Development of a Size Targeted Formulation to Treat Pulmonary Arterial Hypertension

The aim of this thesis is to develop a novel formulation for the treatment of Pulmonary Arterial Hypertension (PAH). PAH is a rare but serious disease which is invariably fatal without treatment. Vascular remodelling and an increase in vascular resistance lead to increased pulmonary arterial pressure and right ventricular overload, which ultimately result in right-sided heart failure and death. While treatments are available for PAH, they suffer from a lack of proven effect on mortality, serious administration problems and systemic side effects which can have a significant effect on patients’ quality of life. This project follows the development of a new approach to tackling the problems with current PAH treatments. A novel nanoparticle aggregate formulation has been produced using the biodegradable and biocompatible polymer, poly(glycerol adipate). This formulation is intended to use particle size to become mechanically trapped in the lung vasculature following intravenous administration, allowing the prostacyclin to be released in situ with the hope that this will improve drug efficacy and decrease the occurrence of side effects, thereby improving the quality of life and life expectancy of patients with PAH. A range of modifications of PGA were produced for use in this project. These included novel polymer-drug conjugates such as PGA-Iloprost and PGA- Ambrisentan. A range of techniques have been used to characterise the enzymatic degradation of PGA and provide an indication of the way the polymer will behave and release drug payloads in vivo. The results of these degradation studies confirm PGA is deserving of the labels biodegradable and biocompatible. The influence of a variety of factors on the particle size of both microparticle and nanoparticle aggregate formulations has been studied. In contrast to much of the literature, processing parameters were found to have no effect on particle size, which was instead dependent on the modifications to the polymer backbone and the way in which the polymer chains interacted. Finally, the cytotoxicity of PGA has been assessed, with the polymer having no effect on the metabolic activity of BAE-1 bovine aortic endothelial cells. PGA- Iloprost nanoparticles were found to elevate the levels of cyclic adenosine monophosphate in human pulmonary arterial smooth muscle cells isolated from a patient with PAH, indicating pharmacological efficacy. Overall, the results presented in this thesis suggest that size-targeted lung delivery of a prostacyclin is a viable approach to treating PAH which warrants further investigation

Development of a Size Targeted Formulation to Treat Pulmonary Arterial Hypertension

The aim of this thesis is to develop a novel formulation for the treatment of Pulmonary Arterial Hypertension (PAH). PAH is a rare but serious disease which is invariably fatal without treatment. Vascular remodelling and an increase in vascular resistance lead to increased pulmonary arterial pressure and right ventricular overload, which ultimately result in right-sided heart failure and death. While treatments are available for PAH, they suffer from a lack of proven effect on mortality, serious administration problems and systemic side effects which can have a significant effect on patients’ quality of life. This project follows the development of a new approach to tackling the problems with current PAH treatments. A novel nanoparticle aggregate formulation has been produced using the biodegradable and biocompatible polymer, poly(glycerol adipate). This formulation is intended to use particle size to become mechanically trapped in the lung vasculature following intravenous administration, allowing the prostacyclin to be released in situ with the hope that this will improve drug efficacy and decrease the occurrence of side effects, thereby improving the quality of life and life expectancy of patients with PAH. A range of modifications of PGA were produced for use in this project. These included novel polymer-drug conjugates such as PGA-Iloprost and PGA- Ambrisentan. A range of techniques have been used to characterise the enzymatic degradation of PGA and provide an indication of the way the polymer will behave and release drug payloads in vivo. The results of these degradation studies confirm PGA is deserving of the labels biodegradable and biocompatible. The influence of a variety of factors on the particle size of both microparticle and nanoparticle aggregate formulations has been studied. In contrast to much of the literature, processing parameters were found to have no effect on particle size, which was instead dependent on the modifications to the polymer backbone and the way in which the polymer chains interacted. Finally, the cytotoxicity of PGA has been assessed, with the polymer having no effect on the metabolic activity of BAE-1 bovine aortic endothelial cells. PGA- Iloprost nanoparticles were found to elevate the levels of cyclic adenosine monophosphate in human pulmonary arterial smooth muscle cells isolated from a patient with PAH, indicating pharmacological efficacy. Overall, the results presented in this thesis suggest that size-targeted lung delivery of a prostacyclin is a viable approach to treating PAH which warrants further investigation

Starch/Poly (Glycerol-Adipate) Nanocomposite Film as Novel Biocompatible Materials

Starch is one of the most abundant polysaccharides on the earth and it is the most important source of energy intake for humans. Thermoplastic starch (TPS) is also widely used for new bio-based materials. The blending of starch with other molecules may lead to new interesting biodegradable scaffolds to be exploited in food, medical, and pharmaceutical fields. In this work, we used native starch films as biopolymeric matrix carriers of chemo enzymatically-synthesized poly (glycerol-adipate) (PGA) nanoparticles (NPs) to produce a novel and biocompatible material. The prototype films had a crystallinity ranging from 4% to 7%. The intrinsic and thermo-mechanical properties of the composite showed that the incorporation of NPs in the starch films decreases the glass transition temperature. The utilization of these film prototypes as the basis for new biocompatible material showed promise, particularly because they have a very low or even zero cytotoxicity. Coumarin was used to monitor the distribution of the PGA NPs in the films and demonstrated a possible interaction between the two polymers. These novel hybrid nanocomposite films show great promise and could be used in the future as biodegradable and biocompatible platforms for the controlled release of amphiphilic and hydrophobic active ingredients