Design of modular and responsive hydrogels for drug delivery using supramolecular interactions
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Date
2024
Publication Type
Doctoral Thesis
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yes
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Abstract
Currently, therapeutics delivery relies heavily on systemic oral or intravenous administration to the patient. To reduce off-site effects and possible premature degradation of the therapeutics, drug delivery platforms are being engineered to enable local, sustained and controlled delivery of therapeutics. Hydrogels have shown their potential as drug delivery platforms because of their biocompatibility, high water content, and ease of therapeutic encapsulation. To allow for simple administration, physical hydrogels leveraging supramolecular interactions as crosslinks are promising. Indeed, the reversible interactions forming the polymer network enable local injection. Of interest, polymer–nanoparticle (PNP) hydrogels are a class of injectable nanocomposite based on reversible interactions between polymer and nanoparticles, which have sown potential drug delivery platforms. Current design of PNP hydrogels is, however, limited to few supramolecular motifs and our understanding of the impact of the crosslinking interactions on the macroscopic properties of the hydrogels is incomplete. In this thesis, we expanded our understanding of how to leverage supramolecular interactions for the rational design of modular nanoparticulate hydrogels by relating molecular interactions, microarchitecture and mechanical properties. We first leveraged a simple supramolecular motif based on α-cyclodextrin (αCD) for the reinforcement of PNP hydrogels. The simple addition of αCD resulted in a concentration dependent increase in mechanical properties through increased polypseudorotaxane formation. Furthermore, the supramolecular motif resulted in increased nanoparticle–nanoparticle interactions, enabling the decoupling of the mechanical properties from the building blocks, allowing the use of interchangeable building blocks from a wide range of biopolymer and nanoparticles. Nonetheless, the origin of the emerging mechanical properties of PNP hydrogel remained poorly described. Building upon this strategy, we engineered a PNP hydrogel using host–guest crosslinks for the investigation of the impact of the supramolecular interactions that form the network on the macroscopic properties of the system. By combining molecular analysis with rheological characterization, we shed light on several underlying mechanisms governing the emergence of the macroscopic properties of PNP hydrogel. Namely, we elucidated the dominant contribution of nanoparticles in network formation, while the polymer mostly provided the required viscosity for gelation. In addition, we leveraged fluorescent and super resolution optical microscopy for the visualization of PNP hydrogel microstructure. We were able to resolve the nanoparticle distribution and investigated the impact of αCD addition on the microarchitecture of the hydrogel. Lastly, we incorporated responsive interactions in the design of a nanogel drug delivery system for the selective delivery of therapeutics upon internalization of the nanocarrier. Through rational chemical design, coupling to protein could be achieved in mild aqueous condition while enabling the chemical-free release of the therapeutic upon exposure to a biological stimulus. Overall, we investigated and leveraged supramolecular and responsive interactions for the design of nanoparticulate-hydrogels targeted to drug delivery application. This work advances the field of supramolecular hydrogel design by creative utilization and extended understanding of the impact of supramolecular interaction on the micro and macro scale properties.
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Contributors
Examiner: Tibbitt, Mark W.
Examiner : Fenton, Owen
Examiner : Weder, Christoph
Examiner: Mommer, Stefan
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ETH Zurich
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Subject
Hydrogel; supramolecular chemistry; Microscopy; Biomaterial; Drug delivery; Nanocomposites; Nanoparticle
Organisational unit
09472 - Tibbitt, Mark / Tibbitt, Mark
Notes
Funding
184697 - Next-generation moldable gels via combined polymer-colloid self-assembly and supramolecular chemistry (SNF)