Alternating Magnetic Field Radiofrequency Mediated Release of Potential Therapeutic mir-148b Mimic in Non-Small Cell Lung Cancer Cells
Open Access
- Author:
- Casey, Jonathan
- Graduate Program:
- Bioengineering
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- January 15, 2021
- Committee Members:
- Daniel J Hayes, Dissertation Advisor/Co-Advisor
Daniel J Hayes, Committee Chair/Co-Chair
Justin Lee Brown, Committee Member
Scott H Medina, Committee Member
James Hansell Adair, Outside Member
Cheng Dong, Program Head/Chair - Keywords:
- Diels-Alder
Magnetic Nanoparticles
Iron Oxide
MicroRNA
miRNA
miRNA-148b
Alternating Magnetic Field
RadioFrequency
AMF-RF
Cobalt Iron Oxide
Hysteretic Heating - Abstract:
- The microRNAs (miRNAs) are naturally occurring small nucleic acid molecules which play a role in the regulation of gene expression in numerous biological processes. The different biological process miRNAs have been known to affect include embryonic development, specialized cell development (i.e., muscle, nervous, and connective), and cancer cell pathology. The use of interfering RNAs have been investigated as potential therapeutics in treating a variety of different types of cancer. A current limitation of this technology in clinical application has been the controlled spatial and temporal delivery of these therapeutics to affected areas. Off target effects, such as miRNAs ability to affect stem cell differentiation, organ function and modulate vascular function increase risk of health complications from miRNA mimic use. The use of magnetic nanoparticles and their heating response to alternating magnetic field radiofrequency (AMF-RF), potentially allow for controlled delivery of therapeutics at specific times and locations by driving chemical reactions on the surface of the particle. In addition, to the tissue penetration of radiofrequency fields, allows for deep tissue cancers (i.e., lung, liver, pancreatic, etc.) to be more effectively treated using this technology. Exploring possible use of this technology, two different magnetic nanoparticles were investigated, along with various Diels Alder (DA) linkers for the eventual construction of a functioning miRNA mimic delivery system. Iron oxide and cobalt iron oxide nanoparticles, were characterized and their properties investigated. The heating and release profiles of similar Diels-Alder cycloadducts were established on different size and composition nanoparticles. With this system we were able to demonstrate controlled surface release of the payload using different nanoparticles. In the second study two different Diels Alder cycloadducts with different reverse reaction energies were examined. In this study, computational modeling was performed on different DA linkers, heating studies demonstrating payload release at different temperatures ranges, and nanoparticle surface charges were performed. Using these tools, we demonstrated the release of miR-148b mimic in A549 lung cancer cells in-vitro. Using the retro-Diel-Alder reaction, and the response of iron oxide nanoparticles to AMF-RF stimulation, selective release of miR-148b mimic inside A549 lung cancer cells and a reduction in viable cancer cells were achieved. This dissertation investigates different composition and size nanoparticles, different Diels Alder linkers with a range of retro-Diels-Alder forward and reverse reaction energies, and the controlled delivery of miR-148b mimic in A549 cells using modified IONPs.