Light-responsive polymer-based drug delivery systems

Classical therapy protocols have many limitations due to the molecular characteristics of the active pharmaceutical ingredient (API), and pharmaceutical/biomedical engineers and scientists seek to improve them. There is a continual market need for improved drug delivery systems (DDSs). The use of smart drug delivery systems (SDDSs) capable of the controlled release of drugs at specific locations/times is a very exciting area of research pursued by researchers in academia and industry. The main purpose of SDDSs is to improve the pharmacological activities of the APIs administered. The formulations, approaches and technologies that enable the introduction and movement of pharmaceutical substances in the body and enhance their efficacy and safety are of key importance in SDDSs. The use of polymer-based DDSs will be discussed and an overview of the chemical structures of those polymers will offer an understanding of the mechanisms of drug release, stimuli essential for the drug release and the uses and applications of light responsive polymers. The main aim of the research project is the synthesis of biocompatible light responsive polymers for drug delivery. The first chapter of results in this thesis will illustrate the preparation and characterisation of photoswitchable bioconjugates composed of the hydrophilic natural linear polysaccharide hyaluronic acid (HA) with the hydrophobic 2-diazo-1,2-napthoquinone (DNQ) conjugated to the backbone of the HA. These bioconjugates might offer enhanced therapeutic effects via improving the solubility of poorly water soluble drugs (e.g. doxorubicin, Cabozantinib, Nintedanib, Curcumin, Paclitaxel), pharmacokinetics, clearance, and potential to target cancer stem cells that overexpress cluster of differentiation 44 (CD44). Moreover, the HA-DNQ bioconjugates may assemble into micelle-like structures because of their inherently surfactant-like properties. Interestingly, the HA-DNA bioconjugates are photoresponsive because the DNQ can undergo a UV-induced Wolff rearrangement reaction rendering it hydrophilic, and therefore the micelle-like structures are potentially able to undergo triggered disassembly in response to the application of light. The loading and controlled release of dyes from the HA-DNQ micelle-like structures was studied using various dyes as model drugs. The second chapter of results in this thesis involves the synthesis and characterisation of photocleavable cross-linkers to prepare photoactive polyethyleneglycol (PEG)-based hydrogels with varying quantities of photolabile crosslinkers; their properties were compared to non-photoactive PEG-based hydrogels with equivalent quantities of non-photolabile crosslinkers. In addition, photocleavable PEG derivatives (PEG-ONB-PEG) were also generated. The last chapter of results in this thesis deals with a new compound that was synthesised in Dr John Hardy’s lab by other members of the team (a PhD student Mark Ashton and an MSc student Alex Davey). The results from this chapter include light-sensitive changes to the PEG-hemin conjugates, optionally with a clinically relevant anti-inflammatory drug (dexamethasone 21-phosphate disodium). Keywords Smart drug delivery systems; Drug delivery vehicles; Cancer; Polymer based drug delivery; Photodynamic therapy; Polymeric micelles; Hydrogel with low-molecule-weight; and Light responsive polymer