Development of Novel Ultra-Deformable Cationic Liposomes for siRNA Delivery to Fibrous Tumors
Open Access
- Author:
- Sutermaster, Bryan A
- Graduate Program:
- Bioengineering
- Degree:
- Master of Science
- Document Type:
- Master Thesis
- Date of Defense:
- None
- Committee Members:
- Peter J Butler, Thesis Advisor/Co-Advisor
- Keywords:
- liposome
siRNA
cancer
drug delivery - Abstract:
- Nanoliposomes continue to be an interesting candidate for overcoming disadvantages in conventional systemic drug delivery, including off-target toxicities and short circulation times. Various modifications, like surface functionalization, use of charged lipids, and antibody conjugation, can be made to liposomes to assist them in ultimately reaching their intended targets in the body. While these common liposome modifications have been exhaustively studied, nanoliposomal mechanics, a feature that may be important for delivery, has not yet been studied due to lack of reliable mechanical characterization modalities. Recently in our lab, we have found that nanoliposomal mechanics can be measured through a series of time-resolved fluorescence experiments. Interestingly, it has been shown that the mechanical properties of drug carriers can affect the rate of phagocytosis by cells; specifically that softer carriers are less readily taken up by cells, making them less likely to be taken up by non-targeted cells in the reticuloendothelial system (RES) and more likely to diffuse through fibrotic tissues characteristic of many cancers. Researchers have noticed that adding mild detergents to the liposome lipid compositions have resulted in a new class of ultra-flexible nanoliposomes for use in topically administered therapies. We hypothesized that the ultra-deformable nanoliposomes, like those being used for topical drug therapies, could display increased circulation time in the bloodstream due to their soft mechanical properties, allowing passive targeting to tumors through the enhanced permeability and retention (EPR) effect. Thus, we set out to design a novel ultra-deformable, cationic, PEGylated nanoliposome of approximately 100nm in diameter for use in siRNA cancer therapeutics. In this thesis we have begun to fine-tune the formulations, synthesis protocols, and characterization protocols to enable future studies to test our hypotheses.