Prodrug Amphiphile Nanoassemblies for Targeted Treatment of Pancreatic Cancer

Abstract

Cancer is a diverse and complex condition. Tackling cancer effectively requires a multidisciplinary team and close collaboration between clinicians, biologists, chemists and material scientists. The project outlined is a collaboration between CSIRO and the Kolling Institute of Medical Research to develop a series of lipid-based cisplatin and gemcitabine prodrug amphiphiles with the capacity to self-assemble when dispersed in aqueous solution to form functional nanoparticles. Nanoparticles have garnered interest for their ability to deliver high payloads of drug, utilize targeting moieties to enhance localization into tumours and reduce side effects. Lipid prodrug self-assembly systems are advantageous as they are endogenous and different prodrug lipids can be combined to tailor the nanoparticle to a specific need. Nanoparticles can be prepared to mimic biological components such as high-density lipoproteins (HDLs) to avoid detection by the Reticuloendothelial (RES) system. Furthermore, the associated apolipoproteins on the surface of the rHDLs such as ApoA-II have the capacity to direct them towards tumours, enhancing the efficacy of the nanoparticle. This thesis explored the complex strategy behind the development of a series of cisplatin and gemcitabine prodrug amphiphiles, their resulting nanoparticle dispersions and their efficacy in vitro and in vivo. A variety of disciplines were covered, from organic synthesis, structural characterization including NMR spectroscopies, ESI\MS, and HPLC, physicochemical characterization including DSC, TGA, POM, SSAXS, cryo-TEM and DLS, in vitro cytotoxicity assays, and a preclinical in vivo study using cell line derived tumours xenografted in mice to evaluate antitumour efficacy, biodistribution and histological features of the tumour. The result is the diverse, comprehensive and rigorous investigation and characterization of nanoparticles which may become a translatable therapeutic in the future.