Belli, Valentina (2014) “Rational design of nanoparticles to improve anticancer drug delivery”. [Tesi di dottorato]

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Abstract

The need to improve current cancer therapies is a pivotal point in the drug delivery systems. A major challenge is to disclose new strategies that can combine the use of targeted nanoparticles (NPs) to the efficient delivery of chemotherapeutic agents in the vicinity of tumor masses, minimizing the side effects on healthy cells. To this purpose, a preliminary step is that of defining the optimal NP characteristics able to improve drug delivery at target tissues. However, these aspects need to be defined in suitable models that can actually mimic the main cell activities, including adhesion, migration and differentiation. These features are instead missed when cells are grown on flat plastic dishes, as it occurs in traditional two dimensional (2D) systems; thus, the 2D unnatural environment can provide inaccurate data, failing to predict the in vivo real cell response to NP treatments. In this context, the main goal of this thesis has been that of identifying the key parameters useful for a rational design of anticancer drug delivery systems. To this aim, the following issues have been addressed: - the effect of three dimensional (3D) extracellular matrix, made up of collagen type I, in controlling the diffusion and cellular uptake of NPs with variable size and surface charge; - the cytotoxic efficacy of biodegradable NPs to deliver the Doxorubicin (Dox) anticancer drug in three dimensional matrices, as a function of size; - the possibility to control “on demand” Dox release, in order to reach a more efficient tumor-specific targeting. Results indicate that, in 3D environment, size, surface charge and functionalization are all crucial NP features that can modulate their ability to diffuse through the ECM and finally reach the cells. In parallel, the same properties also influence the cytotoxic effects and the cellular responses, with smaller sizes facilitating diffusion through the collagen matrix and increasing the efficiency of NP treatments. Finally, the covalent conjugation of Dox to NPs through cleavable linkers allowed obtaining a more controlled drug release. This type of nanocarrier was made specifically responsive to matrix metalloproteinase-2 (MMP2), which is known to be over-expressed in the tumor extracellular matrix, so that the drug release from NPs, as the relative cytotoxic effect, were specifically triggered by MMP2 cleavage. Altogether, the results obtained indicate that the physical-chemical characteristics of NPs and their behaviour in a 3D environment, that better mimics in vivo growth conditions, are crucial parameters that need to be taken into consideration for a more rational design of nanocarriers finalized to drug delivery in tumor tissues.

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