Phase-separated liposomes for efficient macromolecular delivery

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dc.contributor.advisorStachowiak, Jeanne Casstevens
dc.contributor.committeeMemberSmyth, Hugh
dc.contributor.committeeMemberBaker, Aaron
dc.contributor.committeeMemberGordon, Vernita
dc.contributor.committeeMemberZoldan, Janeta
dc.creatorImam, Zachary Ibrahim
dc.date.accessioned2020-10-12T22:07:12Z
dc.date.available2020-10-12T22:07:12Z
dc.date.created2018-08
dc.date.issued2018-07-25
dc.date.submittedAugust 2018
dc.date.updated2020-10-12T22:07:12Z
dc.description.abstractFrom viruses to organelles, fusion of biological membranes is used by diverse biological systems to deliver molecules across membrane barriers. Membrane fusion is a potentially efficient mechanism for the delivery of macromolecular therapeutics and chemotherapeutics to the cellular cytoplasm. However, a key shortcoming of existing fusogenic delivery systems is their inefficiency, requiring a high concentration of fusion-promoting lipids to cross cellular membrane barriers. To address this limitation, my work has explored the extent to which membrane fusion can be amplified through the process of lipid membrane phase-separation to concentrate fusion-promoting lipids within distinct regions on the membrane surface. Towards building a fusogenic phase-separated liposomal system for direct delivery, I began by investigating the impact of incorporating membrane-bound polymers onto the surface of phase-separated liposomes. Membrane-bound polymers like polyethylene glycol (PEG) are used to increase the circulation time of liposomes in vivo and are known to influence lipid phase behavior. My work demonstrates that membrane-bound PEGs crowded on liposome surfaces can generate significant steric pressure, which is sufficient to destabilize phase-separated lipid domains. These data show the importance of optimizing membrane coverage of polymers on the surface of phase-separated liposomes. I next report the development of fusogenic phase-separated liposomes. Specifically, I show that concentrating fusion-promoting lipids within phase-separated domains on liposome surfaces significantly increases the efficiency of liposome fusion with model membranes and cellular membranes. In particular, membrane phase-separation enhances delivery of lipids and model macromolecules to the cytoplasm by at least 4-fold relative to homogenous liposomes. Furthermore, I demonstrate that phase-separated fusogenic liposomes can be loaded with the chemotherapeutic doxorubicin using conventional active loading protocols. These fusogenic phase-separated liposomes reduced the therapeutically effective dose of encapsulated doxorubicin by 4-fold relative to homogeneous liposomes and control liposomes lacking fusogenic lipids. My findings demonstrate that membrane phase-separation can enhance membrane fusion by locally concentrating fusion-promoting lipids on the surface of liposomes. This work represents the first application of lipid membrane phase-separation in the design of biomaterials-based delivery systems. Additionally, these results lay the ground work for developing fusogenic liposomes that are triggered by physical and molecular cues associated with target cells
dc.description.departmentBiomedical Engineering
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/2152/83183
dc.identifier.urihttp://dx.doi.org/10.26153/tsw/10182
dc.language.isoen
dc.subjectPhase-separation
dc.subjectLiposomes
dc.subjectMacromolecular delivery
dc.subjectFusion
dc.subjectChemotherapeutics
dc.subjectSteric pressure
dc.subjectMembrane-bound polymer
dc.titlePhase-separated liposomes for efficient macromolecular delivery
dc.typeThesis
dc.type.materialtext
thesis.degree.departmentBiomedical Engineering
thesis.degree.disciplineBiomedical Engineering
thesis.degree.grantorThe University of Texas at Austin
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

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