes in ultrasonic drug and gene delivery

Liposome-based drug and gene delivery systems have potential for significant roles in a variety of therapeutic applications. Recently, liposomes have been used to entrap gas and drugs for ultrasound-controlled drug release and ultrasound-enhanced drug delivery. Echogenic liposomes have been produced by different preparation methods, including lyophilization, pressurization, and biotin-avidin binding. Presently, significant in vivo applications of liposomal ultrasound-based drug and gene delivery are being made in cardiac disease, stroke and tumor therapy. Translation of these vehicles into the clinic will require a better understanding of improved physical properties to avoid rapid clearance, as well as of possible side effects, including those of the ultrasound. The aim of this review is to provide orientation for new researchers in the area of ultrasound-enhanced liposome drug and gene delivery.     

Strategies for overcoming the stratum corneum

Transdermal drug delivery has many advantages over the oral administration of drugs. This is the reason why many researchers have extensively investigated the transdermal absorption of drugs. However, a much smaller number of drugs are marketed using this route of delivery, compared to oral dosage forms, because drug absorption across the skin is very low due to the stratum corneum (the main barrier for drug absorption across the skin). Overcoming the penetration barrier would significantly improve the development of an efficient transdermal drug delivery system. Several techniques have been developed, or are under development, to bypass the stratum corneum. Approaches that have been made to overcome the stratum corneum fit into five different categories: (i) device and formulation; (ii) modification of stratum corneum by chemical enhancers; (iii) ablation; (iv) bypassing the stratum corneum via appendages; and (v) electrically assisted methods such as iontophoresis and electroporation. Furthermore, possible combinatorial uses of several approaches have been studied. Although the safety issues of these synergistic approaches still require clarification, several combinations could be promising. Finally, there is a necessity to regulate the intradermal disposition of drugs to develop a more efficient transdermal drug delivery system after overcoming the skin barrier.     

Phase-shift, stimuli-responsive drug carriers for targeted delivery

The intersection of particles and directed energy is a rich source of novel and useful technology that is only recently being realized for medicine. One of the most promising applications is directed drug delivery. This review focuses on phase-shift nanoparticles (that is, particles of submicron size) as well as micron-scale particles whose action depends on an external-energy triggered, first-order phase shift from a liquid to gas state of either the particle itself or of the surrounding medium. These particles have tremendous potential for actively disrupting their environment for altering transport properties and unloading drugs. This review covers in detail ultrasound and laser-activated phase-shift nano- and micro-particles and their use in drug delivery. Phase-shift based drug-delivery mechanisms and competing technologies are discussed.     

Ultrasound targeted microbubble destruction for drug and gene delivery

Background: Gas-filled microbubbles have been used as ultrasound contrast agents for some decades. More recently, such microbubbles have evolved as experimental tools for organ- and tissue-specific drug and gene delivery. When sonified with ultrasound near their resonance frequency, microbubbles oscillate. With higher ultrasound energies, oscillation amplitudes increase, leading to microbubble destruction. This phenomenon can be used to deliver a substance into a target organ, if microbubbles are co-administered loaded with drugs or gene therapy vectors before i.v. injection. Objective: This review focuses on different experimental applications of microbubbles as tools for drug and gene delivery. Different organ systems and different classes of bioactive substances that have been used in previous studies will be discussed. Methods: All the available literature was reviewed to highlight the potential of this non-invasive, organ-specific delivery system. Conclusion: Ultrasound targeted microbubble destruction has been used in various organ systems and in tumours to successfully deliver drugs, proteins, gene therapy vectors and gene silencing constructs. Many proof of principle studies have demonstrated its potential as a non-invasive delivery tool. However, too few large animal studies and studies with therapeutic aims have been performed to see a clinical application of this technique in the near future. Nevertheless, there is great hope that preclinical large animal studies will confirm the successful results already obtained in small animals.     

Ultrasound, cavitation bubbles and their interaction with cells

This article reviews the basic physics of ultrasound generation, acoustic field, and both inertial and non-inertial acoustic cavitation in the context of localized gene and drug delivery as well as non-linear oscillation of an encapsulated microbubble and its associated microstreaming and radiation force generated by ultrasound. The ultrasound thermal and mechanical bioeffects and relevant safety issues for in vivo applications are also discussed.     

Cell-based drug delivery

Drug delivery has been greatly improved over the years by means of chemical and physical agents that increase bioavailability, improve pharmacokinetic and reduce toxicities. At the same time, cell based delivery systems have also been developed. These possesses a number of advantages including prolonged delivery times, targeting of drugs to specialized cell compartments and biocompatibility. Here we'll focus on erythrocyte-based drug delivery. These systems are especially efficient in releasing drugs in circulations for weeks, have a large capacity, can be easily processed and could accommodate traditional and biologic drugs. These carriers have also been used for delivering antigens and/or contrasting agents. Carrier erythrocytes have been evaluated in thousands of drug administration in humans proving safety and efficacy of the treatments. Erythrocyte-based delivery of new and conventional drugs is thus experiencing increasing interests in drug delivery and in managing complex pathologies especially when side effects could become serious issues.     

Ultrasound targeted microbubble destruction for drug and gene delivery

Background: Gas-filled microbubbles have been used as ultrasound contrast agents for some decades. More recently, such microbubbles have evolved as experimental tools for organ- and tissue-specific drug and gene delivery. When sonified with ultrasound near their resonance frequency, microbubbles oscillate. With higher ultrasound energies, oscillation amplitudes increase, leading to microbubble destruction. This phenomenon can be used to deliver a substance into a target organ, if microbubbles are co-administered loaded with drugs or gene therapy vectors before i.v. injection. Objective: This review focuses on different experimental applications of microbubbles as tools for drug and gene delivery. Different organ systems and different classes of bioactive substances that have been used in previous studies will be discussed. Methods: All the available literature was reviewed to highlight the potential of this non-invasive, organ-specific delivery system. Conclusion: Ultrasound targeted microbubble destruction has been used in various organ systems and in tumours to successfully deliver drugs, proteins, gene therapy vectors and gene silencing constructs. Many proof of principle studies have demonstrated its potential as a non-invasive delivery tool. However, too few large animal studies and studies with therapeutic aims have been performed to see a clinical application of this technique in the near future. Nevertheless, there is great hope that preclinical large animal studies will confirm the successful results already obtained in small animals.     

Lipid, sugar and liposaccharide based delivery systems

Although there are formidable barriers to the oral delivery of biologically active drugs, considerable progress in the field has been made, using both physical and chemical strategies of absorption enhancement. A possible method to enhance oral absorption is to exploit the phenomenon of lipophilic modification and mono and oligosaccharide conjugation. Depending on the uptake mechanism targeted, different modifications can be employed. To target passive diffusion, lipid modification has been used, whereas the targeting of sugar transport systems has been achieved through drugs conjugated with sugars. These drug delivery units can be specifically tailored to transport a wide variety of poorly absorbed drugs through the skin, and across the barriers that normally inhibit absorption from the gut or into the brain. The delivery system can be conjugated to the drug in such a way as to release the active compound after it has been absorbed (i.e. the drug becomes a prodrug), or to form a biologically stable and active molecule (i.e. the conjugate becomes a new drug moiety). Examples where lipid, sugar and lipid-sugar conjugates have resulted in enhanced drug delivery will be highlighted in this review.     

Nasal and pulmonary drug delivery systems

The respiratory route of administration has long been the medically desired drug delivery portal for the administration of topical anti-inflammatory drugs. These drugs are administered either to the lung, i.e., the lower respiratory system to treat asthma, or to the nasal cavity, i.e., the upper respiratory system to treat allergic rhinitis. This therapeutic focus dominates the drug delivery applications for the respiratory system. More recently, the respiratory system has provided a non-invasive method for the administration of biotherapeutics. And finally, formulation and device advancements have led to the consideration of the respiratory route for a number of other therapeutic applications where systemic delivery is desirable. All of these factors have resulted in the therapeutic patents that are discussed in this review.     

Nasal mucoadhesive drug delivery: background, applications, trends and future perspectives

Nasal drug delivery has now been recognized as a very promising route for delivery of therapeutic compounds including biopharmaceuticals. It has been demonstrated that low absorption of drugs can be countered by using absorption enhancers or increasing the drug residence time in the nasal cavity, and that some mucoadhesive polymers can serve both functions. This article reviews the background of nasal mucoadhesive drug delivery with special references to the biological and pharmaceutical considerations for nasal mucoadhesive drug administration. Applications of nasal mucoadhesives for the delivery of small organic molecules, antibiotics, proteins, vaccines and DNA are also discussed. Furthermore, new classes of functionalized mucoadhesive polymers, the characterization and safety aspects of nasal drug products as well as the opportunities presented by nasal drug delivery are extensively discussed.     

Oral colon-specific drug delivery: a review

The development of delivery systems which enable selective release of drugs in the large intestine has gained much interest during the past decade. Two important therapeutic applications which can be found for oral colon-specific drug delivery are the treatment of local disorders of the colon and the delivery of protein and peptide drugs via the oral route. With the explosion of new peptide and protein products under development in the biotechnology industry, there has been increasing interest in utilizing the colon as site for drug absorption. Indeed, the large intestine may be the best site for peptide delivery because of the high residence time and the low digestive enzymatic activity. Due to the localization of the colon, it is difficult to reach. However, using different approaches, several potential colonic targeting systems have been developed. Among these, the most promissing are coating drugs with pH-sensitive and bacterial degradable polymers; delivery of drugs through bacterial degradable hydrogels or matrix systems; and delivery of drugs via bacterial degradable prodrugs. A major advantage of delivery systems based upon colon-specific enzymes from bacterial origin is the site-specificity. Therefore, other enzyme systems of bacterial origin may be explored in the future.     

Why and how do microbubbles enhance the effectiveness of diagnostic and therapeutic interventions in cerebrovascular disease?

Rapid advances in microbubble pharmacology together with novel ultrasound technologies for contrast-specific imaging of the macro- and microcirculation have led to a number of new applications for assessment of stroke patients. In particular, ultrasound perfusion imaging has added new perspectives for diagnosis and monitoring of both ischemic and hemorrhagic stroke. Recently, real-time brain perfusion imaging of middle cerebral artery infarctions has been introduced and new quantitative algorithms for evaluation of regional cerebral blood flow are being applied for the first time in humans. Microbubbles enable visualization of carotid artery plaque neovascularization to detect plaque vulnerability. There is growing interest in therapeutic applications of ultrasound, particularly in the field of sonothrombolysis. The treatment of acute ischemic stroke can be improved by ultrasound and microbubbles in combination with thrombolytic drugs. Excitingly, ultrasound and microbubbles may be effective in clot lysis of ischemic stroke even without additional thrombolytic drugs. New therapeutic avenues include opening of the blood-brain barrier (BBB) with ultrasound and microbubbles to enable novel drug delivery to the brain. Microbubbles are also assuming a central role in ultrasound molecular imaging with many targets of interest for evaluating pathophysiologic processes involved in cerebrovascular disease including angiogenesis, inflammation, and thrombus formation.     

Ultrasound-mediated drug delivery for cardiovascular disease

Introduction: Ultrasound (US) has been developed as both a valuable diagnostic tool and a potent promoter of beneficial tissue bioeffects for the treatment of cardiovascular disease. These effects can be mediated by mechanical oscillations of circulating microbubbles, or US contrast agents, which may also encapsulate and shield a therapeutic agent in the bloodstream. Oscillating microbubbles can create stresses directly on nearby tissue or induce fluid effects that effect drug penetration into vascular tissue, lyse thrombi or direct drugs to optimal locations for delivery.

Areas covered: The present review summarizes investigations that have provided evidence for US-mediated drug delivery as a potent method to deliver therapeutics to diseased tissue for cardiovascular treatment. In particular, the focus will be on investigations of specific aspects relating to US-mediated drug delivery, such as delivery vehicles, drug transport routes, biochemical mechanisms and molecular targeting strategies.

Expert opinion: These investigations have spurred continued research into alternative therapeutic applications, such as bioactive gas delivery and new US technologies. Successful implementation of US-mediated drug delivery has the potential to change the way many drugs are administered systemically, resulting in more effective and economical therapeutics, and less-invasive treatments.     

Evaluation of the targeted delivery of 5-fluorouracil and ascorbic acid into the brain with ultrasound-responsive nanobubbles

Recently, ultrasound-induced drug delivery into the brain using bubble formulations has been developed. After the brain delivery, however, the information on pharmacokinetics of hydrophilic drugs in the brain is lacking. In this study, to clarify the time-course pharmacokinetics of hydrophilic drugs, we used a brain microdialysis method. Using ultrasound-responsive nanobubbles (bubble liposomes (BLs)) with ultrasound irradiation, two hydrophilic drugs, 5-fluorouracil (5-FU) and ascorbic acid, were delivered into the brain of mice and rats and their time-course pharmacokinetics were evaluated with microdialysis. The results indicated that the time-course pharmacodynamics of ascorbic acid evaluated by examining its antioxidant capacity supported the time-course pharmacokinetics. Additionally, to strengthen the evidences of our evaluation, we varied the effect of BLs dose and duration and intensity of ultrasound irradiation on drug delivery. Among them, when the dose of BLs was changed, the trend of 5-FU intracerebral migration was consistent with other report. In conclusion, we succeeded in clarifying the time-course pharmacokinetics of the two hydrophilic drugs after the brain delivery with bubble formulations and ultrasound irradiation using mice and rats.