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Dissertation
Therapeutic and diagnostic applications of ultrasound contrast media for breast, ovarian and skin cancers
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2008
DOI:
https://doi.org/10.17918/etd-3469
Abstract
Using contrast enhanced ultrasound, molecular markers of disease can be noninvasively imaged. This method is dependent on the administration of a microbubble contrast agent (CA) made site-targeted by the surface attachment of engineered peptides or antibodies that bind to the disease related receptor molecules. The microbubbles selectively retained by the tissues can then be detected using ultrasound. The overall objective of this research is to engineer the surface poly (DL-lactic acid) (PLA) and poly (DL-lactic-co- glycolic acid) (PLGA) based microbubble CAs to facilitate efficient targeting of molecular markers in vitro that can potentially enable the early detection and treatment of breast, skin and ovarian cancers. To enhance the diagnostic application of CAs, this research demonstrated that: (1) echogenic microbubbles can be created with a carboxyl containing surfactant (PEMA) which allowed more targeting ligand to be conjugated to its surface than that of microbubbles made with a hydroxyl containing surfactant (PVA) (p<0.05), although it did not improve cellular targeting ability (p>0.05); (2) a method of physically incorporating a lipid-ligand conjugate (DSPE-PEG-biotin) can be achieved for attaching a variety of targeting ligands; (3) rough-surfaced PLGA 50:50 based microbubbles have a significantly greater cellular attachment than smooth surface microbubbles once ligated with GRGDS (p<0.05); (4) an ultrasound CA targeting CA-125 receptors using anti-CA-125 antibodies bound to the surface of the microbubbles created significant CA attachment (p<0.05) to OVCAR-3 cells. To explore the potential for therapeutic applications a novel ultrasound CA that acts via signal transduction was examined. A TRAIL-modified CA induced a signaling cascade resulting in apoptosis in breast, ovarian and skin cancer cells. Furthermore, TRAIL-modified CA exhibited significantly greater apoptotic effects when combined with a proteasome inhibitor Velcade in melanoma cells (p<0.05). The various aspects of this research were conducted with the intent of combining them with drug delivery in future applications. This would bring together the advantages of site-targeting, drug delivery, and signal transduction with the benefits of ultrasound imaging to effect a significant improvement in cancer detection and treatment.
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Details
- Title
- Therapeutic and diagnostic applications of ultrasound contrast media for breast, ovarian and skin cancers
- Creators
- Kelleny Oum - DU
- Contributors
- Margaret A. Wheatley (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 3469; 991014632257404721