Magnetic field-induced intramolecular cyclization as a trigger for nanoparticle-based delivery systems.

nanoparticle;drug delivery;iron oxide-gold;intramolecular cyclization

Sara Katherine Biladeau

University:University of Louisville

Department:Chemistry

关键词: nanoparticle;    drug delivery;    iron oxide-gold;    intramolecular cyclization;   

Others  :  https://ir.library.louisville.edu/cgi/viewcontent.cgi?article=3916&context=etd

美国|英语

来源: The Universite of Louisville's Institutional Repository

【 摘 要 】

Magnetic nanoparticles (MNPs) are used in a variety of applications, including as agents for magnetic resonance imaging, generation of local hyperthermia, and as platforms for drug delivery. Iron-based MNPs are often coated with a shell, such as silica or gold, to increase biocompatibility for drug delivery applications. Many MNPs used for cancer therapy rely on either an internal trigger, such as a difference in pH, or an external trigger, such as light or an alternating magnetic field (AMF), to cause release of a payload, typically a chemotherapeutic drug. Internal triggers are appealing because drug release can be targeted to a tumor environment, but a major drawback is untriggered release, or release prior to reaching the targeted area. To address the problem of untriggered release, researchers have explored the use of thermally responsive triggers on iron oxide nanoparticles. In these cases, payload release occurs as a result of local hyperthermia that is induced by application of an alternating magnetic field. NP-linker-drug motifs containing an azo functionality or a substructure prone to retro-Diels Alder reaction are examples of thermally responsive triggers. This thesis work expands AMF-mediated drug delivery by demonstrating a new mechanism for substrate release: intramolecular cyclization of a linking tether between payload and nanoparticle. Described is a linker system (LS) fitted with a thiol moiety, a secondary amine, carbonate functionality, and a payload. Attachment of the linker system to gold-coated iron oxide nanoparticles delivers a thermally responsive drug delivery system (Fe@Au-LS-drug). On exposure to an AMF, the magnetic nanoparticles generate heat that powers cyclization of the amine onto the carbonate for payload release to occur. The cyclization mechanism was confirmed by synthesis and testing of an amine-free linker to rule out carbonate hydrolysis as the mode of payload release. Testing the system with a water-soluble fluorophore as payload showed 40% release in response to AMF application with minimal release from the amine-free linker under identical conditions. Payload release could be increased to nearly 100% by addition of PEG-coated iron oxide nanoparticles as a means to increase local hyperthermia. This work shows for the first time that the highly flexible process of intramolecular cyclization can serve in conjunction with magnetic iron-gold nanoparticles as a delivery system trigger for externally triggered applications. Chapter 1 reviews the role of iron oxide nanoparticles in delivery applications and summarizes the challenges of drug delivery using various internally and externally responsive linkers. Chapter 2 describes different