In the UK, there are approximately 46,403 new lung cancer cases and 35,600 deaths in 2016 due to lung cancer, with a survival rate estimated to be less than 10 years in 95% of cases. Cisplatin treatment is being considered in all stage non-small cell lung cancer patients with overall benefits of only a 1-year survival gain. Cisplatin has a number of major drawback such as toxicities and the acquisition of cisplatin resistance which undermines its potential effectiveness.Therefore there is a great demand for effective therapeutic strategies to improve current cisplatin treatment. The overall aims of this project are to evaluate the effectiveness of cisplatin and topotecan (TPT) as a double therapy or as triple therapy with radiation. This include using a variety of molecular biology techniques to establish the cell kill potential of cisplatin in combination with TPT and radiation therapy on human lung cancer cell lines (H460 and A549).These survival studies were then underpinned to provide a mechanistic rationale. Another aim is to encapsulate cisplatin and TPT within lipid nanoparticles such as non-ionic surfactant vesicles (NIVs), as a drug delivery system for the treatment of lung cancer by inhalation. NIV formulation was developed and characterized and the efficacy of the NIVs encapsulated chemotherapeutic drugs as single agents and in combination were then compared with the efficacy of non-encapsulated agents by clonogenic assays.This study also includes studying physicochemical properties, such as particle size, surface charge, and entrapment efficiency of NIV formulations postpreparation, to determine their stability as a pulmonary drug delivery carrier. Finally, aerosol formulations of TPT NIVs or TPT solution were nebulized using a mesh nebulizer to determine drug deposition and aerosol particle size distribution using an in vitro lung simulator device.In vitro studies confirmed that the combination therapy of cisplatin and TPT with radiation as a triple therapy has the potential to increase DNA damage and to inhibit the DNA damage repair pathways of cancer cells, and achieving a greater cytotoxicity with lower doses than would be required to achieve therapeutic efficacy with a single agent while maintaining the potential antitumor activity.The characterisation studies showed that the size and negative charge of TPT NIVs were 1264 to 1191 nm and -51 to -46, respectively over 7 days. While cisplatin NIVs size and charge values were 565.85 to 641.5 nm and -57.30 to -68.4, respectively. These results have enhanced the physicochemical characteristics and were capable of maintaining the encapsulated dug to accumulate in the target tissue. The total active drug deposited in the lung with TPT NIVs was significantly higher than TPT solution at the deeper stages (≤ 3μm) of the lung simulator. These results indicate that NIVs encapsulating TPT provide a superior deposition efficiency when compared to free drug.In conclusion, combination therapy of TPT and cisplatin has the potential to achieve greater cytotoxicity with lower doses than single therapy and NIVs as a vesicular delivery vehicle have a great capability of maintaining the encapsulated drug for the administration of cisplatin and topotecan to be accumulated in the target tissue.
|Date of Award||29 Mar 2019|
- University Of Strathclyde
|Supervisor||Marie Boyd (Supervisor) & Katharine Carter (Supervisor)|