Developing Biomaterial-Based Approaches to Improve Treatment of Ovarian Cancer
2021-04
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Developing Biomaterial-Based Approaches to Improve Treatment of Ovarian Cancer
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2021-04
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In ovarian cancer, the standard of care treatment, which is surgery followed by chemotherapy, has remained relatively unchanged for over the last forty years. However, the overall survival rate for ovarian cancer has stagnated to only ~ 40%. This is due to long-standing clinical challenges in the treatment of ovarian cancer including patients often having advanced stage disease at the time of diagnosis and majority of patients will exhibit recurrence and eventually acquire chemoresistant disease. Unfortunately, after patients no longer respond to chemotherapy, most will succumb to their disease due to the lack of efficacious alternative treatment modalities.The goal of this dissertation was to develop biomaterial-based approaches which can help improve ovarian cancer treatment. In Chapter 2, a biomaterial platform immobilizing ovarian cancer cells into stiff yet porous silica gels is described. The response to immobilization in stiff silica gels by ovarian cancer cells was extensively characterized, and it was shown that this platform can select for ovarian cancer cells with an enhanced ability to enter a non-proliferative state in order to tolerate the stress of physical confinement. Further, these cells could be removed from silica gels and were more resistant to platinum- and taxane-based chemotherapy, despite being proliferative at the time of drug treatment. It was also observed that silica gels could distinguish ovarian cancer cells with enhanced chemoresistance relative to more chemosensitive cells, as seen by enhanced survival upon immobilization. When compared to other in vitro platforms commonly used to induce quiescence, the silica gel immobilization platform could better select for ovarian cancer cells with enhanced chemoresistance.
Chapter 3 discusses a facile method to incorporate iron oxide particles into microporous poly(caprolactone) (PCL) scaffolds previously developed in our group. These scaffolds have previously been shown to recruit metastatic breast cancer cells in vivo, and we sought to modify the scaffolds to be able to non-invasively kill cells after they arrived at this known targetable site. After successful incorporation of iron oxide into the scaffolds, it was demonstrated that they exhibited heating when placed under an alternating magnetic field
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(AMF). Simple design parameters like the amount of iron oxide loaded into scaffolds or magnetic field strength could be tuned to alter the overall temperature rise exhibited by iron oxide-loaded scaffolds under AMF. The iron oxide itself did not cause cytotoxic effects, but iron oxide-loaded scaffolds under AMF could be used to successfully heat and kill loaded ovarian cancer cells in vitro. After implantation in the peritoneal cavity of female mice, iron oxide-loaded scaffolds became infiltrated with tissue after 6-7 weeks, and ex vivo AMF treatment of these iron oxide-loaded scaffolds could be used to kill infiltrated cells. Lastly, non-invasive hyperthermic treatment could be administered to mice with implanted iron oxide-loaded scaffolds, and iron oxide-loaded scaffolds under AMF could effectively kill infiltrated cells in vivo.
Chapter 4 further explores the potential of the PCL-only and iron oxide-loaded scaffolds to be used as a therapy for ovarian cancer. The use of an advanced stage ID8 ovarian cancer mouse model is first described, since our group has not used this type of cancer model before. The mouse model exhibited hallmarks of advanced stage disease, including ascites accumulation and extensive metastases within the peritoneal cavity. Because the ID8 ovarian cancer cells were not labeled, a method to quantify the extent of disease during disease progression and at study end-points was implemented. More importantly, the ability of the scaffolds to capture disseminated ovarian cancer cells in vivo was investigated. PCL-only scaffolds were able to capture disseminated ovarian cancer cells in vivo, regardless of whether they were implanted prior to cancer cell injection or during disease progression. Most notably, iron oxide-loaded scaffolds successfully captured disseminated ovarian cancer cells throughout disease progression, and significant disease formation was not necessary for cancer cell capture at iron oxide-loaded scaffolds. Lastly, future studies to expand upon the work described here are recommended in Chapter 5. Overall, the biomaterial-based approaches developed and discussed in this dissertation could be used to help improve the treatment of ovarian cancer.
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University of Minnesota Ph.D. dissertation. 2021. Major: Chemical Engineering. Advisor: Samira Azarin. 1 computer file (PDF); v, 144 pages.
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Lam, Tiffany. (2021). Developing Biomaterial-Based Approaches to Improve Treatment of Ovarian Cancer. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/220596.
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