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The Role of Acoustic Cavitation in Ultrasound-triggered Drug Release from Echogenic Liposomes

Kopechek, Jonathan A.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1318878799

Abstract Details

2011, PhD, University of Cincinnati, Engineering and Applied Science: Biomedical Engineering.
Cardiovascular disease (CVD) is the leading cause of death in the United States and globally. CVD-related mortality, including coronary heart disease, heart failure, or stroke, generally occurs due to atherosclerosis, a condition in which plaques build up within arterial walls, potentially causing blockage or rupture. Targeted therapies are needed to achieve more effective treatments. Echogenic liposomes (ELIP), which consist of a lipid membrane surrounding an aqueous core, have been developed to encapsulate a therapeutic agent and/or gas bubbles for targeted delivery and ultrasound image enhancement. Under certain conditions ultrasound can cause nonlinear bubble growth and collapse, known as “cavitation.” Cavitation activity has been associated with enhanced drug delivery across cellular membranes. However, the mechanisms of ultrasound-mediated drug release from ELIP have not been previously investigated. Thus, the objective of this dissertation is to elucidate the role of acoustic cavitation in ultrasound-mediated drug release from ELIP. To determine the acoustic and physical properties of ELIP, the frequency-dependent attenuation and backscatter coefficients were measured between 3 and 30 MHz. The results were compared to a theoretical model by measuring the ELIP size distribution in order to determine properties of the lipid membrane. It was found that ELIP have a broad size distribution and can provide enhanced ultrasound image contrast across a broad range of clinically-relevant frequencies. Calcein, a hydrophilic fluorescent dye, and papaverine, a lipophilic vasodilator, were separately encapsulated in ELIP and exposed to color Doppler ultrasound pulses from a clinical diagnostic ultrasound scanner in a flow system. Spectrophotometric techniques (fluorescence and absorbance measurements) were used to detect calcein or papaverine release. As a positive control, Triton X-100 (a non-ionic detergent) was added to ELIP samples not exposed to ultrasound in order to release encapsulated agents completely. Also, sham samples without Triton X-100 or ultrasound exposure were used as negative controls. Color Doppler ultrasound did not release encapsulated calcein or papaverine from ELIP even though there was a complete loss of echogenicity. In subsequent experiments, calcein and rosiglitazone, a hydrophobic anti-diabetic drug, were separately encapsulated in ELIP and exposed to pulsed Doppler ultrasound in a flow system while monitoring cavitation. Samples were exposed to ultrasound pressures above and below cavitation thresholds. In addition, Triton X-100 was used for positive control samples and sham samples were also tested without ultrasound exposure. Adding Triton X-100 resulted in complete release of encapsulated calcein or rosiglitzone. However, Doppler ultrasound exposure did not induce calcein or rosiglitazone release from ELIP in the flow system even when there was persistent cavitation activity and a loss of echogenicity. The results of this dissertation indicate that cavitation of encapsulated bubbles in ELIP solutions is not sufficient to induce drug release. It is possible that ultrasound-mediated thermal processes may have a stronger effect on ELIP permeability than cavitation activity. Perhaps ultrasound-triggered drug release will be possible by improving the ELIP formulation or encapsulating a different gas instead of air. However, cavitation is not a reliable indicator of ultrasound-mediated drug release with the ELIP formulations used in this dissertation.
Christy Holland, PhD (Committee Chair)
Melvin Klegerman, PhD (Committee Member)
David Manka, PhD (Committee Member)
T. Douglas Mast, PhD (Committee Member)
Daria Narmoneva, PhD (Committee Member)
George Shaw, PhD (Committee Member)
151 p.
Biomedical Research
ultrasound; drug release; echogenic liposomes; acoustic cavitation; contrast agents; cardiovascular disease

Recommended Citations

Citations

  • Kopechek, J. A. (2011). The Role of Acoustic Cavitation in Ultrasound-triggered Drug Release from Echogenic Liposomes [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1318878799

    APA Style (7th edition)

  • Kopechek, Jonathan. The Role of Acoustic Cavitation in Ultrasound-triggered Drug Release from Echogenic Liposomes. 2011. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1318878799.

    MLA Style (8th edition)

  • Kopechek, Jonathan. "The Role of Acoustic Cavitation in Ultrasound-triggered Drug Release from Echogenic Liposomes." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1318878799

    Chicago Manual of Style (17th edition)

ucin1318878799
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© 2011, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.