Evaluating the properties and uses of metal-organic framework (MOF) and polymer nanoparticles for applications in vaccines and pulmonary drug delivery
Date
2022
Authors
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Publisher
University of Delaware
Abstract
Pulmonary administration offers many advantages for biomedical applications because of the ability to deliver cargo locally and systemically. For drug delivery, the pulmonary route of administration generally has high bioavailability of delivered therapeutics and can avoid off-target effects for pulmonary diseases alongside avoidance of first-pass clearance. In particular, nanomedicine approaches to pulmonary drug delivery using biomaterials have risen in prominence because of the ability to have ready cellular internalization of nanomaterials and high loading capacity of therapeutic cargo. However, identifying nanomaterials that have tunable applications and ideal suitability for pulmonary drug delivery remains a challenge. ☐ In this work, we evaluate two types of nanomaterials for pulmonary therapeutic delivery applications: poly(ethylene glycol) (PEG) hydrogel and metal- organic framework (MOF) nanoparticles. PEG has impressive biocompatibility and can lead to sustained release of cargo; however, the properties of PEG-based nanoparticles (NPs) are often conflated with macroscopic gels. In this dissertation, we characterize the degradation rate and products of PEG-based NPs to better understand the effects of these characteristics for tuning interactions with pulmonary innate immune cells, macrophages. We discover that a variety of PEG-based NP formulations, particularly those with degradable crosslinkers, increase the survival of macrophages in a tunable manner. These results could affect a number of cell-based therapies that rely on survival of macrophages such cancer vaccines. ☐ The second class of NPs evaluated is that of MOFs. MOFs have advantages for drug delivery and vaccine applications because of their high porosity, variable chemistry in their organic linkers and metal clusters, and tunable physiochemical properties. In this dissertation, we first explore the use of UiO-66, a zirconium-based MOF, as a pulmonary drug delivery vehicle. Through the modulation of the synthesis of UiO-66 via precise modulation of water and linker amounts, we present a strategy to control NP size as well as missing linker extents and report the discovery of inherent UiO-66 fluorescence, a huge boon for theranostic applications. We demonstrate that the aerodynamic properties of UiO-66 are of the range leading to efficient aerosol delivery and the NP framework shows biocompatible both in vitro and in vivo. Moreover, UiO-66 NPs can successfully be loaded with cargo that is selectively released in environments that mimic intracellular pH. Building from these successes, we evaluate a series of aluminum-based MOFs for pulmonary vaccination, given their structural similarities to alum, a vaccine adjuvant that elicits strong humoral immune responses. In vitro and in vivo examinations reveal that the Al-based MOF NPs activated macrophages more effectively than alum and were able to generate robust mucosal IgA and serum IgG antibodies, specifically IgG2a, following a murine pulmonary vaccination study that indicates creation of effective local and cellular immune responses. Furthermore, many of the Al-based MOF NPs fell into the ideal aerodynamic size range for alveolar deposition, unlike alum. The results demonstrate great potential for use of Al-based MOFs for pulmonary vaccination and highlight overall the potential for molecularly-defined NPs as novel pulmonary delivery strategies.
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Keywords
Drug delivery, Metal-organic framework, Nanoparticle, Polymer, Pulmonary, Vaccines