Stimuli-responsive biomaterials for drug delivery

Abdelmohsen, Hend and Hardy, John and Copeland, Nikki (2024) Stimuli-responsive biomaterials for drug delivery. PhD thesis, Lancaster University.

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Abstract

Corneal neovascularization is one of the most severe ocular diseases. Current therapy is limited to repeated intraocular injections of antiangiogenic drugs, associated with significant side effects including infection, bleeding and retinal detachment. The work presented herein attempts to address these issues through the development of degradable and cytocompatible light responsive drug delivery systems. These biomaterials facilitate the delivery of therapeutic drugs and nucleic acids, with tuneable, on demand qualities, which highlights their potential for treating a variety of conditions. The translucency of eyes and advances in laser technology in ophthalmology make light-responsive delivery of drugs feasible. Importantly, light can be applied in a non-invasive fashion; therefore, light-triggered drug delivery systems have great potential for clinical application. Novel methacrylate-based photo-responsive polymers are reported here, demonstrating the ability to process them into spherical nanogels. The nanogels comprising an immobilized metformin photocage were shown to release a consistent amount of drug with temporal control when stimulated with light. These nanogels were optimized to release metformin with tailored profiles based on their chemical characteristics. In order to explore the potential for co-delivery of different drugs independently, synthesis of photocleavable drug cage with bathochromic shift was successfully accomplished and incorporated into nanogels. The resulted particles were shown to exhibit sequential wavelength dependent release profiles of ciprofloxacin and metformin in line with their irradiation with infrared light. Methacrylate nanogels suffer from compromised degradability due to the reduced labile groups in their polymer backbone. Therefore, our approach was to modify them via co-polymerization with cyclic ketene acetals via ring opening mechanism. The formulated nanogels displayed improved degradation potential with enzymatic treatment. This should diminish the prospects for inflammatory conditions, thus reducing possible impacts on the patient and the healthcare system. The prepared nanogels in these studies have been shown to generate cytocompatible and degradable polymers that can be processed into drug delivery system suitable for triggered release of payloads. These polymers demonstrated marked ability to suppress the formation of new blood vessels in an in vitro cell model for corneal neovascularization. This project encompasses novel materials utilising photocleavable units to enable stimuli-responsive drug delivery. A range of polymeric nanogels have demonstrated the ability to consistently release controlled amounts of loaded drugs in response to light triggering, which may enable suppression of neovascularization. We anticipate these nanogels will perform well in vivo by selecting the site of ocular administration and non-invasive irradiation with light and thereby improve patient compliance, which will be the subject of future studies.