Photosensitizers and microparticles as tools against malignant cells

Student thesis: Doctoral thesis


In the last years, different strategies have been developed to specifically destroy cancer cells minimizing side effects on healthy ones. One of these strategies is photodynamic therapy (PDT), a technique that uses a photosensitizer (PS) in combination with a specific wavelength in the presence of oxygen. When the PS is excited, reactive oxygen species (ROS) are produced, which would kill the surrounding cells. To selectively direct PSs to target cells, they can be attached to drug carries, like nano- and microparticles (NPs and µPs, respectively). In this way, biofunctionalizing NPs or µPs with PSs and molecules able to recognize malignant cells would improve cell targeting, increasing the effectivity of PDT. Another strategy to destroy malignant cells is the use of other therapeutic drugs that interact with intracellular targets to kill the cell. These drugs can also be carried by NPs or µPs to improve cell targeting, but the main limitation of this approach is their entrapment in the endolysosomal compartment after internalization by cells. To overcome this problem, escape enhancing strategies have been developed, like photochemical internalization (PCI), which is based in the same principles as PDT, but in this case the PS must accumulate in the endolysosomal membranes. In this way, disruption of the endolysomal membranes after PS excitation would allow the release of the endocytosed cargo. The aim of the present thesis is to contribute in the development of the aforementioned strategies for the selective destruction of malignant cells. In the first work, photodynamic treatments with two PSs (Na-H2TCPP and its zinc derivative Na-ZnTCPP) were found to induce a decrease in cell survival in both tumoral (SKBR3) and non-tumoral (MCF10A) cells, though the latter showed higher resistance at low PSs concentrations. Moreover, different cell death mechanisms were triggered depending on both the PS and the cell line, a result that could be exploited to selectively protect non-malignant cells in photodynamic treatments. In a second work, HER2 was found to be a suitable target to direct anti-HER2 biofunctionalized µPs to a tumorigenic cell line overexpressing this receptor. We also demonstrated that different culture conditions (monoculture or coculture in static or microfluidics systems) influenced µPs internalization, emphasising the importance of performing in vitro studies on cells- µPs interactions in an environment more similar to in vivo conditions (cocultures in microfluidic systems). Finally, in our third work, we found that PCI effectively induces endolysosomal membrane disruption, allowing the release of soluble molecules into the cytosol, but not complete membrane disintegration, which would be needed for the release of entrapped µPs. In conclusion, the present thesis provides new knowledge towards the development of better therapeutic agents and treatments based on the use of PSs and µPs for the selective destruction of malignant cells.
Date of Award27 Jul 2018
Original languageEnglish
SupervisorElena Ibáñez (Director), Maria del Carme Nogues Sanmiquel (Director) & Leonardo Barrios Sanromà (Director)

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