Abstract by Heidi Kyung Noddeland

Stimuli-responsive drug delivery systems can be tailored to respond to disease-related triggers through appropriate material selection. Patients suffering from chronic inflammatory skin diseases such as psoriasis or atopic dermatitis often experience poor disease control due to the unpredictable and relapsing course of their condition. However, research has shown that enzymes such as matrix metalloproteinases (MMPs) are highly upregulated in inflamed skin compared to healthy skin, offering potential for new treatment interventions. MMP-responsive hydrogels are of particular interest because of their excellent biocompatibility, versatile formulation components, and ability to encapsulate a wide range of therapeutics. As hydrogels are highly hydrated networks, they have the potential to be embedded in the skin to monitor the environment and release their cargo on-demand, boosting the release during inflammation, while minimizing the exposure to healthy cells.

The main objective of the PhD project was to develop and characterise MMP-responsive hydrogels in vitro and in vivo, to establish a pre-clinical proof of concept for treatment of inflammatory skin diseases. Initially, MMP-responsive bulk hydrogels (Ø = 7 mm) were designed and formulated using biscysteine peptide linkers with optimised sensitivity towards MMPs (CGPGG↓LAGGC) and branched 4-arm and 8-arm polyethylene glycols (PEGs) with amide conjugated norbornene by photopolymerisation. The JAK-inhibitor tofacitinib citrate (TC) was used as the model drug throughout the project. Physiochemical characterisation, in vitro release testing, evaluation of cytotoxicity, and efficacy with dermal cells demonstrated desirable physiochemical properties, MMP-responsive release of TC, efficacy in dermal cell assays without signs of cytotoxicity in the conditions investigated. To enable an injectable formulation, MMP-responsive microparticles were formulated using the same materials as for the bulk hydrogels by inverse suspension photopolymerisation. The obtained MMP-responsive microparticles were spherical in shape (Ø = 35 ± 13 µm), enabled encapsulation of TC, and could readily be dispensed through 27G needles. Although a higher release rate of TC was seen for the microparticles compared to the bulk hydrogels, a significant MMP-responsive release could be achieved. After exposure to MMP-9, the microparticles exhibited morphological and mechanical changes, indicating network degradation.

Finally, the MMP-responsive microparticles were evaluated in a pilot study using the imiquimod (IMQ) induced skin inflammation mouse model. Investigation of this model by targeted proteomics revealed that IMQ-treated skin exhibited a significantly higher abundance and broader representation of MMPs compared to control skin. The feasibility of measuring low doses of intradermally injected TC was verified, and a strong indication of MMP-responsive release was seen. This led to development of a comprehensive in vivo study protocol for further investigation of the MMP-responsive microparticles in the IMQ-model. In conclusion, the findings of this thesis present great potential for the MMP-responsive concept to treat inflammatory skin diseases and provide an initial validation for further development and refinement.