Lopez Davila, V; (2015) Efficacy of Organic Nanocarriers in a 3D Colorectal Cancer In Vitro Model. Doctoral thesis , UCL (University College London).

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Abstract

The thesis addresses two rapidly advancing fields: improvement of drug efficacy using smart targeting and nanotechnology approaches; and testing drug efficacy in clinically relevant in vitro models. The specific aim was to create organic nanoformulations of novel chemotherapeutic agents and test their efficacy in a 3D colorectal cancer in vitro model. The first phase consisted in determining the best candidate for nanoformulations, in cell monolayers, using routine cell and molecular investigations. Different combinations of therapeutic agents were tested on colorectal cancer cells, including inhibitors of the mitogen activated protein kinase (MAPK) pathway, antagonists of the endothelin receptor A (ETAR) and short interfering RNA (siRNA) targeted against key molecules. AZD6244, an inhibitor of the MAPK pathway, produced significant inhibition of proliferation (p<0.05) and was chosen for nanoformulations. AZD6244 was encapsulated in cationic GCPQ micelles and DOPE/DC-Cholesterol liposomes using ultrasonication and extrusion methods, and tested in colorectal cancer cell monolayers. Both nanoparticles exhibited superior inhibitory effects compared to the free drug, shown by proliferation and metabolic activity assays (p<0.05). Additionally, experiments with control nanoparticles and western blot analysis of target proteins suggested that the superior efficacy of the nanoformulations was mainly due to a more efficient delivery of the drug, as opposed to additional toxicity from the nanoparticles. When the nanoformulations were tested in a collagen-based 3D model of colorectal cancer, the superior efficacy of the nanoformulations was reduced, while the efficacy of the free drug increased. Studies performed with fluorescent dye-carrying nanoparticles in these models revealed that nanoparticle efficacy was hindered by poor penetration into the tissue. These results highlight both the potential of organic nanoformulations as therapeutic delivery systems for cancer and the need to include three-dimensional in vitro models in the drug testing process prior to in vivo work.

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