UBC Theses and Dissertations
Development of Zein nanoparticles for in vivo use : proof of concept and preliminary investigation of X-Ray triggered drug release van Ballegooie, Courtney Elizabeth
The gold standard for treating non-resectable, late-stage squamous cell carcinomas in the head and neck regions is through a combined modality approach of radiation therapy (RT) and chemotherapy. Despite its clinical success, a large percentage of patients suffer significant toxicities, which ultimately impact their compliance and quality-of-life. To remedy this, a drug delivery platform utilizing nanoparticles (NPs) could be employed where the NP would sequester the drug during circulation and would preferentially release its payload at the site of the tumor due to an external stimulus, such as RT. The protein, Zein, was selected as the NP platform as it is biocompatible, formulated using non-toxic reagents, and approved by the FDA. While Zein is able to make NPs due to the protein’s intrinsic properties, challenges regarding the reproducibility as well as its stability in physiological conditions are still being investigated. To overcome these limitations, the synthesis method of formulating Zein NPs was first investigated. It was found that Zein NPs synthesized using microfluidics produced consistent formulations. Moreover, the size and polydispersity of the formulations could predictively be modulated and selected in accordance with their intended application. Additionally, Zein NPs when combined with gold NPs demonstrated triggered release in preliminary studies using RT. To make the Zein NPs suitable for in vivo use, the chemical modification of Zein with polyethylene glycol (PEG) was investigated. PEG conjugation was investigated both pre- and post- NP formation and it was discovered that pre- functionalization of the Zein was a more robust method in forming PEG-Zein NPs. When injected intravenously into animals, both high and low PEG containing PEG-Zein NP formulations displayed no acute or chronic toxicities at the doses given (70 mg/kg). Despite the significant potential of PEG-Zein NPs uncovered, multi-dose administration of PEG-Zein NPs caused significant clinical signs upon the second administration (e.g. labored breathing, visible pain, and even death). Therefore, further considerations will be necessary to devise an optimal strategy for PEG-Zein NPs, such as priming of the immune system before PEG-Zein NP administration (e.g. the use of prophylactic therapy) and/or selecting dosing schedules which align with the constraints of the technology.
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