Ultrasonic drug delivery – a general review

Abstract

Ultrasound (US) has an ever-increasing role in the delivery of therapeutic agents including genetic material, proteins, and chemotherapeutic agents. Cavitating gas bodies such as microbubbles are the mediators through which the energy of relatively non-interactive pressure waves is concentrated to produce forces that permeabilize cell membranes and disrupt the vesicles that carry drugs. Thus the presence of microbubbles enormously enhances delivery of genetic material, proteins and smaller chemical agents. Delivery of genetic material is greatly enhanced by ultrasound in the presence of microbubbles. Attaching the DNA directly to the microbubbles or to gas-containing liposomes enhances gene uptake even further. US-enhanced gene delivery has been studied in various tissues including cardiac, vascular, skeletal muscle, tumor and even fetal tissue. US-enhanced delivery of proteins has found most application in transdermal delivery of insulin. Cavitation events reversibly disrupt the structure of the stratus corneum to allow transport of these large molecules. Other hormones and small proteins could also be delivered transdermally. Small chemotherapeutic molecules are delivered in research settings from micelles and liposomes exposed to ultrasound. Cavitation appears to play two roles: it disrupts the structure of the carrier vesicle and releases the drug; it also makes the cell membranes and capillaries more permeable to drugs. There remains a need to better understand the physics of cavitation of microbubbles and the impact that such cavitation has upon cells and drug-carrying vesicles.

Sonoluminescence and acoustic emission spectra at different stages of cavitation zone development

“…Peaks 2f 0 and 3f 0 may appear in the first stage. In the second stage, higher 8 harmonics, nf 0 (n = 1, 2, 3…), subharmonic, 1/2 f 0 , and frequencies, cf(n + 1/2) f 0 , can be seen in the spectra. Harmonics up to (5-7)f 0 can normally be seen at the second stage.…”

“…This interest is motivated by the promising results obtained during the study of ultrasonically induced biological effects including, I) enhanced cell membrane permeability which improves the delivery of small compounds, macromolecules and other therapeutics into cells and tissues, i.e. sonoporation [6][7][8][9]; II) DNA-mediated transfection [10,11]; III) tumour growth reduction [12,13], and IV) the activation of specific compounds triggering antitumor or antimicrobial activity [14][15][16][17]. It is believed that cavitation plays an important role in these bio-effects.…”

“…It is believed that cavitation plays an important role in these bio-effects. Three types of ultrasound action on biological cells have been identified [6][7][8][9][10][11][12][13][14][15][16][17][18]; damping viability, reversible cell damage (sonoporation) and irreversible damage/cytotoxicity. It is possible that these types of action derive from the different properties that cavitation displays under different conditions, meaning that the monitoring and control of cavitation is therefore an important factor in the successful use of ultrasound in medicine and biology.…”

Tumor pH-responsive flower-like micelles of poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(l-histidine)

“…In tumor treatment the micelles system has proven effective in regression of tumor size while minimizing damage to the healthy tissues [4] and is being actively investigated in conjunction with hyperthermia [5], ultrasound [6], specific enzyme-induced cleavable bonds [7][8][9], and specific ligands or antibodies [10][11][12][13] for active targeting purposes.…”

“…In all measurements (involving either invasive or noninvasive methods) of the pH e of human and animal solid tumors, more than 80% of all measured values consistently fall below a pH of 7.2 [27][28][29]. The development of pH-sensitive drug-carriers therefore maybe a unique strategy and confer advantages over using external stimuli, such as hyperthermia [5] and ultrasound [6] which require exact location of tumors for triggered release [30].…”