Villapiano, Fabrizio (2025) Physicochemical and bioengineering studies of drug-macromolecules interactions for therapeutic applications. [Tesi di dottorato]

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Abstract

Abstract Cancer is a leading global cause of mortality, pushing continuous efforts in scientific research toward the development of new therapeutic approaches. Polymeric nanoparticles are pivotal in this perspective due to possibility of obtaining drug targeting and a preferential accumulation in tumors. The main objective of this thesis was to engineer nanoparticles based on poly(lactic-co-glycolic acid) (PLGA) as advanced systems to overcome the pharmacokinetic limitations of conventional chemotherapeutics. The research was divided into three main phases. In the first part, the impact of different surface properties on the in vivo biodistribution of nanoparticles was studied. To this aim, nanoparticles composed of only PLGA (P NPs) and a blend of PLGA and Poloxamers (PP NPs) were produced and loaded with fluorescent dye. The presence of Poloxamers resulted in smaller mean diameters and only partial crystallinity. Biodistribution studies in mouse models showed that, while both formulations had comparable blood concentrations, only PP NPs exhibited a relevant sequestration in lungs and, to a lesser extent, in the kidneys, whereas P NPs were undetected in the analysed organs. A second part of the study was focused on the encapsulation of silibinin (SLB), which is the active component of silymarin, a flavonoid derived from the seeds of milk thistle. SLB has many interesting properties which make it attractive in tumor treatment. Indeed, SLB possesses inhibitory effects on tumor invasion, and metastasis and can reverse multidrug resistance. Nonetheless, the bioavailability of SLB is strongly hindered by its low aqueous solubility, which causes the need for high doses to elicit adequate plasma levels. SLB have been loaded in polymeric NPs. The resulting nanoparticles showed encapsulation efficiency greater than 84%, with the SLB present in an amorphous state. In vitro release mechanism was found to be dependent on drug loading. Crucially, bioactivity tests on several lung cancer cell lines (H1299, H1975, and H358) demonstrated that encapsulated SLB has significantly greater efficacy than the free drug. Finally, the NPs were endowed with active targeting ability by coating with hyaluronic acid (HA) through physical interaction. The main focus of this research was to determine the combined effect of active targeting and X-ray on NPs internalization by breast cancer cells. The results showed that high-dose irradiation induces a significant upregulation of CD44 receptor, consequently leading to a marked increase in the internalization of HA coated NPs via a receptor mediated mechanism. This contributes to paving the way for a combined therapeutic strategy. Overall, in this work a versatile, surface-tunable biodegradable nanocarrier platform capable of overcoming critical pharmacokinetic barriers, developed through a one-step procedure based on physical blending. The main outcomes of this work indicate that rational surface engineering can provide NPs with different targeting abilities, potentially contribute to improved therapeutic outcomes in oncology.

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