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Thesis
Development of a Co-loaded Lonidamine and Paclitaxel Ultrasound Contrast Agent for Treatment of Multi-Drug Resistant Tumors
Master of Science (M.S.), Drexel University
Jun 2021
DOI:
https://doi.org/10.17918/00000427
Abstract
Multi-drug resistance (MDR) is a condition often found in breast cancer that significantly reduces the efficacy of chemotherapy. Many factors contribute to this, including tumor hypoxia, which further serves to increase the resistance of tumors to radiotherapy. Combination therapy has been shown to be effective at reversing the effects of MDR through the combined effects of various therapeutics targeting different mechanisms of the tumor. One such combination involves the co-delivery of lonidamine (LND) and paclitaxel (PTX), which has shown greater efficiency in treating and reversing MDR tumors than the delivery of single drug alone. Multimodal therapy takes this principle a step further, and employs combinations of chemotherapy, radiotherapy, surgery, and phototherapy to treat cancer, and has shown greater survival rates in patients than monomodal therapy alone. Currently, our group has developed a LND loaded D-[alpha]-Tocopherol polyethylene glycol 1000 succinate (TPGS) and sorbitan monostearate surfactant stabilized microbubble (LND-SE61 MBs) with an oxygen core for the application of sensitizing hypoxic tumors to radiotherapy. This MB also doubles as an ultrasound contrast agent (UCA), allowing for enhanced ultrasound imaging. The aim of this proof-of-principle study was to further leverage the LND-SE61 MB to include PTX within its surfactant shell in an effort to expand its capability to treat MDR tumors using chemotherapy, as well as to make the tumor more sensitive to radiotherapy, through a multimodal approach. As PTX had not been previously loaded onto the SE61 MB through TPGS micelle solubilization, the first aim of this study was to ensure that this was possible, and that the loading of the drug did not affect its acoustical properties. PTX SE61 MBs were created following a similar protocol to the existing LND SE61 MBs and tested for their drug load and acoustical properties. The PTX SE61 MBs met the required drug load needed for therapeutic benefit (1.7 [mu]g PTX/mL MB), as well as retained the properties of an UCA (enhancement >15 dB, half-life > 1.5min, and diameter < 6 [mu]m). The next step included exploring the dual LND and PTX loading of the SE61 MB. As LND and PTX have very different molecular weights and hydrophilicities, three different methods of LND-PTX dual drug loading were explored in an effort to account for any potential problems that could arise from their differences in chemical structure. Overall, all three methods resulted in MBs with the required drug load for therapeutic benefit for both LND and PTX (1.7 [mu]g PTX/mL MB and 2 [mu]g LND/mL MB). The MBs also maintained their general acoustic properties for an UCA. The next step included creating sterilized PTX and LND-PTX SE61 MBs. There was an overall negligible effect of sterilization found on the drug loaded MB acoustical properties, size populations or drug load.
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Details
- Title
- Development of a Co-loaded Lonidamine and Paclitaxel Ultrasound Contrast Agent for Treatment of Multi-Drug Resistant Tumors
- Creators
- Raj S. Patel
- Contributors
- Margaret A. Wheatley (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- ix, 86 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems; Drexel University
- Other Identifier
- 991015242079004721