Development of Cargo-specific Delivery Systems for the Treatment of Myocardial Infarction
The controlled, site specific delivery of therapeutic agents in a minimally invasive manner is an approach that aims to reduce off-target effects and enhance overall efficacy for a variety of disease states. Conversely, the manifestation of off-target effects is correlated with concentrations of therapeutic agents in healthy tissue. These principles have been acknowledged by researchers for a considerable period of time. However, the vast majority of drug and cell delivery is still performed in arguably a suboptimal fashion, which fails to fully exploit these concepts. An alternative is the use of biomaterials for site specific delivery, to enable longer retention of therapeutic agents within the target tissue. The overall aim of this research was to investigate the use of a number of biomaterials for the controlled delivery of regenerative therapeutics to the heart as on-demand treatment options for tissue damage accrued as a result of a myocardial infarction. These materials were Chitosan/β-Glycerophosphate (GP) thermoresponsive hydrogels loaded with thermosensitive liposomes for the controlled release of pro-angiogenic small molecule drugs (Chapter 2 and Chapter 3). Collagen cardiac patches loaded with alginate microparticles for the controlled release of pro-angiogenic growth factors (Chapter 4). In addition, a cardiac pocket that can enhance retention and enable minimally invasive replenishments of stem cells and small molecule therapeutics within the heart, in a site-specific manner. In Chapter 2, chitosan/β-GP hydrogels were combined with Lysolipid Thermosensitive Liposomes (LTSLs) loaded with the pro-angiogenic small-molecule drug, desferrioxamine (DFO). This formulation (denoted Lipogel) is conceived as an on-demand drug delivery platform that can be injected into the heart in a minimally invasive manner. We demonstrate that Lipogel can provide scheduled release of DFO from the LTSLs in response to a mild hyperthermic stimulus. This formulation demonstrates enhanced retention of DFO within the hydrogel for an extended period of time. Lipogel can be activated and resulting DFO release can provide a dose-responsive increase in the pro-angiogenic cytokine Vascular Endothelial Growth Factor (VEGF).
The flexibility of the Lipogel formulation to provide a variety of release kinetics was investigated in Chapter 3. It was possible to tune the release kinetics of different drugs independently by free loading one therapeutic agent within the gel and activating a second LTSL encapsulated agent via a hyperthermic stimulus. In addition, it was possible to modify the drug dosage within lipogel by varying the duration of hyperthermia. This can allow for adaption of drug dosing in real time. Chapter 4 investigated the potential of a collagen based epicardial patch loaded with alginate microparticles containing both HGF and IGF-1 (denoted CardioColl) to promote the recruitment and expansion of endogenous cardiac stem cells. Release of both growth factors could be extended and was shown to enhance the response of stem cells resident within the heart. Chapter 5 investigated a biocompatible pocket (denoted Thericardium) that can be placed around the heart to enhance retention and permit minimally invasive replenishments of cell therapy and small molecule therapy to the heart. This cardiac pocket enhanced cell retention in the myocardium 24 hours after infarction. In addition, cells could be replenished through an access port 96 hours after infarction and cell retention was enhanced 10 fold. This could also be achieved with a model small molecule drug, enhancing retention 50 fold 96 hours after infarction. In addition, a scaled up pocket for use on a porcine heart permitted the site specific delivery of small molecules to the heart. Collectively, the research presented in this thesis has demonstrated that a number of biomaterials demonstrate a unique potential and flexibility to deliver a variety of therapeutic agents. Lipogel demonstrates remarkable flexibility in terms of drug scheduling and sequencing, this cohesion and controlled release could enable significant enhancements in efficacy and safety. CardioColl represents a novel treatment option to regenerate damaged myocardium. The patch is envisaged as an off-the-shelf option, which would activate stem cell compartments resident in the heart. Finally, the potential for localised delivery with TheriCardium is vast. This cardiac pocket enhances retention of cells and small molecules and can permit their replenishment in a minimally invasive, site-specific manner.