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Advanced Mesoporous Silica Nanoparticles for the Treatment of Brain Tumors

Bielecki, Peter
http://orcid.org/0000-0002-3917-9322
http://rave.ohiolink.edu/etdc/view?acc_num=case159558503832021

Abstract Details

2020, Doctor of Philosophy, Case Western Reserve University, Biomedical Engineering.
Glioblastoma multiforme (GBM) is resilient to the current standard of care treatment of surgical resection followed by concurrent radiotherapy and temozolomide (TMZ) chemotherapy. GBM patient responses are poor and variable, resulting in more than 90% tumor recurrence and grim survival. The high mortality of GBM is attributed to its invasive peripheral growth, partially intact blood-brain barrier (BBB), regions of hypoxia, and high cellular heterogeneity that includes brain tumor initiating cells (BTICs) and immunosuppressive cells. These features of GBM work together to restrict the delivery of drugs throughout the tumor, suppress immune recognition of tumor cells, and facilitate tumor progression. Nanoparticles are well-suited to address limitations associated with the treatment of GBM by enhancing drug delivery to the tumor and reducing side effects. The overall objective of the work in this dissertation is to develop systemically administered nanoparticles that overcome barriers to drug distribution and cellular heterogeneity in GBM to improve therapeutic responses. In murine GBM models, the effective delivery of Doxorubicin (DOX) chemotherapy, BTIC inhibitor, and immune-stimulating agonists were evaluated using two distinct mesoporous silica nanoparticles (MSNs): 1) the Fe@MSN particle and 2) the immuno-MSN particle. First, drug release from the Fe@MSN particle was triggered using an external radiofrequency (RF) field to enhance the distribution of DOX and/or BTIC inhibitor across the partially intact BBB and into the tumor interstitium. The effective delivery of drugs facilitated by Fe@MSN particles translated into suppressed GBM growth, depleted stem-like cell phenotypes in hypoxic regions, and prolonged or cancer-free survival. Second, towards further improving GBM treatment strategies, the immuno-MSN particle delivered immune-stimulating agonists to dysfunctional immune cells in GBM to reverse the effects of immunosuppression. Immuno-MSN particles facilitated the recruitment of key immune cells to the tumor microenvironment (TME) while sparing healthy brain tissue and peripheral organs, resulting in elevated circulating CD8+ T cells. The findings from this dissertation provide key insights into overcoming physical and cellular barriers to drug delivery in GBM using systemically administered nanoparticles and have potential to improve patient responses to systemic treatments that are otherwise ineffective. Future work includes refining the mesoporous silica nanoparticles and experimenting with combination therapy.
Efstathios Karathanasis, Ph.D. (Advisor)
Agata Exner, Ph.D. (Advisor)
Dominique Durand, Ph.D. (Committee Chair)
Jennifer Yu, M.D., Ph.D. (Committee Member)
154 p.
Biomedical Engineering; Immunology
mesoporous silica nanoparticle; nanoparticle; glioblastoma multiforme; brain tumor; triggered drug release; drug delivery; STING agonist; immunotherapy; glioma stem cell; brain tumor initiating cell

Recommended Citations

Citations

  • Bielecki, P. (2020). Advanced Mesoporous Silica Nanoparticles for the Treatment of Brain Tumors [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case159558503832021

    APA Style (7th edition)

  • Bielecki, Peter. Advanced Mesoporous Silica Nanoparticles for the Treatment of Brain Tumors. 2020. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case159558503832021.

    MLA Style (8th edition)

  • Bielecki, Peter. "Advanced Mesoporous Silica Nanoparticles for the Treatment of Brain Tumors." Doctoral dissertation, Case Western Reserve University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case159558503832021

    Chicago Manual of Style (17th edition)

case159558503832021
309
© 2020, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.