Drug delivery systems for glioblastoma therapy
| dc.contributor.author | Norouzi, Mohammad | |
| dc.contributor.examiningcommittee | Moussavi, Zahra (Biomedical Engineering) Gu, Xiaochen (Restorative Dentistry) Panyam, Jayanth (Pharmaceutics, University of Minnesota) | en_US |
| dc.contributor.supervisor | Miller, Donald W. (Pharmacology and Therapeutics) | en_US |
| dc.date.accessioned | 2020-01-17T17:44:52Z | |
| dc.date.available | 2020-01-17T17:44:52Z | |
| dc.date.issued | 2020 | en_US |
| dc.date.submitted | 2020-01-14T17:54:27Z | en |
| dc.degree.discipline | Biomedical Engineering | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Many chemotherapeutics suffer from an inability to penetrate the blood-brain barrier (BBB) and to reach the target site within the brain to treat Gliomas. In the present study, various drug delivery systems were developed with the goal of overcoming the BBB and delivering chemotherapeutics (i.e. doxorubicin, and salinomycin) for the treatment of glioblastoma multiforme (GBM). In the first scenario, biocompatible magnetic iron oxide nanoparticles (IONPs) with negative and positive charge coatings were developed as drug delivery systems of doxorubicin and salinomycin, respectively. The drug-loaded IONPs exhibited a gradual release of their payloads within 4 days and were found to be effective in ROS induction, and activation of both caspases and tumor suppressors (i.e. p53, MEG3 and GAS5) in human GBM cells. Utilizing an in vitro BBB-GBM co-culture model, the permeability of both salinomycin- and doxorubicin-loaded IONPs through the confluent cell monolayer was significantly enhanced using an external magnetic field and transient enhanced permeability of the BBB (using either hyperosmotic mannitol or a cyclic cadherin binding peptide). In the second scenario, injectable thermosensitive hydrogels were developed as local drug delivery systems of salinomycin at the tumor site. The drug-loaded Pluronic released salinomycin over a week and decreased GBM cell viability by ca. 90% within 48 hours of treatment, which was significantly more effective than that of free salinomycin (cell viability reduction of ca. 50%). Animal studies in subcutaneous U251 xenografted nude mice also revealed that salinomycin -loaded Pluronic reduced the tumor growth compared to the free salinomycin- and PBS-treated mice by 2-fold and 2.6-fold, respectively within 11 days. Taken together, it is envisaged that the developed drug-loaded IONPs in combination with an external magnetic field and transient enhanced permeability of the BBB can provide an efficient approach to overcome the limited BBB permeability and deliver chemotherapeutics at the tumor site within the brain. Also, the salinomycin-loaded Pluronic hydrogel provides a local drug delivery approach to treat brain tumors by which not only the BBB is bypassed, but also the systemic drug exposure and toxicity are diminished and high doses of the chemotherapeutic can locally be administered at the tumor site. | en_US |
| dc.description.note | May 2020 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/34520 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Iron oxide nanoparticles | en_US |
| dc.subject | Injectable hydrogels | en_US |
| dc.subject | Glioblastoma | en_US |
| dc.subject | Drug delivery | en_US |
| dc.title | Drug delivery systems for glioblastoma therapy | en_US |
| dc.type | doctoral thesis | en_US |