The high toxicity of potent chemotherapeutic drugs like Doxorubicin (Dox) limit their therapeutic window; however, this window can be expanded by controlling the drug delivery in both space (selective to the tumor volume) and time (timing and duration of release) such that surrounding tissues are not adversely affected. Our recent research showed that ultrasound (US) can control the release of Dox from special micellar carriers (Plurogels) in vitro. The release appears to also occur in vivo in a rat tumor model such that a targeted tumor had smaller volume than a bilateral non-targeted tumor (p=0.006), and the heart appeared to be spared from the cardiotoxicity of Dox. These previous studies were done with low frequency ultrasound that is difficult to focus.
The aims of this research are to test our hypotheses regarding the role of ultrasound in causing the drug release and show that 500 kHz ultrasound can be focused to provide local release. In vitro studies will test the hypothesis that cavitation bubble activity causes release of the drug. Markers of cavitational activity will be measured, and static pressure will be varied to prove the role of cavitation. A bilateral tumor model in rats will show whether localized release can be accomplished in vivo with focused ultrasound. One tumor will be exposed to ultrasound of various frequencies, intensities, and durations, and both tumors will be measured to determine which acoustic parameters cause selective regression of the targeted tumor. We will also measure cardiotoxicity, which is a common side effect when treating with Dox, but which we hypothesize will be minimized by sequestering the Dox in the Plurogel carrier. We will also test the hypothesis that cavitation activity perturbs cells in the focal region such that the insonated cells take up more drug than otherwise. Such cell permeation will also be correlated with markers of cavitational activity to verify the role of cavitation. The research outcomes will prove hypotheses, which will become the basis for understanding and exploiting this therapy in the treatment of localized cancers, hopefully paving the way for clinical application.
| Diaz de la Rosa, Mario A; Husseini, Ghaleb A; Pitt, William G (2013) Mathematical modeling of microbubble cavitation at 70 kHz and the importance of the subharmonic in drug delivery from micelles. Ultrasonics 53:97-110 |
| Diaz de la Rosa, Mario A; Husseini, Ghaleb A; Pitt, William G (2013) Comparing microbubble cavitation at 500 kHz and 70 kHz related to micellar drug delivery using ultrasound. Ultrasonics 53:377-86 |
| Singh, Ram; Husseini, Ghaleb A; Pitt, William G (2012) Phase transitions of nanoemulsions using ultrasound: experimental observations. Ultrason Sonochem 19:1120-5 |
| Staples, Bryant J; Pitt, William G; Roeder, Beverly L et al. (2010) Distribution of doxorubicin in rats undergoing ultrasonic drug delivery. J Pharm Sci 99:3122-31 |
| Husseini, Ghaleb A; Stevenson-Abouelnasr, Dana; Pitt, William G et al. (2010) Kinetics and Thermodynamics of Acoustic Release of Doxorubicin from Non-stabilized polymeric Micelles. Colloids Surf A Physicochem Eng Asp 359:18-24 |
| Husseini, Ghaleb A; Pitt, William G (2009) Ultrasonic-activated micellar drug delivery for cancer treatment. J Pharm Sci 98:795-811 |
| Husseini, Ghaleb A; Pitt, William G; Christensen, Douglas A et al. (2009) Degradation kinetics of stabilized Pluronic micelles under the action of ultrasound. J Control Release 138:45-8 |
| Staples, Bryant J; Roeder, Beverly L; Husseini, Ghaleb A et al. (2009) Role of frequency and mechanical index in ultrasonic-enhanced chemotherapy in rats. Cancer Chemother Pharmacol 64:593-600 |
| Stringham, S Briant; Viskovska, Maria A; Richardson, Eric S et al. (2009) Over-pressure suppresses ultrasonic-induced drug uptake. Ultrasound Med Biol 35:409-15 |
| Husseini, Ghaleb A; Pitt, William G (2008) Micelles and nanoparticles for ultrasonic drug and gene delivery. Adv Drug Deliv Rev 60:1137-52 |
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