Alexandria Digital Research Library

Hybrid thermosensitive liposome : nanoparticle drug carrier with triggered release

Forbes, Natalie A.
Degree Grantor:
University of California, Santa Barbara. Chemical Engineering
Degree Supervisor:
Patrick S. Daugherty and Joseph A. Zasadzinski
Place of Publication:
[Santa Barbara, Calif.]
University of California, Santa Barbara
Creation Date:
Issued Date:
Nanotechnology, Engineering, Biomedical, and Engineering, Chemical
Drug Delivery
Dissertations, Academic and Online resources
Ph.D.--University of California, Santa Barbara, 2014

Four key elements are conventionally recognized for an effective drug carrier: "retain, evade, target, and release." Liposomes have been developed that effectively retain drug within the interior, contain a polymer surface coating for extended circulation, and will passively accumulate at the tumor. However, retaining drugs, evading the body's defenses, and accumulating in tumors are not enough. The challenge still facing liposomal drug carriers is initiating and controlling drug release when desired, without compromising drug retention.

We present a novel drug carrier consisting of a thermosensitive liposome coupled to a plasmonic nanoparticle. Continuous-wave irradiation by physiologically friendly near infra-red light at 800 nm generates heating localized to the liposome membrane. The heating increases the liposome permeability in an irradiation dose-dependent manner. Liposome permeability is enhanced through the inclusion of a small molar fraction of single-chained lipid, or lysolipid, resulting in rapid release of small molecules. This enables precise control of contents release with low temperature gradients confined to areas irradiated by the laser focus. Critical to this design is the ability to engineer a liposome with temperature-dependent membrane permeability. We describe the role of lipid structure on membrane transition from the less permeable solid gel to the more permeable fluid phase, and tune the membrane to undergo its transition at a temperature slightly above physiological. We demonstrate enhanced release achieved by the presence of lysolipid, and then present techniques for incorporating micellar-forming agents into pre-formed liposomes in order to synthesize large unilamellar vesicles. This gives us two distinct structures of hybrid liposome-nanoparticle drug carrier---small (200 nm) liposomes with nanoparticles tethered to the exterior surface and large (micron diameter) liposomes with nanoparticles encapsulated within the interior. We attach either hollow gold nanoshells or copper (II) sulfide nanoparticles to the liposome carrier, and then demonstrate rapid and controllable contents release due to the interconversion of light into heat by the nanoparticles. We further demonstrate release in response to localized nanoparticle heating, freeing the system from relying on regional hyperthermia. Finally, we use this system to deliver a common anticancer drug, doxorubicin, to prostate cancer cells in vitro and demonstrate enhanced cell killing.

Physical Description:
1 online resource (171 pages)
UCSB electronic theses and dissertations
Catalog System Number:
Inc.icon only.dark In Copyright
Copyright Holder:
Natalie Forbes
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