The Use of Ultrasound and Micelles in Cancer Treatment

Chemical Engineering Department, American University of Sharjah, Sharjah, United Arab Emirates.
Journal of Nanoscience and Nanotechnology (Impact Factor: 1.56). 06/2008; 8(5):2205-15. DOI: 10.1166/jnn.2008.225
Source: PubMed


The high toxicity of potent chemotherapeutic drugs like Doxorubicin (Dox) limits the therapeutic window in which they can be applied. This window can be expanded by controlling the drug delivery in both space and time such that non-targeted tissues are not adversely affected. Recent research has shown that ultrasound (US) can be used to control the release of Dox and other hydrophobic drugs from polymeric micelles in both time and space. It has also been shown using an in vivo rat tumor model that Dox activity can be enhanced by ultrasound in one region, while in an adjacent region there is little or no effect of the drug. In this article, we review the in vivo and in vitro research being conducted in the area of using ultrasound to enhance and target micellar drug delivery to cancerous tissues. Additionally, we summarize our previously published mathematical models that attempt to represent the release and re-encapsulation phenomena of Dox from Pluronic P105 micelles upon the application of ultrasound. The potential benefits of such controlled chemotherapy compels a thorough investigation of the role of ultrasound (US) and the mechanisms by which US accomplishes drug release and/or enhances drug potency. Therefore we will summarize our findings related to the mechanism involved in acoustically activated micellar drug delivery to tumors.

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Available from: Ghaleb A. Husseini
    • "The majority of clinical research using ultrasound for vascular imaging has employed the use of microbubbles (MBs) as contrast agents to enhance the acoustic signal from the blood. MBs are gas-in-liquid bubbles most often stabilized with albumin, galactose, lipid, or polymers [35]. The average diameters of the MBs are generally around 2.5 μm and can range from 1 to 10 μm. "
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    ABSTRACT: This paper reviews the literature regarding the use of acoustic droplet vaporization (ADV) in clinical applications of imaging, embolic therapy, and therapeutic delivery. ADV is a physical process in which the pressure waves of ultrasound induce a phase transition that causes superheated liquid nanodroplets to form gas bubbles. The bubbles provide ultrasonic imaging contrast and other functions. ADV of perfluoropentane was used extensively in imaging for preclinical trials in the 1990s, but its use declined rapidly with the advent of other imaging agents. In the last decade, ADV was proposed and explored for embolic occlusion therapy, drug delivery, aberration correction, and high intensity focused ultrasound (HIFU) sensitization. Vessel occlusion via ADV has been explored in rodents and dogs and may be approaching clinical use. ADV for drug delivery is still in preclinical stages with initial applications to treat tumors in mice. Other techniques are still in preclinical studies but have potential for clinical use in specialty applications. Overall, ADV has a bright future in clinical application because the small size of nanodroplets greatly reduces the rate of clearance compared to larger contrast agent bubbles and yet provides the advantages of ultrasonographic contrast, acoustic cavitation, and nontoxicity of conventional perfluorocarbon contrast agent bubbles.
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    • "Since US-mediated microbubble destruction is able to reversibly disrupt biological barriers, particularly cell membranes, large quantities of molecules may then be delivered into tumor cells, particularly drug-resistant cells. The mechanism by which this occurs is considered to be sonoporation, resulting from oscillations of the gas bubbles in the media, which cause cavitation close to the cell surface and subsequent membrane disruption that allows increased drug internalization (2). It has been demonstrated that intracellular uptake is greatly enhanced by diagnostic microbubbles used for US imaging (3–5). "
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    ABSTRACT: Combination therapy is used to optimize anticancer efficacy and reduce the toxicity and side-effects of drugs upon systemic administration. Ultrasound (US) combined with micro-bubbles (UM) enhances the intracellular uptake of cytotoxic drugs by tumor cells, particularly drug-resistant cells. In the present study, low-frequency and low-energy US (US irradiation conditions: frequency, 21 kHz; power density, 0.113 W/cm(2); exposure time, 2 min at a duty cycle of 70%; and valid treatment time, 84 sec) were used in combination with microbubbles (100 μl/ml) to deliver mitoxantrone HCl (MIT) to DU145 cells. The results showed that UM did not change the cell viability in the short- or long-term. However, UM statistically enhanced the therapeutic effects and up to 31.26±3.34% of the cells exposed to UM were permeabilized compared with 9.74±2.55% of cells in the control, when using calcein (MW, 622.53) as a fluorogenic marker. Notably, UM affected the migration capability of the DU145 cells at 6 h post-treatment. In conclusion, the ultrasonic parameters used in the present study enhanced the chemotherapeutic effect and reduced the unwanted side-effects of MIT.
    Full-text · Article · Aug 2013 · Oncology letters
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    • "Yet, another effect of ultrasound, especially when using low frequency ultrasound (LFUS), is cavitation; the formation of cavities in a liquid and the subsequent implosion of the cavities which can result in shear forces affecting the nearby tissue [35]. In several studies, release of lipophilic agents from nanoparticles, such as polymeric micelles [36] [37] and liposomes [38] [39] using LFUS due to the induction of cavitation has been demonstrated . Cavitation, however, may also occur in between the transducer and the focal point with LFUS, leading to unwanted damage of healthy tissue. "
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    ABSTRACT: A promising approach for local drug delivery is high-intensity focused ultrasound (HIFU)-triggered release of drugs from stimuli-responsive nanoparticles such as liposomes. The aim of this study was to investigate whether another release mechanism is involved with HIFU-triggered release from liposomes beside cavitation and temperature. Furthermore, it was studied whether this new release mechanism allows the release of lipophilic compounds. Therefore, both a lipophilic (Nile red) and a hydrophilic (fluorescein) compound were loaded into thermosensitive (TSL) or non-thermosensitive liposomes (NTSL) and the liposomes were subjected both to continuous wave- (CW) and pulsed wave (PW)-HIFU. The mean liposome size varied from 97-139 nm with a PDI ≤ 0.06 for the different formulations. The Tm of the phospholipid bilayer of the TSL was around 42 °C. Approximately 80% of fluorescein was released within 15 min from TSL at temperatures ≥ 42 °C. In contrast, no fluorescein release from NTSL and NR release from both TSL and NTSL was observed at temperatures up to 60 °C. Continuous wave (CW)-HIFU exposure of TSL resulted in rapid temperature elevation up to 52 °C and subsequently almost quantitative fluorescein release. Fluorescein release from NTSL was also substantial (~64% after 16 min at 20 W). Surprisingly, CW-HIFU exposure (20 W for 16 min) resulted in the release of NR from TSL (~66% of the loaded amount), and this was even higher from NTSL (~78%). Pulsed wave HIFU (PW-HIFU) exposure did not result in temperatures above the Tm of TSL. However, nearly 85% of fluorescein was released from TSL after 32 min at 20 W of PW-HIFU exposure, whereas the release from NTSL was around 27%. Interestingly, NR release from NTSL was ~30% after 2 min PW-HIFU exposure and increased to ~70% after 32 min. Furthermore, addition of microbubbles to the liposomes prior to PW-HIFU exposure did not result in more release, which suggests that cavitation can be excluded as the main mechanism responsible for the triggered release of both a hydrophilic and a lipophilic model compound from liposomes. DLS analysis showed that the mean size and PDI of the liposomes did not significantly change after CW- and PW-HIFU exposure. Taken together, it is therefore concluded that neither temperature elevation nor inertial cavitation are essential for the release of both hydrophilic and lipophilic compounds from liposomes. It is assumed that the release originates from radiation force-induced acoustic streaming, causing the liposomes to collide at the walls of the exposure chamber leading to shear forces which in turn results in reversible liposome destabilization and release of both hydrophilic and lipophilic compounds.
    Full-text · Article · Apr 2013 · Journal of Controlled Release
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