Degree

Doctor of Philosophy (PhD)

Department

Chemistry

Document Type

Dissertation

Abstract

Delivery of most conventional nanomedicines for tumor treatment is through exploiting the enhanced permeability and retention effect with limited targeting potency. Furthermore, the inability of some nanocarriers to enter the cells via endocytosis, or their limited endocytic escape restrict their applications for intracellular delivery. Liposomal carrier systems offer a solution as they are capable of precisely spatiotemporal releasing the payloads upon sensing specifically targeted environments.

In 2008, the McCarley group demonstrated an example of redox-responsive triggered release of the liposomes, named Q3DOPE, which can potentially take advantage of elevated quinone reductase activities of hNOQ1 in several cancers. The subsequent research projects focus on elaborating the mechanism of content release of Q3DOPE-based liposomes, whose fusion property is not clearly understood. To that end, the research here involved (1) study of membrane asymmetry caused by asymmetrical cleavage of the Q3 group from the outer leaflet of Q3PE-based liposomes determining the liposomal bilayer stability and their fusion properties (2) investigation of symmetrical cleavage of the Q3 group from both leaflets of the liposomes, and its effect on the leakage and fusion of the resulted vesicles. The observations lead to the hypothesis that the membrane asymmetry caused by asymmetrical cleavage of the Q3 group at the outer leaflet of the Q3PE-based liposomes destabilizes their bilayers, which is the key factor dictating the bilayer contact and phase transition with the inclusion of PE lipids in the liposomal composition resulting in a rapid content release. In addition, the fusion of Q3PE-based liposomes is facilitated when their inner leaflet is enriched by POPE lipid but not by DOPE, which emphasizes the importance of the lipids’ lamellar to hexagonal phase transition temperatures to the fusion. The observed fusion in this research is relevant to the fusion of cellular membranes whose bilayers exhibit an uneven distribution of lipids between the two leaflets.

Date

11-22-2019

Committee Chair

McCarley, Robin

Available for download on Wednesday, November 16, 2022

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