Self-assembled nanoparticles as new smart contrast agents for magnetic resonance imaging

Simão, Teresa

http://hdl.handle.net/10400.1/1735

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Authors

Simão, Teresa

Advisor(s)

Mouffouk, Fouzi

Santos, Nuno Rodrigues dos

Abstract(s)

The aim of this thesis is to develop smart and targeted nanoparticle contrast agents for Magnetic Resonance Imaging. These nanoparticles were designed to improve the sensitivity of this high resolution imaging technique and thereby improve early cancer detection, which is a major factor for the reduction of cancer mortality. The designed nanoparticles are expected to accumulate in the tumor through passive and active targeting. In addition, when exposed to the characteristic low pH of the cancer microenvironment, the nanoparticles will release the contrast agent, which will turn on its imaging capability. This contrast agent consists of pH-sensitive polymeric micelles formed by self-assembly, loaded with Gadolinium (III) complexes and bioconjugated with the C595 monoclonal antibody against the human MUC1 protein, which is overexpressed during tumorigenesis since its early stages. The capability of micelles to disintegrate and release the encapsulated contrast in acidic conditions was proved by 1.5T MRI experiments. The MRI study showed no image signal from the sample with intact micelles whereas a signal enhancement was observed from the sample at low pH. After one mouse has been intramuscularly injected with Gadolinium(III)-loaded micelles in both hind legs, the MR image demonstrated a stronger signal from the right hind leg, which was previously injected with an acid solution. To assess in vitro cytotoxicity of free and encapsulated Gadolinium (III) complexes in polymeric micelles, MTT assays were performed on different cancer cell lines. Encapsulated Gadolinium (III) complexes showed significantly lower cytotoxicity than free Gadolinium (III) complexes, even at the highest concentration. To verify the target capability of nanoparticles, fluorescent dye-loaded polymeric micelles were incubated with breast cancer cells expressing MUC1 (verified by semi-quantitative RT-PCR, Western blotting and flow cytometry) and mouse bone marrow stroma cells. Antibody-conjugated micelles had superior affinity for MUC1-expressing human breast cancer cells than for mouse bone marrow cells.