Thesis
Development of an ultrasound-sensitive platform for co-delivery of oxygen and lonidamine to hypoxic tumor sites
Master of Science (M.S.), Drexel University
Sep 2018
DOI:
https://doi.org/10.17918/00000283
Abstract
Tumor hypoxia, arising from the disorganized vasculature of angiogenesis, remains a barrier to the success of radiation therapy in treating cancer. Hypoxia confers radioresistance onto cancer cells, enabling them to repair DNA that is damaged by ionizing radiation. SE61O2 is an oxygen (O2) microbubble (MB) stabilized by a surfactant shell composed of Span60 and D-[alpha]-Tocopherol polyethylene glycol 1000 succinate (TPGS). These MBs can be injected intravenously to increase the reflection of ultrasound (US) in soft tissues, functioning as an ultrasound contrast agent (UCA). SE61O2 has also shown promise as a platform to deliver O2 to hypoxic tumors, reversing tumor hypoxia and inducing radiosusceptibility in laboratory mice. The duration of this effect, however, is not long enough to be clinically viable in humans. To extend the duration of oxygenation, SE61O2 MBs containing the drug lonidamine (LND), an aerobic respiration inhibitor, have been developed. A protocol for fabricating drug-loaded SE61O2 MBs was first developed using Nile red (NR) as a model hydrophobic drug. This protocol was then used to fabricate LND-loaded SE61O2 MBs (SE61O2-LND). SE61O2-LND MBs were required to demonstrate an acoustic enhancement [greater than or equal to] 15dB, a half-life [greater than or equal to] 1.5 min, and a size [less than or equal to] 6[mu]m. Additionally, they had to be able to deliver an LND dose of at least 2[mu]g/mL. Acoustic characterization of the SE61O2-LND MBs revealed that while they demonstrated sufficient enhancement (23.832 ± 1.317dB), their half-life was 1.333 ± 0.288 minutes. DLS measurements of the MBs revealed that they were 1.597 ± 0.327[mu]m in diameter, well below the 6[mu]m requirement. These findings were not significantly different from those of the MBs made with NR. While LND-loaded MBs were found to contain 5.10 ± 4.48[mu]g/mL LND, loading was inconsistent. Of the 8 samples made, 4 contained less than 2[mu]g/mL LND. Additional work is needed to increase LND loading and improve consistency. A method to assess the in vitro effects of LND using lactate quantification via fluorescence was also explored. This method failed to detect a change in L-lactate concentration following treatment with LND and it was concluded that more sensitive detection methods would have to be used in future work. Implementation of SE61O2-LND MBs has the potential to deliver O2 to reverse tumor hypoxia and slow its consumption by cancer cells by inhibiting aerobic metabolism via LND. This would extend the duration of tumor radiosusceptibility and increase the efficacy of radiation therapies, improving prognoses for patients with both early and late stage cancers.
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Details
- Title
- Development of an ultrasound-sensitive platform for co-delivery of oxygen and lonidamine to hypoxic tumor sites
- Creators
- Nicholas Daroshefski
- Contributors
- Margaret A. Wheatley (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 76 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 991014695546004721