Longobardi, Giuseppe (2024) MULTIFUNCTIONAL POLYMERIC NANOPARTICLES TO OVERCOME MULTIDRUG RESISTANCE IN CANCER THERAPY. [Tesi di dottorato]

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Abstract

Multidrug resistance (MDR) presents a critical challenge in cancer treatment, often reducing the effectiveness of conventional therapies such as chemotherapy and radiotherapy. These treatments can increase genomic instability, impacting both cancerous and healthy cells, and sometimes diminishing their anti-tumor effects. In contrast, targeted therapies offer a more refined approach, but frequently encounter early adaptive responses or acquired resistance. Overcoming MDR requires innovative strategies that address the specific biological mechanisms cancer cells use to evade treatment, including tumor heterogeneity, physical barriers, and immune system interactions. This thesis explores the development of nanotechnology-based platforms to combat MDR in aggressive solid tumors. By integrating diverse therapeutic modalities—light-activated therapies, combination treatments, gene therapy, and targeted delivery—this research aims to create more effective and less toxic cancer treatments. Polymeric nanoparticles (NPs) were engineered with diverse architectures and compositions tailored to the therapeutic agents and the unique features of the target tumors. One strategy employed PEGylated NPs designed for light-activated therapies, where core-shell NPs delivered photodonors and photosensitizers. Upon light exposure, these NPs generated reactive oxygen and nitrogen species (ROS/RNS) within the tumor microenvironment, selectively inducing cytotoxicity in cancer cells while sparing healthy tissue, thus overcoming resistance without the drawbacks of traditional MDR mechanisms. Another strategy focused on NPs that target the CD44 receptor, overexpressed in many cancer types, to deliver combination therapies. These NPs co-delivered 5-FU with either bioactive natural products or novel peptides, which inhibit MDR mechanisms such as drug efflux pumps or anti-apoptotic pathways, restoring drug sensitivity. Additionally, the use of siRNA-loaded NPs allowed for gene therapy to silence resistance-related genes at the molecular level, further enhancing treatment efficacy. The third platform involved functionalizing NPs with targeting peptides, specifically NGR peptides, which enabled dual targeting of both tumor vasculature and cancer cells. This ensured that the therapeutic agents were precisely delivered to the tumor site, maximizing their effectiveness and minimizing off-target effects. Overall, this thesis demonstrates how innovative nanotechnology-based approaches can overcome MDR by combining advanced NP design with diverse therapeutic strategies, offering a pathway towards more targeted, effective, and less toxic cancer treatments.

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