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Advanced Drug Delivery Reviews (v.60, #10)

Editorial Board (pp. ii).

Ultrasound in drug and gene delivery by William G. Pitt Theme Editor; Ghaleb A. Husseini Theme Editor (pp. 1095-1096).

Driving delivery vehicles with ultrasound by Katherine W. Ferrara (pp. 1097-1102).

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.

Keywords: Ultrasound; Therapy; Drug delivery; Gene delivery; Sonoporation; Cavitation

Ultrasound, cavitation bubbles and their interaction with cells by Junru Wu; Wesley L. Nyborg (pp. 1103-1116).

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.

Keywords: Ultrasound; Bioeffects; Acoustic cavitation; Non-linear acoustics; Microstreaming; Acoustic radiation force; Shear stress

Response of contrast agents to ultrasound by Vassilis Sboros (pp. 1117-1136).

Microbubbles are used as ultrasonic contrast agents that enhance the ultrasound signals of the vascular bed. The recent development of site-targeted microbubbles opened up the possibility for molecular imaging as well as localised drug and gene delivery. Initially the microbubbles' physical properties and their response to the ultrasound beam were not fully understood. However, the introduction of fast acquisition microscopy has allowed the observation of the microbubble behaviour in the presence of ultrasound. In addition, acoustical techniques can determine the scatter of single microbubbles. Sonoporation experiments promise high-specificity drug and gene delivery, but the responsible physical mechanisms, particularly for in vivo applications, are not fully understood. An improvement of microbubble technology may address variability related problems in both imaging and drug/gene delivery.

Keywords: Microbubbles; Ultrasound contrast agents; Sonoporation; Molecular imaging; Targeted microbubbles; Drug/gene delivery; Resonance; Cavitation

Micelles and nanoparticles for ultrasonic drug and gene delivery by Ghaleb A. Husseini; William G. Pitt (pp. 1137-1152).

Drug delivery research employing micelles and nanoparticles has expanded in recent years. Of particular interest is the use of these nanovehicles that deliver high concentrations of cytotoxic drugs to diseased tissues selectively, thus reducing the agent's side effects on the rest of the body. Ultrasound, traditionally used in diagnostic medicine, is finding a place in drug delivery in connection with these nanoparticles. In addition to their non-invasive nature and the fact that they can be focused on targeted tissues, acoustic waves have been credited with releasing pharmacological agents from nanocarriers, as well as rendering cell membranes more permeable. In this article, we summarize new technologies that combine the use of nanoparticles with acoustic power both in drug and gene delivery.Ultrasonic drug delivery from micelles usually employs polyether block copolymers and has been found effective in vivo for treating tumors. Ultrasound releases drug from micelles, most probably via shear stress and shock waves from the collapse of cavitation bubbles. Liquid emulsions and solid nanoparticles are used with ultrasound to deliver genes in vitro and in vivo. The small packaging allows nanoparticles to extravasate into tumor tissues. Ultrasonic drug and gene delivery from nanocarriers has tremendous potential because of the wide variety of drugs and genes that could be delivered to targeted tissues by fairly non-invasive means.

Keywords: Targeted delivery; Polymeric micelles; Thermo-responsive polymers; Ultrasound; Non-viral gene transfection; Drug delivery; Nanoemulsions; Solid nanoparticles; Liposomes

Microbubbles in ultrasound-triggered drug and gene delivery by Sophie Hernot; Alexander L. Klibanov (pp. 1153-1166).

Ultrasound contrast agents, in the form of gas-filled microbubbles, are becoming popular in perfusion monitoring; they are employed as molecular imaging agents. Microbubbles are manufactured from biocompatible materials, they can be injected intravenously, and some are approved for clinical use. Microbubbles can be destroyed by ultrasound irradiation. This destruction phenomenon can be applied to targeted drug delivery and enhancement of drug action. The ultrasonic field can be focused at the target tissues and organs; thus, selectivity of the treatment can be improved, reducing undesirable side effects. Microbubbles enhance ultrasound energy deposition in the tissues and serve as cavitation nuclei, increasing intracellular drug delivery. DNA delivery and successful tissue transfection are observed in the areas of the body where ultrasound is applied after intravascular administration of microbubbles and plasmid DNA. Accelerated blood clot dissolution in the areas of insonation by cooperative action of thrombolytic agents and microbubbles is demonstrated in several clinical trials.

Keywords: Ultrasound; Ultrasound contrast agent; Molecular imaging; Microbubbles; Echo; Acoustic; Triggered release

Liposomes in ultrasonic drug and gene delivery by Shao-Ling Huang (pp. 1167-1176).

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.

Keywords: Liposomes; Ultrasound; Drug delivery; Gene delivery; Gases; Nitric oxide

Ultrasonic gene and drug delivery to the cardiovascular system by Christian R. Mayer; Raffi Bekeredjian (pp. 1177-1192).

Ultrasound targeted microbubble destruction has evolved as a promising tool for organ specific gene and drug delivery. This technique has initially been developed as a method in myocardial contrast echocardiography, destroying intramyocardial microbubbles to characterize refill kinetics. When loading similar microbubbles with a bioactive substance, ultrasonic destruction of microbubbles may release the transported substance in the targeted organ. Furthermore, high amplitude oscillations of microbubbles lead to increased capillary and cell membrane permeability, thus facilitating tissue and cell penetration of the released substance. While this technique has been successfully used in many organs, its application in the cardiovascular system has dominated so far. Drug delivery using microbubbles has played a minor role in the cardiovascular system. In contrast, gene transfer has been successfully achieved in many studies. Both viral and non-viral vectors were used for loading on microbubbles. This review article will give an overview on studies that have applied ultrasound targeted microbubble destruction to deliver substances in the heart and blood vessels. It will show potential therapeutic targets, especially for gene therapy, describe feasible substances that can be loaded on microbubbles, and critically discuss prospects and limitations of this technique.

Keywords: Abbreviation; AAV-X; Adeno-associated virus serotype X; AC-VI; adenylyl cyclase type VI; ASK1; Signal-regulating kinase 1; βAR; β-adrenergicreceptor; βARK; β-adrenergicreceptor kinase; βARKct; β-adrenergicreceptor kinase inhibitor; BBB; the blood brain barrier; BM-MNCs; bone-marrow-derived mononuclear cells; CAD; coronary artery disease; CAT; chloramphenicol acetyltransferase; CHF; congestive heart failure; CLI; critical limb ischemia; eNOS; endothelial nitric oxide synthase; FGF-2; Fibroblast growth factor 2; G-CSF; granulocyte colony-stimulating factor; HGF; Hepatocyte growth factor; Hif-1α; Hypoxia induced factor 1 alpha; HRE; hypoxia response elements; I-1; inhibitor-1; ICMP; ischemic cardiomyopathy; LVEF; left ventricular ejection fraction; MB; microbubbles; MCE; myocardial contrast echocardiography; MI; mechanical index; tPA; as tissue-type plasminogen; PAD; peripheral artery disease; PLN; phospholamban; SERCA; sarcoplasmic endoplasmic reticulum calcium ATPase; TIMI; thombolysis in myocardial infarction; TIMP-3; tissue inhibitor of metalloproteinase 3; UTMD; ultrasound targeted microbubble destruction; VEGF; Vascular endothelial growth factor; VSMC; vascular smooth muscle cellsMicrobubble; Ultrasound; Gene therapy; Drug delivery; Cardiovascular system; Heart

Ultrasound mediated delivery of drugs and genes to solid tumors by Victor Frenkel (pp. 1193-1208).

It has long been shown that therapeutic ultrasound can be used effectively to ablate solid tumors, and a variety of cancers are presently being treated in the clinic using these types of ultrasound exposures. There is, however, an ever-increasing body of preclinical literature that demonstrates how ultrasound energy can also be used non-destructively for increasing the efficacy of drugs and genes for improving cancer treatment. In this review, a summary of the most important ultrasound mechanisms will be given with a detailed description of how each one can be employed for a variety of applications. This includes the manner by which acoustic energy deposition can be used to create changes in tissue permeability for enhancing the delivery of conventional agents, as well as for deploying and activating drugs and genes via specially tailored vehicles and formulations.

Keywords: High intensity focused ultrasound (HIFU); Drug and gene delivery; Hyperthermia; Acoustic cavitation; Acoustic radiation forces

Ultrasound for drug and gene delivery to the brain by Kullervo Hynynen (pp. 1209-1217).

Noninvasive, transient, and local image-guided blood-brain barrier disruption (BBBD) has been demonstrated with focused ultrasound exposure in animal models. Most studies have combined low pressure amplitude and low time average acoustic power burst sonications with intravascular injection of pre-formed micro-bubbles to produce BBBD without damage to the neurons. The BBB has been shown to be healed within a few hours after the exposure. The combination of focused ultrasound beams with MR image guidance allows precise anatomical targeting as demonstrated by the delivery of several marker molecules in different animal models. This method may in the future have a significant impact on the diagnosis and treatment of central nervous system (CNS) disorders. Most notably, the delivery of the chemotherapy agents (liposomal Doxorubicin and Herceptin) has been shown in a rat model.

Keywords: Ultrasonics; Magnetic resonance imaging; Drug delivery systems; Ultrasound contrast agents; Blood-brain barrier; Brain; Targeted drug delivery; Image-guided therapy; Drug delivery; HIFU; Focused ultrasound; Ultrasound

Low-frequency sonophoresis: Current status and future prospects by Makoto Ogura; Sumit Paliwal; Samir Mitragotri (pp. 1218-1223).

Application of ultrasound enhances skin permeability to drugs, a phenomenon referred to as sonophoresis. Significant strides have been made in sonophoresis research in recent years, especially under low-frequency conditions (20 kHz< f<100 kHz). This article reviews the mechanistic principles and current status of sonophoresis under low-frequency conditions. Several therapeutic macromolecules including insulin, low-molecular weight heparin, and vaccines have been delivered using low-frequency sonophoresis in vivo. Clinical trials have been performed with several drugs including lidocaine and cyclosporin. Novel theoretical and experimental approaches have provided insights into the mechanisms of low-frequency sonophoresis. Current understanding of these mechanisms is presented.

Keywords: Ultrasound; Cavitation; Transdermal delivery; Skin

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Advanced Drug Delivery Reviews (v.60, #10)